Paul A. Fitzgerald, MD
DISEASES OF THE HYPOTHALAMUS & PITUITARY GLAND
ESSENTIALS OF DIAGNOSIS
Partial or complete deficiency of one or any combination of anterior pituitary hormones.
Adrenocorticotropic hormone deficiency: reduced adrenal secretion of cortisol and epinephrine; aldosterone secretion remains intact.
Growth hormone (GH) deficiency: short stature in children; asthenia, obesity, and increased cardiovascular risk in adults.
Prolactin deficiency: postpartum lactation failure.
Thyroid-stimulating hormone (TSH) deficiency: secondary hypothyroidism.
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiency: hypogonadism and infertility in men and women.
Hypopituitarism can be caused by either hypothalamic or pituitary dysfunction. Patients with hypopituitarism may have single or multiple hormonal deficiencies (Table 26–1). When one hormonal deficiency is discovered, others may be present.
Table 26–1. Pituitary hormones.
Pituitary autoimmune disease is characterized by an infiltration of the pituitary by lymphocytes, macrophages, and plasma cells. Lymphocytic hypophysitis is an autoimmune disorder that most typically affects women during pregnancy or postpartum. Affected individuals may present with headache or visual field impairment. The appearance of hypophysitis on MRI scanning is variable, but it often appears as a homogeneous sellar mass that mimics a tumor and can extend above the sella. It usually results in ACTH deficiency but can cause deficiencies in any pituitary hormone. The serum prolactin may be elevated if the lesion damages the pituitary stalk. About 25% of cases are associated with other autoimmune conditions, such as systemic lupus erythematosus. Hypophysitis can also be caused by chemotherapy with ipilimumab, an anti-CTLA4 monoclonal antibody that activates T-lymphocytes and enhances immunity.
Acquired hypopituitarism without mass lesions can result from closed-head brain injury, cranial radiation therapy, pituitary surgery, encephalitis, hemochromatosis, autoimmunity, or coronary artery bypass grafting (CABG). At least one pituitary hormone deficiency develops in about 25–30% of survivors of moderate to severe traumatic brain injury and in about 55% of survivors of aneurysmal subarachnoid hemorrhage. Some degree of hypopituitarism, most commonly GH deficiency and hypogonadotropic hypogonadism, occurs in one-third of ischemic stroke patients. Mitotane, given for adrenal cortical carcinoma, can suppress TSH secretion and cause reversible secondary hypothyroidism. Therapy with exogenous corticosteroids (parenteral, oral, inhaled, or topical) can suppress adrenocorticotropic hormone (ACTH) secretion and causes functional isolated secondary adrenal insufficiency.
Functional hypopituitarism can occur with normal aging because of variable degrees of GH deficiency. Similarly, aging men develop variable degrees of hypogonadotropic hypogonadism, with serum free testosterone levels that are slightly low or near the lower end of normal reference ranges, while serum FSH and LH levels remain in the normal range. Obesity also causes variable degrees of GH deficiency and male hypogonadotropic hypogonadism that are typically reversible with sufficient weight loss. Hypothalamic amenorrhea commonly occurs in women during severe emotional or physical stress, caloric restriction or eating disorders, or very high levels of exercise. Hypogonadotropic hypogonadism also occurs with severe illness, alcoholism, opioid analgesics, anabolic steroids; Cushing syndrome due to corticosteroid medication or excessive endogenous cortisol; hyperprolactinemia (drug-induced or spontaneous); anorexia nervosa; and malnutrition.
Acquired GH deficiency is quite common. The pituitary somatotroph cell is particularly sensitive to damage from radiation therapy, compression, or trauma. Therefore, GH deficiency often heralds other pituitary hormone deficiencies that may occur simultaneously or years later. Also, when other more recognizable pituitary hormone deficits are present, there is a high likelihood of concurrent GH deficiency.
GH deficiency varies in severity from mild to severe, resulting in a variable spectrum of nonspecific symptoms that include mild to moderate central obesity, reduced physical and mental energy, impaired concentration and memory, and depression. Patients may also have variably reduced muscle and bone mass, increased low-density lipoprotein (LDL) cholesterol, and reduced cardiac output with exercise.
Laron syndrome is an autosomal recessive disorder that is mainly caused by mutations in the gene that encodes the GH receptor, resulting in GH-resistance. This causes a severe deficiency in serum IGF-I, resulting in short stature (dwarfism). Affected individuals have a prominent forehead, depressed nasal bridge, small mandible, and central obesity. They may have recurrent hypoglycemic seizures. Partial resistance to GH may cause some cases of idiopathic short stature without features of Laron syndrome.
Congenital gonadotropin deficiency is characterized by partial or complete lack of pubertal development. It can be one deficit in congenital panhypopituitarism. Isolated hypogonadotropic hypogonadism occurs with an estimated prevalence between 1 in 4000 and 1 in 10,000 males; it is less common in females. In affected patients, the sense of olfaction (smell) is entirely normal in 58% (normosmic isolated hypogonadotropic hypogonadism), or hypoosmic or anosmic in 42% (Kallmann syndrome). Regardless of their olfaction status, patients with isolated hypogonadotropic hypogonadism frequently have abnormal genitalia (25%), including small phallus, cryptorchidism; renal anomalies (28%); midline craniofacial defects (50%), including cleft lip, high-arched or cleft palate, absent nasal cartilage, dental agenesis, hypertelorism; neurologic deficits (42%), including cognitive problems, bimanual synkinesis, cerebellar ataxia, oculomotor dysfunction, color blindness, or neurosensory hearing loss; musculoskeletal malformations, including pectus excavatum, syndactyly, clinodactaly, camptodactyly. Some affected women have menarche followed by secondary amenorrhea. Some patients with isolated hypogonadotropic hypogonadism also have congenital adrenal hypoplasia with X-linked inheritance. Most such boys with isolated hypogonadotropic hypogonadism who survive beyond childhood are diagnosed when they fail to enter puberty. However, isolated hypogonadotropic hypogonadism and subtle signs of adrenal failure can present in adulthood in males.
Patients with Prader-Willi syndrome have variable features of both gonadotropin deficiency and primary gonadal dysfunction; boys have cryptorchidism. Other features of Prader-Willi syndrome can include mental retardation, short stature, hyperflexibility, autonomic dysregulation, cognitive impairment, and hyperphagia with obesity.
Acquired gonadotropin deficiency is characterized by the gradual loss of facial, axillary, pubic, and body hair (more prominent in patients who are also hypoadrenal). Men may note diminished libido, erectile dysfunction, muscle atrophy, infertility, and osteopenia. (See Male Hypogonadism.) Women have amenorrhea, infertility, and predisposition to osteoporosis. Like men, women with hypogonadism have androgen deficiency and may note muscle atrophy.
Fasting hypoglycemia may be present with secondary hypoadrenalism, hypothyroidism, or GH deficiency. Hyponatremia is often present due to hypothyroidism or hypoadrenalism.
For men, an accurate serum total and free testosterone measurement must be obtained. If the serum total or free testosterone is low, then serum gonadotropins (FSH and LH) levels are obtained to distinguish pituitary dysfunction from primary hypogonadism. A serum prolactin is required for men with hypogonadotropic hypogonadism. An elevated serum prolactin may be seen with pituitary prolactinomas, acromegaly, or injury to the hypothalamus or pituitary infundibulum.
For women with amenorrhea, irregular menses, or an unreliable menstrual history, a serum hCG is obtained to exclude pregnancy. Women with hypogonadotropic hypogonadism have a low serum estradiol and a normal or low serum FSH. A serum prolactin is obtained in nonpregnant women with amenorrhea or galactorrhea; an elevated serum prolactin may be seen with a pituitary prolactinomas, acromegaly, or injury to the hypothalamus or pituitary infundibulum. For postmenopausal women, an elevated serum FSH argues for an otherwise healthy anterior pituitary.
In patients with secondary hypothyroidism, the serum free thyroxine (FT4) level is low while the serum TSH is low or low-normal.
ACTH deficiency usually causes functional atrophy of the adrenal cortex within 2 weeks of pituitary destruction. Therefore, the diagnosis of secondary hypoadrenalism can usually be confirmed with the cosyntropin test. For the cosyntropin test, patients should be either taking no corticosteroids or a short-acting corticosteroid (such as hydrocortisone), which is held after midnight on the morning of the test. At 8 AM, blood is drawn for serum cortisol, ACTH, and dehydroepiandrosterone (DHEA); then 0.25 mg of cosyntropin (synthetic ACTH1–24) is administered intramuscularly or intravenously. Another blood sample is obtained 45 minutes after the cosyntropin injection to measure the stimulated serum cortisol levels. A stimulated serum cortisol of < 20 mcg/dL (550 nmol/mL) indicates adrenal insufficiency. With gradual pituitary damage and early in the course of ACTH deficiency, patients can have a stimulated serum cortisol of ≥ 20 mcg/dL but a baseline 8 AM serum cortisol < 5 mcg/dL (137.5 nmol/L), which is suspicious for adrenal insufficiency. The baseline ACTH level is low or normal in secondary hypoadrenalism, distinguishing it from primary adrenal disease. The serum DHEA levels are usually low in patients with adrenal deficiency, helping confirm the diagnosis. For patients with symptoms of secondary adrenal insufficiency (hyponatremia, hypotension, pituitary tumor) but borderline cosyntropin test results, treatment can be instituted empirically and the test repeated at a later date. Insulin tolerance testing and metyrapone testing are usually unnecessary.
Epinephrine deficiency occurs with secondary adrenal insufficiency due to the adrenal medulla lacking the local high concentrations of cortisol that are required to induce the production of the enzyme phenylethanolamine N-methyltransferase (PNMT) that catalyzes the conversion of norepinephrine to epinephrine.
The diagnosis of GH deficiency in adults is difficult, since GH secretion is normally pulsatile and serum GH levels are nearly undetectable for most of the day. Also, adults (particularly men) physiologically tend to produce less GH when they are over age 50 or have abdominal obesity. Therefore, pathologic GH deficiency is often inferred by symptoms of GH deficiency in the presence of pituitary destruction or other pituitary hormone deficiencies. GH deficiency is present in 96% of patients with three or more other pituitary hormone deficiencies. While GH stimulates the production of IGF-I, the serum IGF-I level is neither a sensitive (about 50%) nor specific test for GH deficiency in adults. While very low serum IGF-I levels (< 84 mcg/L) are usually indicative of GH deficiency, they also occur in malnutrition, prolonged fasting, oral estrogen, hypothyroidism, uncontrolled diabetes mellitus, and liver failure. In GH deficiency (but also in most adults over age 40), exercise-stimulated serum GH levels remain at < 5 ng/mL and usually fail to rise.
Provocative GH stimulation testing may be used to help diagnose adult GH deficiency, but such testing has a sensitivity of only 66% for GH deficiency. Therefore, a therapeutic trial of GH therapy should be considered for symptomatic patients who have either a serum IGF-I < 84 mcg/L or three other pituitary hormone deficiencies.
Provocative GH-stimulation tests are sometimes indicated or required for insurance coverage of GH therapy. In the absence of a serum IGF-1 level < 84 mcg/L or multiple other pituitary hormone deficiencies, provocative GH-stimulation testing may be indicated for the following patients in whom GH deficiency is suspected: (1) young adult patients who have completed GH therapy for childhood GH deficiency and have achieved maximal linear growth; (2) patients who have a hypothalamic or pituitary tumor or who have received surgery or radiation therapy to these areas; and (3) patients who have had prior head trauma, cerebrovascular accident, or encephalitis. When required, such testing usually entails measuring serum GH following provocative stimuli. The glucagon stimulation test has emerged as a practical alternative to traditional provocative GH stimulation testing. Glucagon 1.0 mg (or 1.5 mg if > 200 lbs [or > 90kg]) is administered intramuscularly to well-nourished patients who have not eaten for 8–9 hours. Serum GH is measured before the injection and every 30 minutes for 3 hours. In patients with GH deficiency, the maximum serum GH is usually < 3 mcg/L. Late hypoglycemia can occur after glucagon, so patients are advised to eat following completion of the test. However, the glucagon test may indicate GH deficiency in otherwise normal aging or obese patients. Whether long-term administration of GH to such patients is helpful or safe remains to be established.
The differential diagnosis of GH deficiency is congenital GH resistance with deficiency of IGF-I. At its worst, IGF-I deficiency results in Laron dwarfism that is completely resistant to GH therapy. The condition responds to therapy with biosynthetic IGF-I (mecasermin).
Patients with lymphocytic hypophysitis frequently have elevated serum antinuclear or anticytoplasmic antibodies. Patients with hypopituitarism without an established etiology should be screened for hemochromatosis with a serum iron and transferrin saturation or ferritin since hemochromatosis can cause hypopituitarism.
MRI of the hypothalamus and pituitary region is indicated when there is a suspicion for a mass lesion, particularly for the following conditions: men over age 16 with a serum testosterone < 150 ng/dL with a low or normal serum LH; two or more pituitary hormone deficiencies; persistent hyperprolactinemia; or symptoms of a mass (headache, visual field defect). MRI is particularly sensitive for detecting mass lesions of the pituitary or hypothalamus. It can also detect thickening of the pituitary stalk that can be caused by various lesions, including neurosarcoidosis, Langerhans cell histiocytosis, lymphocytic hypophysitis, pituitary adenoma, craniopharyngioma, germinoma, astrocytoma, and metastatic malignancy.
MRI shows hypoplasia or agenesis of the olfactory bulbs in 75% of cases of Kallmann syndrome and in 8% of patients with normosmic hypogonadotropic hypogonadism. MRI is not indicated in cases of functional hypopituitarism associated with severe obesity, drugs, or nutritional disorders.
The failure to enter puberty may simply reflect delayed puberty, also known as constitutional delay in growth and puberty. Reversible hypogonadotropic hypogonadism may occur with serious illness, malnutrition, anorexia nervosa, or morbid obesity. Men typically develop partial secondary hypogonadism with aging. The clinical situation and the presence of normal adrenal and thyroid function allow ready distinction from hypopituitarism. Profound hypogonadotropic hypogonadism develops in men who receive GnRH analog therapy (leuprolide) for prostate cancer; it usually persists following cessation of therapy. Hypogonadotropic hypogonadism usually develops in patients receiving opioid therapy, including high-dose methadone or long-term intrathecal infusion of opioids; both GH deficiency and secondary adrenal insufficiency occur in 15% of such patients. Secondary adrenal insufficiency may persist for many months following high-dose corticosteroid therapy.
Severe illness causes functional suppression of TSH and T4. Hyperthyroxinemia reversibly suppresses TSH. Administration of triiodothyronine (Cytomel) suppresses TSH and T4. Bexarotene, used to treat cutaneous T cell lymphoma, suppresses TSH secretion, resulting in temporary central hypothyroidism. Corticosteroids or megestrol treatment reversibly suppresses endogenous ACTH and cortisol secretion.
GH deficiency normally occurs with aging. Physiologic GH deficiency that develops in obese patients may return to normal with sufficient weight loss.
Among patients with craniopharyngiomas, diabetes insipidus is found in 16% preoperatively and in 60% postoperatively. Hyponatremia often presents abruptly during the first 2 weeks following pituitary surgery. Visual field impairment may occur. Hypothalamic damage may result in morbid obesity as well as cognitive and emotional problems. Conventional radiation therapy results in an increased incidence of small vessel ischemic strokes and second tumors.
Patients with untreated hypoadrenalism and a stressful illness may become febrile and comatose and die of hyponatremia and shock.
Adults with GH deficiency have experienced an increased cardiovascular morbidity. Rarely, acute hemorrhage may occur in large pituitary tumors, manifested by rapid loss of vision, headache, and evidence of acute pituitary failure (pituitary apoplexy) requiring emergency decompression of the sella.
Transsphenoidal removal of pituitary tumors will sometimes reverse hypopituitarism. Hypogonadism due to PRL excess usually resolves during treatment with cabergoline or other dopamine agonists.
GH-secreting tumors may respond to octreotide (see Acromegaly). Radiation therapy with x-ray, gamma knife, or heavy particles may be necessary but increases the likelihood of hypopituitarism.
The mainstay of substitution therapy for pituitary insufficiency is lifetime hormone replacement.
Hydrocortisone tablets, 15–35 mg/d orally in divided doses, should be given. Most patients do well with 10–20 mg in the morning and 5–15 mg in the late afternoon. Patients with partial ACTH deficiency (basal morning serum cortisol above 8 mg/dL [220 mmol/L]) require hydrocortisone replacement in lower doses of about 5 mg orally twice daily. Some clinicians prefer prednisone (3–7.5 mg/d orally) or methylprednisolone (4–6 mg/d orally), given in divided doses. A mineralocorticoid is rarely needed. To determine the optimal corticosteroid replacement dosage, it is necessary to monitor patients carefully for over- or under-replacement. A white blood cell count (WBC) with a relative differential can be useful, since a relative neutrophilia and lymphopenia can indicate corticosteroid over-replacement, and vice versa. Additional corticosteroids must be given during stress, eg, infection, trauma, or surgical procedures. For mild illness, corticosteroid doses are doubled or tripled. For trauma or surgical stress, hydrocortisone 50 mg is given every 6 hours intravenously or intramuscularly and then reduced to usual doses as the stress subsides. Patients with adrenal insufficiency are advised to wear a medical alert bracelet describing their condition and treatment.
Patients with secondary adrenal insufficiency due to treatment with corticosteroids at supraphysiologic doses require their usual daily dose of corticosteroid during surgery and acute illness; supplemental hydrocortisone is not usually required.
Levothyroxine is given to correct hypothyroidism only after the patient is assessed for cortisol deficiency or is already receiving corticosteroids. (See Hypothyroidism.) The typical maintenance dose is about 1.6 mcg/kg body weight. However, dosage requirements vary widely, averaging 125 mcg daily with a range of 25–300 mcg daily. The optimal replacement dose of thyroxine for each patient must be carefully assessed clinically. In patients receiving optimal thyroxine replacement, serum FT4 levels are usually in the high-normal range while serum T3 levels are in the low-normal range. Assessment of serum TSH is useless for monitoring patients with hypopituitarism, since TSH levels are always low.
Hypogonadotropic hypogonadism often develops in patients with hyperprolactinemia and usually resolves with its treatment (see Hyperprolactinemia).
Androgen and estrogen replacement are discussed in later sections (see Male Hypogonadism and Female Hypogonadism). Adolescents with idiopathic isolated hypogonadotropic hypogonadism, who have received several years of hormone replacement therapy (HRT), may have a trial off hormonal therapy to assess whether spontaneous sexual maturation may have occurred.
Women with panhypopituitarism have profound androgen deficiency caused by the combination of both secondary hypogonadism and adrenal insufficiency. When serum DHEA levels are < 400 ng/mL, such women may be treated with compounded DHEA in doses of about 25–50 mg/d orally. DHEA therapy tends to increase pubic and axillary hair and may modestly improve libido, alertness, stamina, and overall psychological well being after 6 months of therapy.
To improve spermatogenesis, human chorionic gonadotropin (hCG) (equivalent to LH) may be given at a dosage of 2000–3000 units intramuscularly three times weekly and testosterone replacement, discontinued. The dose of hCG is adjusted to normalize serum testosterone levels. After 6–12 months of hCG treatment, if the sperm count remains low, hCG injections are continued along with injections of follitropin beta (synthetic recombinant FSH) or urofollitropins (urine-derived FSH). An alternative for patients with an intact pituitary (eg, Kallmann syndrome) is the use of leuprolide (GnRH analog) by intermittent subcutaneous infusion. With either treatment, testicular volumes double within 5–12 months, and spermatogenesis occurs in most cases. With persistent treatment and the help of intracytoplasmic sperm injection for some cases, the total pregnancy success rate is about 70%. Men often feel better during hCG therapy than during testosterone replacement. Therefore, despite its higher cost, some men may elect to continue hCG therapy long-term.
Clomiphene, 25–50 mg orally daily, can sometimes stimulate a man’s own pituitary gonadotropins (when his pituitary is intact), thereby increasing testosterone and sperm production. For fertility induction in females, ovulation may be induced with clomiphene, 50 mg daily for 5 days every 2 months. Follitropins and hCG can induce multiple births and should be used only by those experienced with their administration. (See Hypogonadism.)
Symptomatic adults with GH deficiency may be treated with a subcutaneous recombinant human growth hormone (rhGH, somatropin) injections starting at a dosage of about 0.2 mg/d (0.6 international units/d), administered three times weekly. The dosage of rhGH is increased every 2–4 weeks by increments of 0.1 mg (0.3 international units) until side effects occur or a sufficient salutary response and a normal serum IGF-I level are achieved. In adults, if the desired effects (eg, improved energy and mentation, reduction in visceral adiposity) are not seen within 3–6 months at maximum tolerated dosage, rhGH therapy is discontinued.
During pregnancy, rhGH may be safely administered to women with hypopituitarism at their usual pregestational dose during the first trimester, tapering the dose during the second trimester, and discontinuing rhGH during the third trimester.
Oral estrogen replacement reduces hepatic IGF-I production. Therefore, prior to commencing rhGH therapy, oral estrogen should be changed to a transdermal or transvaginal estradiol.
Treatment of adult GH deficiency usually improves the patient’s emotional sense of well-being, increases muscle mass, and decreases visceral fat and waist circumference. Long-term treatment with rhGH does not appear to affect mortality.
Side effects of rhGH therapy may include peripheral edema, hand stiffness, arthralgias and myalgias, paresthesias, carpal tunnel syndrome, tarsal tunnel syndrome, headache, pseudotumor cerebri, gynecomastia, hypertension, and proliferative retinopathy. Treatment with rhGH can also cause sleep apnea, insomnia, dyspnea, sweating, and fatigue. Side effects are more common in patients who are older, those with higher BMI, and those with adult-onset GH deficiency. Such symptoms usually remit promptly after a sufficient reduction in dosage. Excessive doses of rhGH could cause acromegaly; patients receiving long-term therapy require careful clinical monitoring. Serum IGF-I levels should be kept in the normal range.
GH should not be administered during critical illness since, in one study, administration of very high doses of rhGH to patients in an intensive care unit was shown to increase overall mortality. There is currently no proven role for GH replacement for the apparent GH deficiency that is seen with abdominal obesity or normal aging.
Biosynthetic IGF-I (mecasermin) is available to treat patients with Laron syndrome.
Selective transsphenoidal resection of pituitary adenomas can often restore normal pituitary function. Cabergoline, bromocriptine, or quinagolide may reverse the hypogonadism seen in hyperprolactinemia. (See Hyperprolactinemia.) Disseminated Langerhans cell histiocytosis may be treated with bisphosphonates to improve bone pain; treatment with 2-chlorodeoxyadenosine (cladribine) has been reported to produce remissions.
Patients with lymphocytic hypophysitis may be treated with corticosteroid therapy; pituitary surgery or low-dose external beam radiation therapy may be required for aggressive cases.
The prognosis depends on the primary cause. Hypopituitarism resulting from a pituitary tumor may be reversible with dopamine agonists or with careful selective resection of the tumor. Spontaneous recovery from hypopituitarism associated with pituitary stalk thickening has been reported. Patients can also recover from functional hypopituitarism, eg, hypogonadism due to starvation or severe illness, suppression of ACTH by corticosteroids, or suppression of TSH by hyperthyroidism. Spontaneous reversal of idiopathic isolated hypogonadotropic hypogonadism occurs in about 10% of patients after several years of HRT. However, hypopituitarism is usually permanent, and lifetime HRT is ordinarily required.
Functionally, most patients with hypopituitarism do very well with hormone replacement. Men with infertility who are treated with hCG/FSH or GnRH are likely to resume spermatogenesis if they have a history of sexual maturation, descended testicles, and a baseline serum inhibin B level over 60 pg/mL. Women under age 40 years, with infertility due to hypogonadotropic hypogonadism, can usually have successful induction of ovulation.
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ESSENTIALS OF DIAGNOSIS
Antidiuretic hormone (ADH) deficiency causes central diabetes insipidus with polyuria (2–20 L/d) and polydipsia.
Hypernatremia occurs if fluid intake is inadequate.
Diabetes insipidus is an uncommon disease characterized by an increase in thirst and the passage of large quantities of urine of low specific gravity (usually < 1.006 with ad libitum fluid intake). The urine is otherwise normal. It is caused by a deficiency of vasopressin or resistance to vasopressin.
Primary central diabetes insipidus (without an identifiable lesion noted on MRI of the pituitary and hypothalamus) accounts for about one-third of all cases of diabetes insipidus. Many such cases appear to be due to autoimmunity against hypothalamic arginine vasopressin (AVP)-secreting cells; pituitary stalk thickening can often be detected on pituitary MRI scanning. The cause may also be genetic. Familial diabetes insipidus occurs as a dominant genetic trait with symptoms developing at about 2 years of age. Diabetes insipidus also occurs in Wolfram syndrome, a rare autosomal recessive disorder that is also known by the acronym DIDMOAD (diabetes insipidus, type 1 diabetes mellitus, optic atrophy, and deafness). DIDMOAD manifestations usually present in childhood but may not occur until adulthood, along with depression and cognitive problems. Diabetes insipidus can also occur in the preleukemic phase of acute myelogenous leukemia associated with myelodysplasia. Secondary central diabetes insipidus is due to damage to the hypothalamus or pituitary stalk by tumor, hypophysitis, infarction, hemorrhage, anoxic encephalopathy, surgical or accidental trauma, infection (eg, encephalitis, tuberculosis, syphilis), or granulomas (sarcoidosis or multifocal Langerhans cell granulomatosis). Metastases to the pituitary are more likely to cause diabetes insipidus (33%) than are pituitary adenomas (1%). Reversible central diabetes insipidus has also occurred during chemotherapy with temozolomide. Central diabetes insipidus can also be idiopathic.
Vasopressinase-induced diabetes insipidus may be seen in the last trimester of pregnancy and in the puerperium. A circulating enzyme destroys native vasopressin; however, synthetic desmopressin is unaffected. Nephrogenic diabetes insipidus is a disorder caused by a defect in the kidney tubules that interferes with water reabsorption. These patients have normal secretion of vasopressin, and the polyuria is unresponsive to it. Congenital nephrogenic diabetes insipidus is present from birth and is due to defective expression of renal vasopressin V2 receptors or vasopressin-sensitive water channels. It occurs as a familial X-linked trait; adults often have hyperuricemia as well. Acquired forms of vasopressin-resistant diabetes insipidus are usually less severe and are seen in pyelonephritis, renal amyloidosis, myeloma, potassium depletion, Sjögren syndrome, sickle cell anemia, or chronic hypercalcemia. Certain drugs (eg, corticosteroids, diuretics, demeclocycline, lithium, foscarnet, or methicillin) may induce nephrogenic diabetes insipidus. The recovery from acute tubular necrosis may also be associated with transient nephrogenic diabetes insipidus. (See Chapter 22.)
The symptoms of the disease are intense thirst, especially with a craving for ice water, and polyuria, the volume of ingested fluid varying from 2 L to 20 L daily, with correspondingly large urine volumes. Partial diabetes insipidus presents with less intense symptoms and should be suspected in patients with unremitting enuresis. Most patients with diabetes insipidus are able to maintain fluid balance by continuing to ingest large volumes of water. However, diabetes insipidus may present with hypernatremia and dehydration in patients without free access to water, or with a damaged hypothalamic thirst center and altered thirst sensation. Diabetes insipidus is aggravated by administration of high-dose corticosteroids, which increases renal free water clearance. Vasopressin-induced diabetes insipidus during pregnancy is often associated with oligohydramnios, preeclampsia, or hepatic dysfunction.
Diagnosis of diabetes insipidus requires clinical judgment; there is no single diagnostic laboratory test. Evaluation should include an accurate 24-hour urine collection for volume and creatinine. A urine volume of < 2 L/24 h (in the absence of hypernatremia) essentially rules out diabetes insipidus. Serum is assayed for glucose, urea nitrogen, calcium, potassium, sodium, and uric acid. Hyperuricemia occurs in many patients with diabetes insipidus, since reduced vasopressin stimulation of the renal V1 receptor causes a reduction in the renal tubular clearance of urate.
A supervised “vasopressin challenge test” may be done: Desmopressin acetate 0.05–0.1 mL (5–10 mcg) intranasally (or 1 mcg subcutaneously or intravenously) is given, with measurement of urine volume for 12 hours before and 12 hours after administration. If symptoms of hyponatremia develop, serum sodium must be assayed immediately. The dosage of desmopressin is doubled if the response is marginal. Patients with central diabetes insipidus notice a distinct reduction in thirst and polyuria; serum sodium stays normal except in some salt-losing conditions.
In nonfamilial central diabetes insipidus, MRI of the pituitary and hypothalamus and of the skull is done to look for mass lesions. The pituitary stalk may be thickened, which may be a manifestation of Langerhans cell histiocytosis, sarcoidosis, or lymphocytic hypophysitis. With central diabetes insipidus, MRI T-1-weighted imaging shows an absence of the usual hyperintense signal (bright spot) in the posterior pituitary. When nephrogenic diabetes insipidus is a diagnostic consideration, measurement of serum vasopressin is done during modest fluid restriction; typically, the vasopressin level is high.
Central diabetes insipidus must be distinguished from polyuria caused by psychogenic polydipsia, diabetes mellitus, Cushing syndrome or corticosteroid treatment, lithium, hypercalcemia, hypokalemia, and the nocturnal polyuria of Parkinson disease. It must also be distinguished from vasopressinase-induced diabetes insipidus and nephrogenic diabetes insipidus (eg, corticosteroid or lithium therapy).
If water is not readily available, the excessive output of urine will lead to severe dehydration. Patients with an impaired thirst mechanism are very prone to hypernatremia, particularly if they also have impaired mentation and forget to take their desmopressin. In patients who are receiving desmopressin acetate therapy, there is a danger of induced water intoxication.
Mild cases of diabetes insipidus require no treatment other than adequate fluid intake. Reduction of aggravating factors (eg, corticosteroids) will improve polyuria.
Desmopressin acetate is the treatment of choice for both central and vasopressinase-induced diabetes insipidus. It is also useful in diabetes insipidus associated with pregnancy or the puerperium, since desmopressin is resistant to degradation by the circulating vasopressinase.
Nasal desmopressin (100 mcg/mL solution) is given every 12–24 hours as needed for thirst and polyuria. It may be administered via metered-dose nasal inhaler containing 0.1 mL/spray or via a plastic calibrated tube. The starting dose is 0.05–0.1 mL every 12–24 hours, and the dose is then individualized according to response. Nasal desmopressin may cause rhinitis or conjunctivitis. Some patients report inconsistent antidiuresis from generic desmopressin and prefer a brand preparation (eg, DDAVP).
Oral desmopressin is also available as tablets and is given in a starting dose of 0.05 mg twice daily and increased to a maximum of 0.4 mg every 8 hours, if required. Oral desmopressin is particularly useful for patients in whom rhinitis or conjunctivitis develops from the nasal preparation. Gastrointestinal symptoms, asthenia, and mild increases in hepatic enzymes can occur with the oral preparation.
Desmopressin can also be given intravenously, intramuscularly, or subcutaneously in doses of 1–4 mcg every 12–24 hours as needed.
Desmopressin may cause hyponatremia, but this is uncommon if minimum effective doses are used and the patient allows thirst to occur periodically. Desmopressin can sometimes cause agitation, emotional changes, and depression with an increased risk of suicide. Erythromelalgia occurs rarely.
All desmopressin preparations are subject to light and heat degradation. Nasal desmopressin should be refrigerated. While traveling, nasal desmopressin maintains stability for up to 3 weeks if kept at temperatures that do not exceed 22oC (72oF). Desmopressin tablets must be stored at controlled room temperatures that do not exceed 25oC (77oF).
Both central and nephrogenic diabetes insipidus respond partially to hydrochlorothiazide, 50–100 mg/d orally (with potassium supplement or amiloride). Nephrogenic diabetes insipidus may respond to combined treatments of indomethacin-hydrochlorothiazide, indomethacin-desmopressin, or indomethacin-amiloride. Indomethacin, 50 mg orally every 8 hours, is effective in acute cases.
Most patients with psychogenic polydipsia require psychotherapy. Thioridazine and lithium are best avoided since they cause polyuria.
Central diabetes insipidus appearing after pituitary surgery usually remits after days to weeks but may be permanent if the upper pituitary stalk is cut.
Chronic central diabetes insipidus is ordinarily more an inconvenience than a dire medical condition. Treatment with desmopressin allows normal sleep and activity. Hypernatremia can occur, especially when the thirst center is damaged, but diabetes insipidus does not otherwise reduce life expectancy, and the prognosis is that of the underlying disorder.
Babey M et al. Familial forms of diabetes insipidus: clinical and molecular characteristics. Nat Rev Endocrinol. 2011 Jul 5;7(12):701–14. [PMID: 21727914]
Bellastella A et al. Subclinical diabetes insipidus. Best Pract Res Clin Endocrinol Metab. 2012 Aug;26(4):471–83. [PMID: 22863389]
Chanson P et al. Treatment of neurogenic diabetes insipidus. Ann Endocrinol (Paris). 2011 Dec;72(6):496–9. [PMID: 22071315]
Devin JK. Hypopituitarism and central diabetes insipidus: perioperative diagnosis and management. Neurosurg Clin N Am. 2012 Oct;23(4):679–89. [PMID: 23040752]
Fenske W et al. Current state and future perspectives in the diagnosis of diabetes insipidus: a clinical review. J Clin Endocrinol Metab. 2012 Oct, 97(10):3426–37. [PMID: 22855338]
Kristof RA et al. Incidence, clinical manifestations, and course of water and electrolyte metabolism disturbances following transsphenoidal pituitary adenoma surgery: a prospective observational study. J Neurosurg. 2009 Sep;111(3):555–62. [PMID: 19199508]
Schreckinger M et al. Diabetes insipidus following resection of pituitary tumors. Clin Neurol Neurosurg. 2013 Feb;115(2):121–6. [PMID: 22921808]
ACROMEGALY & GIGANTISM
ESSENTIALS OF DIAGNOSIS
Excessive growth of hands, feet, jaw, and internal organs; or gigantism before closure of epiphyses.
Amenorrhea, headaches, visual field loss, weakness.
Soft, doughy, sweaty handshake.
Elevated serum IGF-I.
Serum GH not suppressed following oral glucose.
GH exerts much of its growth-promoting effects by stimulating the release of IGF-I from the liver and other tissues.
Acromegaly is nearly always caused by a pituitary adenoma. These tumors may be locally invasive, particularly into the cavernous sinus. Less than 1% are malignant. Most are macroadenomas (over 1 cm in diameter). Acromegaly is usually sporadic but may rarely be familial, with < 3% being due to MEN types 1 or 4. Acromegaly may also be seen rarely in McCune–Albright syndrome and Carney complex. Acromegaly is rarely caused by ectopic secretion of GHRH or GH secreted by a lymphoma, hypothalamic tumor, bronchial carcinoid, or pancreatic tumor.
Excessive GH causes tall stature and gigantism if it occurs in youth, before closure of epiphyses. Afterward, acromegaly develops. The term “acromegaly,” meaning extremity enlargement, seriously understates the manifestations. The hands enlarge and a doughy, moist handshake is characteristic. The fingers widen, causing patients to enlarge their rings. Carpal tunnel syndrome is common. The feet also grow, particularly in shoe width. Facial features coarsen since the bones and sinuses of the skull enlarge; hat size increases. The mandible becomes more prominent, causing prognathism and malocclusion. Tooth spacing widens. Older photographs of the patient can be a useful comparison.
Macroglossia occurs, as does hypertrophy of pharyngeal and laryngeal tissue; this causes a deep, coarse voice and sometimes makes intubation difficult. Obstructive sleep apnea may occur. A goiter may be noted. Hypertension (50%) and cardiomegaly are common. At diagnosis, about 10% of acromegalic patients have overt heart failure, with a dilated left ventricle and a reduced ejection fraction. Weight gain is typical, particularly of muscle and bone. Insulin resistance is usually present and frequently causes diabetes mellitus (30%). Arthralgias and degenerative arthritis occur. Overgrowth of vertebral bone can cause spinal stenosis. Colon polyps are common, especially in patients with skin papillomas. The skin may also manifest hyperhidrosis, thickening, cystic acne, skin tags, and areas of acanthosis nigricans.
GH-secreting pituitary tumors usually cause some degree of hypogonadism, either by cosecretion of PRL or by direct pressure upon normal pituitary tissue. Decreased libido and erectile dysfunction are common. Women with acromegaly may experience irregular menses or amenorrhea; those who become pregnant have an increased risk of gestational diabetes and hypertension. Secondary hypothyroidism sometimes occurs; hypoadrenalism is unusual. Headaches are frequent. Temporal hemianopia may occur as a result of the optic chiasm being impinged by a suprasellar growth of the tumor.
For screening purposes, a random serum IGF-I can be obtained. If it is normal for age, acromegaly is ruled out.
For further evaluation, the patient should be fasting for at least 8 hours (except for water), not be acutely ill, and not have exercised on the day of testing. Assay for the following: serum IGF-I (increased and usually over five times normal in acromegalic patients), PRL (cosecreted by many GH-secreting tumors), glucose (diabetes mellitus is common in acromegaly), liver enzymes and serum creatinine or blood urea nitrogen (BUN) (liver failure or kidney disease can misleadingly elevate GH), serum calcium (to exclude hyperparathyroidism), serum inorganic phosphorus (frequently elevated), serum free T4, and TSH (secondary hypothyroidism is common in acromegaly; primary hypothyroidism may increase PRL). Glucose syrup (100 g) is then administered orally, and serum GH is measured 60 minutes afterward; acromegaly is excluded if the serum GH is < 1 ng/mL. For ultrasensitive GH assays, GH should be suppressed to < 0.3 ng/mL. The serum IGF-I and glucose-suppressed GH are usually complementary tests; however, disparities between IGF-I and GH levels occur in up to 30% of patients.
MRI shows a pituitary tumor in 90% of acromegalic patients. These tumors ordinarily involve the sella and cavernous sinus; rare ectopic tumors may arise in the sphenoid bone. MRI is generally superior to CT scanning, especially in the postoperative setting. Radiographs of the skull may show an enlarged sella and thickened skull. Radiographs may also show tufting of the terminal phalanges of the fingers and toes. A lateral view of the foot shows increased thickness of the heel pad.
Active acromegaly must be distinguished from familial coarse features, large hands and feet, and isolated prognathism and from inactive (“burned-out”) acromegaly in which there has been a spontaneous remission due to infarction of the pituitary adenoma. GH-induced gigantism must be differentiated from familial tall stature and from aromatase deficiency. (See Osteoporosis.)
Misleadingly high serum GH levels can be caused by exercise or eating just prior to the test; acute illness or agitation; liver failure or kidney disease; malnourishment; diabetes mellitus; or concurrent treatment with estrogens, beta-blockers, or clonidine. Acromegaly can be difficult to diagnose during pregnancy, since the placenta produces GH and commercial GH assays may not be able to distinguish between pituitary and placental GH. During normal adolescence, serum IGF-I is usually elevated and GH may fail to be suppressed.
Complications include hypopituitarism, hypertension, glucose intolerance or frank diabetes mellitus, cardiac enlargement, and cardiac failure. Carpal tunnel syndrome may cause thumb weakness and thenar atrophy. Arthritis of hips, knees, and spine can be troublesome. Cord compression may be seen. Visual field defects may be severe and progressive. Acute loss of vision or cranial nerve palsy may occur if the tumor undergoes spontaneous hemorrhage and necrosis (pituitary apoplexy). Colon polyps are more likely to develop in patients with acromegaly.
Pituitary transsphenoidal microsurgery is the treatment of choice for patients with acromegaly. Many patients have an apparent surgical cure and a remission in all clinical symptoms but continue to have a mildly elevated serum GH or IGF-I postoperatively. If no residual tumor is apparent on MRI, the patient may elect to be monitored closely, rather than embark on adjuvant medical therapy that is expensive and carries its own risks (see below).
Transsphenoidal pituitary microsurgery removes the adenoma while preserving anterior pituitary function in most patients. Surgical remission is achieved in about 70% of patients followed over 3 years. GH levels fall immediately; diaphoresis and carpal tunnel syndrome often improve within a day after surgery. Transsphenoidal surgery is usually well tolerated, but complications occur in about 12% of patients, including infection, cerebrospinal fluid (CSF) leak, and hypopituitarism. Transsphenoidal pituitary surgery may be difficult in patients with McCune–Albright syndrome because of fibrous dysplasia of the skull base.
Fluid and electrolyte disturbances occur in most patients postoperatively. Diabetes insipidus can occur within 2 days postoperatively but is usually mild and self-correcting. Hyponatremia can occur abruptly 4–13 days postoperatively in 21% of patients; symptoms may include nausea, vomiting, headache, malaise, or seizure. It is treated with fluid restriction and salt supplements. It is prudent to monitor serum sodium levels postoperatively. Dietary salt supplements for 2 weeks postoperatively may help prevent this complication.
Corticosteroids are administered perioperatively and tapered to replacement doses over 1 week; hydrocortisone is discontinued and cosyntropin stimulation test is performed about 6 weeks after surgery. At that time, the patient is screened for secondary hypothyroidism (by a serum FT4) and secondary hypogonadism (see above).
Acromegalic patients with an incomplete biochemical remission after pituitary surgery may benefit from medical therapy, with dopamine agonists, somatostatin analogues, tamoxifen, or pegvisomant.
Cabergoline is usually the dopamine agonist of choice. It may be used first, since it is an oral medication. Cabergoline therapy is most successful for tumors that secrete both PRL and GH but can also be effective for patients with normal serum PRL levels. Therapy with cabergoline will shrink one-third of pituitary tumors by more than 50%. It appears to be safe during pregnancy. The initial dose is 0.25 mg orally twice weekly, which is gradually increased to a maximum dosage of 1 mg twice weekly (based on serum GH and IGF-I levels). Side effects of cabergoline include nausea, fatigue, constipation, abdominal pain, and dizziness (see Hyperprolactinemia).
Octreotide and lanreotide are somatostatin analogs that are given by subcutaneous injection. Octreotide (Sandostatin LAR depot) is given at a dose of 20–40 mg intragluteally monthly. Lanreotide acetate (Somatuline Depot) is given by subcutaneous intragluteal injection at a dosage of 60–120 mg monthly. Whichever preparation is used, the dosage can be adjusted to achieve serum GH levels under 2 ng/mL. Such long-acting somatostatin analogs can achieve serum GH levels under 2 ng/mL in 79% of patients and normal serum IGF-I levels in 53% of patients. Headaches often improve, and tumor shrinkage of about 30% may be expected. Acromegalic patients with pretreatment serum GH levels exceeding 20 ng/mL are less likely to respond to octreotide or lanreotide therapy. It appears to be safe during pregnancy. Side effects are experienced by about one-third of patients and include injection site pain, loose acholic stools, abdominal discomfort, or cholelithiasis. All somatostatin analogs are expensive and must be continued indefinitely or until other treatment has been effective.
Tamoxifen is a selective estrogen receptor modulator (SERM) that may be particularly useful for persistent acromegaly in men and in women who are postmenopausal or who have had breast cancer. Tamoxifen in oral doses of 20–40 mg daily does not reduce serum GH levels but reduces serum IGF-I levels in 82% of patients and normalizes serum IGF-I levels in 47%. Serum testosterone levels increase in men.
Pegvisomant is a GH receptor antagonist that blocks hepatic IGF-I production. Pegvisomant therapy produces symptomatic relief and normalizes serum IGF-I levels in over 90% of patients. The starting dosage is 10 mg subcutaneously daily. The maintenance dosage can be increased by 5–10 mg every 4–6 weeks, based on serum IGF-I levels and liver transaminase levels; the maximum dosage is 40 mg subcutaneously daily. Pegvisomant does not shrink GH-secreting tumors. Patients need to be monitored carefully with visual field examinations, GH levels, and MRI scanning of the pituitary. It appears to be safe during pregnancy. Pegvisomant has caused hepatitis in a patient with Gilbert syndrome. Other adverse effects include edema, flulike syndrome, nausea, and hypertension. Lipohypertrophy can occur at injection sites, so injection sites must be diligently rotated and inspected. In acromegalic diabetics, hypoglycemic drugs are reduced to avoid hypoglycemia during pegvisomant therapy. The effectiveness of pegvisomant is reduced by coadministration of opioids. Pegvisomant is detected in some GH assays, which could overestimate serum GH levels. Pegvisomant is extremely expensive.
Acromegalic patients who have not had a complete remission with transsphenoidal surgery or medical therapy may be treated with stereotactic radiosurgery administered by gamma knife, heavy particle radiation, or adapted linear accelerator. Gamma knife radiosurgery is preferred, since it has become more widely available and normalization of serum IGF-I has been reported in up to 80% of treated patients. Radiosurgery precisely radiates the pituitary tumor in a single session and reduces radiation to the normal brain. However, it cannot be used for pituitary tumors with suprasellar extension due to the risk of damaging the optic chiasm. Radiosurgery can be used for pituitary tumors invading the cavernous sinus, since cranial nerves III, IV, V, and VI are less susceptible to radiation damage. Radiosurgery can also be used for patients who have not responded to conventional radiation therapy. Following any pituitary radiation therapy, patients are advised to take lifelong daily low-dose aspirin because of the increased risk of small-vessel stroke.
Patients with acromegaly have increased morbidity and mortality from cardiovascular disorders and progressive acromegalic symptoms. Those who are treated and have a random serum GH under 1.0 ng/mL or a glucose-suppressed serum GH under 0.4 ng/mL with a normal age-adjusted serum IGF-I level have reduced morbidity and mortality. Transsphenoidal pituitary surgery is successful in 80% of patients with tumors < 2 cm in diameter and GH levels < 50 ng/mL. Extrasellar extension of the pituitary tumor, particularly cavernous sinus invasion, reduces the likelihood of surgical cure.
Adjuvant medical therapy has been quite successful in treating patients who are not cured by pituitary surgery. Postoperatively, normal pituitary function is usually preserved. Soft tissue swelling regresses but bone enlargement is permanent. Hypertension frequently persists despite successful surgery. Conventional radiation therapy (alone) produces a remission in about 40% of patients by 2 years and 75% of patients by 5 years after treatment. Gamma knife or cyberknife radiosurgery reduces GH levels an average of 77%, with 20% of patients having a full remission after 12 months. Patients with pituitary adenomas that abut the optic chiasm can be treated with cyberknife radiosurgery, controlling tumor growth and preserving vision in most patients. Heavy particle pituitary radiation produces a remission in about 70% of patients by 2 years and 80% of patients by 5 years. Radiation therapy eventually produces some degree of hypopituitarism in most patients. Conventional radiation therapy may cause some degree of organic brain syndrome and predisposes to small strokes. Patients must receive lifelong follow-up, with regular monitoring of serum GH and IGF-I levels. Serum GH levels over 5 ng/mL and rising IGF-I levels usually indicate a recurrent tumor. Most pregnant women with acromegaly do not have an increase in the size of the pituitary tumor and neonatal outcome is unaffected.
Hypopituitarism may occur, due to the tumor itself, pituitary surgery, or radiation therapy. Hypopituitarism may develop years following radiation therapy, so patients must have regular clinical monitoring of their pituitary function.
Balili I et al. Tamoxifen as a therapeutic agent in acromegaly. Pituitary. 2013 Nov 16. [Epub ahead of print] [PMID: 24243064]
Cheng V et al. Pregnancy and acromegaly: a review. Pituitary. 2012 Mar;15(1):59–63. [PMID: 21789529]
Franzin A et al. Results of gamma knife radiosurgery in acromegaly. Int J Endocrinol. 2012;2012:342034. [PMID: 22518119]
Giustina A et al. Current management practices for acromegaly: an international survey. Pituitary. 2011 Jun;14(2):125–33. [PMID: 21063787]
Jane JA Jr et al. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J Clin Endocrinol Metab. 2011 Sep;96(9):2732–40. [PMID: 21715544]
Katznelson L. Approach to the patient with persistent acromegaly after pituitary surgery. J Clin Endocrinol Metab. 2010 Sept;95(9):4114–23. [PMID: 20823464]
Ribeiro-Oliveira A Jr et al. The changing face of acromegaly—advances in diagnosis and treatment. Nat Rev Endocrinol. 2012 Oct;8(10):605–11. [PMID: 22733271]
Sandret L et al. Place of cabergoline in acromegaly: a meta-analysis. J Clin Endocrinol Metab. 2011 May;96(5):1327–35. [PMID: 21325455]
Sherlock M et al. Medical therapy in acromegaly. Nat Rev Endocrinol. 2011 May;7(5):291–300. [PMID: 21448141]
ESSENTIALS OF DIAGNOSIS
Women: Oligomenorrhea, amenorrhea; galactorrhea; infertility.
Prolactin normally elevated during pregnancy.
Men: Hypogonadism; decreased libido and erectile dysfunction; infertility.
Elevated serum PRL.
CT scan or MRI often demonstrates pituitary adenoma.
Non-gestational elevations in serum PRL can be caused by numerous conditions (Table 26–2). PRL-secreting pituitary tumors are more common in women than in men and are usually sporadic but may rarely be familial as part of MEN 1. Most are microadenomas (< 1 cm in diameter) that do not grow even with pregnancy or oral contraceptives. However, some giant prolactinomas (over 3 cm in diameter) can spread into the cavernous sinuses and suprasellar areas; rarely, they may erode the floor of the sella to invade the sinuses.
Table 26–2. Causes of hyperprolactinemia.
Hyperprolactinemia may cause hypogonadotropic hypogonadism and reduced fertility. Men usually have diminished libido and erectile dysfunction that may not respond to testosterone replacement; gynecomastia sometimes occurs but rarely with galactorrhea. The diagnosis of a prolactinoma is often delayed in men, such that pituitary adenomas may grow and present with late manifestations of a pituitary macroprolactinoma.
About 90% of premenopausal women with prolactinomas experience amenorrhea, oligomenorrhea, or infertility. Estrogen deficiency can cause decreased vaginal lubrication, irritability, anxiety, and depression. Galactorrhea (lactation in the absence of nursing) is common. During pregnancy, clinically significant enlargement of a microprolactinoma (diameter < 1 cm) occurs in < 3%; clinically significant enlargement of a macroprolactinoma (diameter ≥ 1 cm) occurs in about 30%.
Pituitary prolactinomas may cosecrete GH and cause acromegaly (see above). Large tumors may cause headaches, visual symptoms, and pituitary insufficiency.
Aside from pituitary tumors, some women secrete an abnormal form of prolactin that appears to cause peripartum cardiomyopathy (see Chapter 10). Suppression of prolactin secretion with dopamine agonists can reverse the cardiomyopathy.
Evaluate for conditions known to cause hyperprolactinemia, particularly pregnancy (serum hCG), hypothyroidism (serum FT4 and TSH), kidney disease (BUN and serum creatinine), cirrhosis (liver tests) and hyperparathyroidism (serum calcium). Men are evaluated for hypogonadism with determinations of serum total and free testosterone, LH, and FSH. Women who have amenorrhea are assessed for hypogonadism with determinations of serum estradiol, LH, and FSH. Patients with large pituitary macroadenomas (> 3 cm in diameter) should have PRL measured on serial dilutions of serum, since immunoradiometric assay assays may otherwise report falsely low titers, the “high-dose hook effect.” Patients with macroprolactinomas or manifestations of possible hypopituitarism should be evaluated for hypopituitarism as described above. An assay for macroprolactinemia should be considered for patients with hyperprolactinemia who are relatively asymptomatic and have no apparent cause for hyperprolactinemia.
Patients with hyperprolactinemia not induced by drugs, hypothyroidism, or pregnancy should be examined by pituitary MRI. Small prolactinomas may thus be demonstrated, but clear differentiation from normal variants is not always possible. In the event that a woman with a macroprolactinoma becomes pregnant and elects not to take dopamine agonists during her pregnancy, MRI is usually not performed since the normal pituitary grows during pregnancy. However, if visual-field defects or other neurologic symptoms develop in a pregnant woman, a limited MRI study should be done, focusing on the pituitary without gadolinium contrast.
The causes of hyperprolactinemia are shown in Table 26–2. Chronic nipple stimulation, nipple piercing, augmentation or reduction mammoplasty, and mastectomy may stimulate PRL secretion. In acromegaly, there may be cosecretion of GH and PRL. Hyperprolactinemia may also be idiopathic. Increased pituitary size is a normal variant in young women. Macroprolactinemia is an increased circulating level of a high molecular weight PRL that is biologically inactive. It occurs in 3.7% of the general population and in 10–25% of patients with hyperprolactinemia; pituitary MRI is normal in 78% of cases.
The differential diagnosis for galactorrhea includes the small amount of breast milk that can be expressed from the nipple in many parous women that is not cause for concern. Nipple stimulation from nipple rings, chest surgery, or acupuncture can cause galactorrhea; serum PRL levels may be normal or minimally elevated. Some women can have galactorrhea with normal serum PRL levels and no discernible cause (idiopathic). Normal breast milk may be various colors besides white. Bloody galactorrhea requires evaluation for breast malignancy.
Medications known to increase PRL should be stopped if possible. Hyperprolactinemia due to hypothyroidism is corrected by thyroxine.
Women with microprolactinomas who have amenorrhea or are desirous of contraception may safely take oral contraceptives or estrogen replacement—there is minimal risk of stimulating enlargement of the microadenoma. Patients with infertility and hyperprolactinemia may be treated with a dopamine agonist in an effort to improve fertility. Women with amenorrhea who elect to receive no treatment have an increased risk of developing osteoporosis; such women require periodic bone densitometry.
Pituitary macroprolactinomas (> 10 mm in diameter) have a higher risk of progressive growth, particularly during treatment with estrogen or testosterone replacement therapy or during pregnancy. Therefore, patients with macroprolactinomas should not be treated with sex HRT unless they are in remission with dopamine agonist medication or surgery. Pregnant women with macroprolactinomas should continue to receive treatment with dopamine agonists throughout the pregnancy to prevent tumor growth. If dopamine agonists are not used during pregnancy in a woman with a macroprolactinoma, visual field testing is required each trimester. During pregnancy, measurement of prolactin is not useful surveillance for tumor growth due to the fact that prolactin increases greatly during normal pregnancy.
Dopamine agonists (cabergoline, bromocriptine, or quinagolide) are the initial treatment of choice for patients with giant prolactinomas and those with hyperprolactinemia desiring restoration of normal sexual function and fertility. Cabergoline is the most effective and usually the best-tolerated ergot-derived dopamine agonist. The beginning dosage is 0.25 mg orally once weekly for 1 week, then 0.25 mg twice weekly for the next week, then 0.5 mg twice weekly. Further dosage increases may be required monthly, based on serum PRL levels, up to a maximum of 1.5 mg twice weekly. Bromocriptine (1.25–20 mg/d orally) is an alternative. Women who experience nausea with oral preparations may find relief with deep vaginal insertion of cabergoline or bromocriptine tablets; vaginal irritation sometimes occurs. Quinagolide (Norprolac; not available in the United States) is a non–ergot-derived dopamine agonist for patients intolerant or resistant to ergot-derived medications; the starting dosage is 0.075 mg/d orally, increasing as needed and tolerated to a maximum of 0.6 mg/d. Patients whose tumor is resistant to one dopamine agonist may be switched to another in an effort to induce a remission.
Dopamine agonists are given at bedtime to minimize side effects of fatigue, nausea, dizziness, and orthostatic hypotension. These symptoms usually improve with dosage reduction and continued use. Erythromelalgia is rare. Dopamine agonists can cause a variety of psychiatric side effects that are not dose related and may take weeks to resolve once the drug is discontinued.
With dopamine agonist treatment, 90% of patients with prolactinomas experience a fall in serum PRL to 10% or less of pretreatment levels and about 80% of treated patients achieve a normal serum PRL level. Shrinkage of a pituitary adenoma occurs early, but the maximum effect may take up to a year. Nearly half of prolactinomas—even massive tumors—shrink more than 50%. Such shrinkage of invasive prolactinomas can result in CSF rhinorrhea. Discontinuing therapy after months or years usually results in the reappearance of hyperprolactinemia and galactorrhea-amenorrhea. After 2 years of cabergoline therapy, the percentage of patients who maintain a normal serum prolactin after withdrawal of the drug are as follows: 32% with idiopathic hyperprolactinemia, 21% with microprolactinomas, and 16% with macroprolactinomas.
Because dopamine agonists usually restore fertility promptly, many pregnancies have resulted; no teratogenicity has been noted. However, women with microadenomas may have treatment withdrawn during pregnancy. Macroadenomas may enlarge significantly during pregnancy; if therapy is withdrawn, patients must be monitored with serum PRL determinations and computer-assisted visual fields. Women with macroprolactinomas who have responded to dopamine agonists may safely receive oral contraceptive agents as long as they continue receiving dopamine agonist therapy.
Transsphenoidal pituitary surgery may be urgently required for large tumors undergoing apoplexy or those severely compromising visual fields. It is also used electively for patients who do not tolerate or respond to dopamine agonists. Surgery is generally well tolerated, with a mortality rate of < 0.5%. For pituitary microprolactinomas, skilled neurosurgeons are successful in normalizing prolactin in 87% of patients. The 10-year recurrence rate is 13% and pituitary function can be preserved in over 95% of cases. However, the surgical success rate for macroprolactinomas is much lower, and the complication rates are higher. Craniotomy is rarely indicated, since even large tumors can usually be decompressed via the transsphenoidal approach.
Complications, such as CSF leakage, meningitis, stroke, or visual loss, occur in about 3% of cases; sinusitis, nasal septal perforation, or infection complicates about 6.5% of surgeries. Diabetes insipidus can occur within 2 days postoperatively but is usually mild and self-correcting. Hyponatremia can occur abruptly 4–13 days postoperatively in 21% of patients; symptoms may include nausea, vomiting, headache, malaise, or seizure. It is treated with fluid restriction and salt supplements. Dietary salt supplements for 2 weeks postoperatively may help prevent this complication.
Radiation therapy is reserved for patients with macroadenomas that are growing despite treatment with dopamine agonists. A single gamma knife or cyberknife treatment is preferable for certain patients whose optic chiasm is clear of tumor, since it is generally safer and more convenient than conventional radiation therapy. Conventional radiation therapy must be given over 5 weeks and carries a high risk of eventual hypopituitarism. Other possible side effects include some degree of memory impairment and an increased long-term risk of second tumors and small vessel ischemic strokes. After radiation therapy, patients are advised to take low-dose aspirin daily for life to reduce their stroke risk.
Some patients with aggressive pituitary macroadenomas or carcinomas are not surgical candidates and do not respond to dopamine agonists or radiation therapy. Temozolomide may be administered, 150–200 mg/m2 orally daily for 5 days of each 28-day cycle; after three cycles, treatment efficacy is determined by prolactin measurement and MRI scanning. A small percentage of patients with aggressive tumors respond to temozolomide.
Pituitary prolactinomas generally respond well to therapy with dopamine agonists. Women with microprolactinomas can take oral contraceptives with little risk of stimulating growth of the pituitary adenoma. During pregnancy, growth of a pituitary prolactinoma occurs in 2.7% of women with a microprolactinoma and in 22.9% of those with a macroprolactinoma (> 1 cm diameter). If cabergoline is stopped after 2 years therapy, hyperprolactinemia recurs in 68% of patients with idiopathic hyperprolactinemia, 79% with microprolactinomas, and 84% with macroprolactinomas.
dos Santos Nunes V et al. Cabergoline versus bromocriptine in the treatment of hyperprolactinemia: a systematic review of randomized controlled trials and meta-analysis. Pituitary. 2011 Sep;14(3):259–65. [PMID: 21221817]
Glezer A et al. Approach to the patient with persistent hyperprolactinemia and negative sellar imaging. J Clin Endocrinol Metab. 2012 Jul;97(7):2211–6. [PMID: 22774208]
Holt RI et al. Antipsychotics and hyperprolactinaemia: mechanisms, consequences and management. Clin Endocrinol (Oxf). 2011 Feb;74(2):141–7. [PMID: 20455888]
Klibanski A. Clinical practice. Prolactinomas. N Engl J Med. 2010 Apr 1;362(13):1219–26. [PMID: 20357284]
Melmed S et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Feb;96(2):273–88. [PMID: 21296991]
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DISEASES OF THE THYROID GLAND
Assays for FT4, total triiodothyronine (T3), and free triiodothyronine (FT3) have largely supplanted measurements of total T4, resin T3 uptake (RT3U), and free thyroxine index (FT4I). It is particularly important to determine “free” serum levels (FT4 and FT3) in conditions associated with high circulating levels of thyroxine-binding globulin (TBG), such as during therapy with oral estrogen. Ultrasensitive assays for serum TSH have largely replaced older TSH assays. Table 26–3 shows the appropriate use of thyroid tests.
Table 26–3. Appropriate use of thyroid tests.
HYPOTHYROIDISM & MYXEDEMA
ESSENTIALS OF DIAGNOSIS
Weakness, fatigue, cold intolerance, constipation, weight change, depression, menorrhagia, hoarseness.
Dry skin, bradycardia, delayed return of deep tendon reflexes, menorrhagia, hoarseness.
Anemia, hyponatremia, hyperlipidemia.
FT4 level is usually low.
TSH elevated in primary hypothyroidism.
Hypothyroidism is common, affecting over 1% of the general population and about 5% of individuals over age 60 years. Thyroid hormone deficiency affects almost all body functions. The degree of severity ranges from mild and unrecognized hypothyroid states to striking myxedema.
Hypothyroidism may be due to failure or resection of the thyroid gland itself or deficiency of pituitary TSH (see Hypopituitarism). The condition must be distinguished from the functional hypothyroidism that occurs in severe nonthyroidal illness, which does not require treatment with thyroxine (see Euthyroid Sick Syndrome).
Maternal hypothyroidism during pregnancy results in offspring with IQ scores that are an average 7 points lower than those of euthyroid mothers.
Goiter may be present with thyroiditis, iodide deficiency, genetic thyroid enzyme defects, drug goitrogens (lithium, iodide, propylthiouracil or methimazole, phenylbutazone, sulfonamides, amiodarone, interferon-alpha, interferon-beta, interleukin-2), food goitrogens in iodide-deficient areas (eg, turnips, cassavas) or, rarely, peripheral resistance to thyroid hormone or infiltrating diseases (eg, cancer, sarcoidosis). A hypothyroid phase occurs in subacute (de Quervain) viral thyroiditis following initial hyperthyroidism. Hashimoto thyroiditis is the most common cause of hypothyroidism (see Thyroiditis section).
Goiter is usually absent when hypothyroidism is due to destruction of the gland by radiation therapy (to the head, neck, chest, and shoulder region) or 131I. Thyroid agenesis and mutations in the TSH receptor cause hypothyroidism that presents in infancy. Thyroidectomy causes hypothyroidism and hypothyroidism after hemithyroidectomy develops in 22% of patients.
Chemotherapeutic agents that can cause silent thyroiditis include the following: tyrosine kinase inhibitors (eg, sunitinib), denileukin diftitox, alemtuzumab, interferon-alpha, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. This usually starts with hyperthyroidism (often unrecognized) and then progresses to hypothyroidism. Radioiodine-based chemotherapies can also cause hypothyroidism. Bexarotene causes a high rate of pituitary insufficiency with central hypothyroidism.
Amiodarone, because of its high iodine content, causes clinically significant hypothyroidism in about 15–20% of patients who receive it. Hypothyroidism occurs most often in patients with preexisting autoimmune thyroiditis and in patients who are not iodine-deficient. The T4 level is low or low-normal, and the TSH is elevated, usually over 20 milli-international unit/L. Another 17% of patients are asymptomatic with milder elevations of TSH. Low-dose amiodarone is less likely to cause hypothyroidism. Cardiac patients with amiodarone-induced symptomatic hypothyroidism are treated with just enough thyroxine to relieve symptoms. Hypothyroidism usually resolves over several months if amiodarone is discontinued. Hypothyroidism may also develop in patients with a high iodine intake from other sources, especially if they have underlying lymphocytic thyroiditis.
Hepatitis C is associated with an increased risk of autoimmune thyroiditis, with 21% of affected patients having antithyroid antibodies and 13% having hypothyroidism. The risk of thyroid dysfunction is even higher when patients are treated with interferon. Interferon-alpha and interferon-beta treatment can induce thyroid dysfunction (usually hypothyroidism, sometimes hyperthyroidism) in 6% of patients. Spontaneous resolution occurs in over 50% of cases once interferon is discontinued.
Some hypothyroid patients with Hashimoto thyroiditis have symptoms that are not due to hypothyroidism but rather to another associated disease. Some conditions that occur more commonly in patients with Hashimoto thyroiditis include Addison disease, hypoparathyroidism, diabetes mellitus, pernicious anemia, Sjögren syndrome, vitiligo, biliary cirrhosis, gluten sensitivity, and celiac disease.
Hypothyroidism is a common disorder and thyroid function tests should be obtained for any patient with its nonspecific symptoms or signs. The single best screening test for hypothyroidism is the serum TSH (Table 26–3). Serum TSH is increased with primary hypothyroidism, while the serum FT4 is low or low-normal. Other laboratory abnormalities can include hyponatremia, hypoglycemia, or anemia (with normal or increased mean corpuscular volume). Additional findings frequently include increased serum levels LDL cholesterol, triglycerides, lipoprotein (a), liver enzymes, creatine kinase, or prolactin. Semen analysis shows an increase in abnormal sperm morphology. In patients with autoimmune thyroiditis, titers of antibodies against thyroperoxidase and thyroglobulin are high; serum antinuclear antibodies may be present but are not usually indicative of lupus.
The normal reference range for ultrasensitive TSH levels is generally 0.4–4.0 mU/L. However, the normal range of TSH varies with age such that elderly patients have a mildly higher reference range. Over 95% of normal adults have serum TSH concentrations under 3.0 mU/L.
Subclinical hypothyroidism is defined as the state of having a normal serum FT4 with a serum TSH that is above the reference range for young adults. It occurs most often in persons aged ≥ 65 years, in whom the prevalence is 13%. Subclinical hypothyroidism is often transient and the TSH normalizes spontaneously in about 35% of cases within 2 years. The likelihood of TSH normalization is higher in patients without antithyroid antibodies and those with a marginally elevated serum TSH. The term “subclinical” is somewhat misleading, since it does not refer to patients’ symptoms but rather refers only to serum hormone levels; in fact, such patients can have subtle manifestations of hypothyroidism (eg, fatigue, depression, hyperlipidemia) that may improve with thyroid hormone replacement. Patients without such symptoms do not require levothyroxine therapy but must be monitored regularly for the emergence of symptomatic hypothyroidism.
Radiologic imaging is usually not necessary for patients with hypothyroidism. However, on CT or MRI, a goiter may be noted in the neck or in the mediastinum (retrosternal goiter). An enlarged thymus is frequently seen in the mediastinum in cases of autoimmune thyroiditis. On MRI, the pituitary is often quite enlarged in primary hypothyroidism, due to reversible hyperplasia of TSH-secreting cells; concomitant hyperprolactinemia can lead to the mistaken diagnosis of a TSH-secreting or PRL-secreting pituitary adenoma.
The differential diagnosis for subclinical hypothyroidism includes antibody interference with the serum TSH assay, macro-TSH, sleep deprivation, exercise, recovery from nonthyroidal illness, and acute psychiatric emergencies (Table 26–4).
Table 26–4. Factors that may cause aberrations in laboratory tests that may be mistaken for primary hypothyroidism.1
Many clinical manifestations of hypothyroidism (see above) are common in the general population without thyroid illness. The differential diagnoses are the conditions and drugs that can cause aberrations in laboratory tests, resulting in a low serum T4 or T3 or high serum TSH in the absence of hypothyroidism (Table 26–4).
Euthyroid sick syndrome should be considered in patients without known thyroid disease who are found to have a low serum FT4 with a serum TSH that is not elevated. This syndrome can be seen in patients with severe illness, caloric deprivation, or major surgery. Serum TSH tends to be suppressed in severe nonthyroidal illness, making the diagnosis of concurrent primary hypothyroidism quite difficult, although the presence of a goiter suggests the diagnosis.
The clinician must decide whether such severely ill patients (with a low serum T4 but no elevated TSH) might have hypothyroidism due to hypopituitarism. Patients without symptoms of prior brain lesion or hypopituitarism are very unlikely to suddenly develop hypopituitarism during an unrelated illness. Patients with diabetes insipidus, hypopituitarism, or other signs of a central nervous system lesion may be given T4 empirically.
Patients receiving prolonged dopamine infusions can develop true secondary hypothyroidism caused by dopamine’s direct suppression of TSH-secreting cells.
Certain antiseizure medications cause low serum FT4 levels by accelerating hepatic conversion of T4 to T3; serum TSH levels are normal.
Preexistent coronary artery disease and heart failure may be exacerbated by levothyroxine therapy. Patients with severe hypothyroidism have an increased susceptibility to bacterial pneumonia. Megacolon has been described in long-standing hypothyroidism. Organic psychoses with paranoid delusions may occur (“myxedema madness”). Rarely, adrenal crisis may be precipitated by thyroid therapy. Hypothyroidism is a rare cause of infertility, which may respond to thyroid replacement. Untreated hypothyroidism during pregnancy often results in miscarriage.
Myxedema crisis refers to severe, life-threatening manifestations of hypothyroidism. Affected patients have impaired cognition, ranging from confusion to somnolence to coma (myxedema coma). Myxedema crisis is most often seen in elderly women who have had a stroke or who have stopped taking their thyroxine medication. It is often induced by an underlying infection; cardiac, respiratory, or central nervous system illness; cold exposure; or drug use. Convulsions and abnormal central nervous system signs may occur. Patients have severe hypothermia, hypoventilation, hyponatremia, hypoglycemia, and hypotension. Rhabdomyolysis and acute kidney injury may occur. Myxedematous patients are unusually sensitive to opioids and average doses may result in respiratory depression, even death. The mortality rate is high.
Before therapy with thyroid hormone is commenced, the hypothyroid patient requires at least a clinical assessment for adrenal insufficiency and angina, for which the patient would require evaluation and treatment.
Synthetic levothyroxine is the preferred preparation for treating hypothyroid patients. However, some clinicians prescribe mixtures of synthetic thyroxine and triiodothyronine or porcine thyroid preparations. Otherwise healthy young and middle-age adults with hypothyroidism may be treated initially with levothyroxine in doses of 25–75 mcg orally daily. The lower doses are used for very mild hypothyroidism, while higher doses are given for more symptomatic hypothyroidism. Women who are pregnant with significant hypothyroidism may begin therapy with levothyroxine at higher doses of 100–150 mcg orally daily. The levothyroxine dosage may be increased according to clinical response and serum TSH, trying to keep the serum TSH level between 0.4 mU/L and 2.0 mU/L. Since food interferes slightly with the absorption of levothyroxine, it is advisable to take levothyroxine with water habitually in the morning after an overnight fast. After beginning daily administration, significant increases in serum T4 levels are seen within 1–2 weeks, and near-peak levels are seen within 3–4 weeks.
Patients with coronary insufficiency or those who are over age 60 years are treated with smaller initial doses of levothyroxine, 25–50 mcg orally daily; higher initial doses may be used if such patients are severely hypothyroid. The dose can be increased by 25 mcg every 1–3 weeks until the patient is euthyroid. Patients with hypothyroidism and known ischemic heart disease may begin thyroxine therapy following restoration of coronary perfusion by percutaneous coronary intervention (PCI) or CABG.
Myxedema crisis requires larger initial doses of levothyroxine intravenously, since myxedema itself can interfere with levothyroxine intestinal absorption. Levothyroxine sodium 400 mcg is given intravenously as a loading dose, followed by 50–100 mcg intravenously daily; the lower dose is given to patients with suspected coronary insufficiency. In patients with myxedema coma, liothyronine (T3, Triostat) can be given intravenously in doses of 5–10 mcg every 8 hours for the first 48 hours. The hypothermic patient is warmed only with blankets, since faster warming can precipitate cardiovascular collapse. Patients with hypercapnia require intubation and assisted mechanical ventilation. Infections must be detected and treated aggressively. Patients in whom concomitant adrenal insufficiency is suspected are treated with hydrocortisone, 100 mg intravenously, followed by 25–50 mg every 8 hours.
Regular clinical and laboratory monitoring is critical to determine the optimal levothyroxine dose for each patient. An elevated serum TSH usually indicates the need for a higher dose of levothyroxine and the initial goal should be to normalize the serum TSH. However, normal serum TSH and FT4 levels may not accurately determine that the patient is clinically euthyroid (see below). The patient should be prescribed sufficient levothyroxine to restore a clinically euthyroid state, while maintaining the serum T3 within their reference ranges. For most patients with hypothyroidism, a stable maintenance dose of levothyroxine can usually be found.
Different levothyroxine preparations vary in their bioavailability by up to 14% and such differences may have a subtle but significant clinical impact. It is optimal for patients to consistently take the same manufacturer’s brand of levothyroxine.
Certain drugs and conditions may increase levothyroxine dosage requirements. Specifically, levothyroxine doses may need to be titrated upward if the patient starts taking medications that increase the hepatic metabolism of levothyroxine (eg, carbamazepine, phenobarbital, primidone, phenytoin, rifabutin, rifampin, sunitinib, and other tyrosine kinase inhibitors). Sertraline can block the effect of thyroxine and increase the thyroxine dosage requirement. Amiodarone can cause an increase or decrease in thyroxine dose requirements. Malabsorption of thyroxine can be caused by coadministration of binding substances, such as iron (eg, in multivitamins), fiber, raloxifene, sucralfate, aluminum hydroxide antacids, sevelemer, orlistat, calcium and magnesium supplements, soymilk, and soy protein supplements. Bile acid-binding resins, such as cholestyramine and colesevelam, can bind levothyroxine and impair its absorption even when administered 5 hours before the levothyroxine. Proton pump inhibitors interfere slightly with the absorption of levothyroxine. Gastrointestinal disorders can interfere with thyroxine absorption, including celiac disease, inflammatory bowel disease, lactose intolerance,Helicobacter pylori gastritis, and atrophic gastritis. Women with hypothyroidism typically require increased doses of levothyroxine during oral estrogen therapy.
Pregnancy usually increases the levothyroxine dosage requirement. An increase in levothyroxine requirement has been noted as early as the fifth week of pregnancy and adequate levothyroxine is critical to the health of the fetus. Therefore, it is prudent to increase levothyroxine dosages by approximately 20–30% as soon as pregnancy is confirmed. The fetus is at least partially dependent on maternal T4 for central nervous system development—particularly in the second trimester. By mid pregnancy, women require an average of 47% increase in their levothyroxine dosage.
It is therefore important to carefully monitor hypothyroid women with serum TSH (FT4I or T4 concentrations in hypopituitarism) determinations every 4 weeks and to increase levothyroxine progressively as required (see Chapter 19).
Serum TSH levels normally drop while FT4I rises during the first trimester of pregnancy. This probably results from high levels of hCG (with structural homology to TSH) that stimulates thyroid hormone production. Most women with a low serum TSH in the first trimester are euthyroid. Serum FT4I is helpful in evaluating the thyroid status of pregnant women, particularly in the first trimester. Postpartum, levothyroxine replacement requirements ordinarily return to prepregnancy levels.
Other drugs and conditions may decrease levothyroxine dosage requirements. Specifically, levothyroxine dosage may need to be titrated downward for patients who start taking teduglutide for short bowel syndrome. Levothyroxine doses must usually be reduced for women who experience decreased estrogen levels after delivery, after bilateral oophorectomy or natural menopause, after cessation of oral estrogen replacement, or during therapy with GnRH agonists.
Some hypothyroid patients receiving levothyroxine who have normal or “low” serum TSH levels (0.04–0.4 mU/L) continue to have hypothyroid-type symptoms, such as lethargy, weight gain, depression, and cognitive disturbances. They must be carefully assessed for another concurrent condition, such as an adverse drug reaction, Addison disease, depression, hypogonadism, anemia, celiac disease, or gluten sensitivity. If such conditions are not present or are treated and hypothyroid-type symptoms persist, a serum T3 level (FT3 in pregnancy and women receiving oral estrogens) is often helpful. If the serum T3 or FT3 level is low, the patient may benefit from a slightly increased dose of levothyroxine. Patients who feel best with a levothyroxine dose that is associated with a “low” serum TSH (0.04–0.4 mU/L) may continue to take that dosage. Such patients who are clinically euthyroid but who have a mildly low serum TSH do not appear to suffer any long-term adverse consequences.
Patients with primary hypothyroidism who take levothyroxine and have a “suppressed” serum TSH (≤ 0.03 mU/L) have an increased risk of cardiovascular disease, dysrhythmias, and osteoporotic fractures. Therefore, a lower dose of levothyroxine is prescribed for such patients. However, some patients feel unmistakably hypothyroid while taking the reduced dose of levothyroxine and have low serum FT3 levels. A higher levothyroxine dose may be resumed for such patients, but they require close long-term surveillance for atrial arrhythmias, osteoporosis, and manifestations of hyperthyroidism.
Hypothyroidism caused by interferon-alpha resolves within 17 months of stopping the drug in 50% of patients. Patients with mild hypothyroidism caused by Hashimoto thyroiditis have a remission rate of 11%. With levothyroxine treatment of hypothyroidism, striking transformations take place both in appearance and mental function. Return to a normal state is usually the rule, but relapses will occur if treatment is interrupted. However, untreated patients with myxedema crisis have a mortality rate approaching 100% and even with optimal treatment, a mortality rate of 20–50%.
When to Refer
When to Admit
Almandoz JP et al. Hypothyroidism: etiology, diagnosis, and management. Med Clin North Am. 2012 Mar;96(2):203–21. [PMID: 22443971]
Biondi B et al. Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism? J Clin Endocrinol Metab. 2012 Jul;97(7):2256–71. [PMID: 22593590]
Chakera AJ et al. Treatment for primary hypothyroidism: current approaches and future possibilities. Drug Des Devel Ther. 2012;6:1–11. [PMID: 22291465]
De Groot L et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012 Aug;97(8):2543–65. [PMID: 22869843]
Hamnvik OP et al. Thyroid dysfunction from antineoplastic agents. J Natl Cancer Inst. 2011 Nov;103(21):1572–87. [PMID: 22010182]
Makita N et al. Tyrosine kinase inhibitor-induced thyroid disorders: a review and hypothesis. Thyroid. 2013 Feb;23(2):151–9. [PMID: 23398161]
O’Reilly DS. Thyroid hormone replacement: an iatrogenic problem. Int J Clin Pract. 2010 Jun;64(7):991–4. [PMID: 20584231]
Padmanabhan H. Amiodarone and thyroid dysfunction. South Med J. 2010 Sep;103(9):922–30. [PMID: 20689491]
ESSENTIALS OF DIAGNOSIS
Sweating, weight loss or gain, anxiety, palpitations, loose stools, heat intolerance, irritability, fatigue, weakness, menstrual irregularity.
Tachycardia; warm, moist skin; stare; tremor.
In Graves disease: goiter (often with bruit); ophthalmopathy.
Suppressed TSH in primary hyperthyroidism; increased T4, FT4, T3, FT3.
The term “thyrotoxicosis” refers to the clinical manifestations associated with serum levels of T4 or T3 that are excessive for the individual (hyperthyroidism). Serum TSH levels are suppressed in primary hyperthyroidism. However, certain drugs and conditions can affect laboratory tests and lead to the erroneous diagnosis of hyperthyroidism in euthyroid individuals (Table 26–5). The causes of hyperthyroidism are many and diverse, as described below.
Table 26–5. Factors that can cause aberrations in laboratory tests that may be mistaken for spontaneous clinical primary hyperthyroidism.1
Graves disease (known as Basedow disease in Europe) is the most common cause of thyrotoxicosis. It is an autoimmune disorder affecting the thyroid gland, characterized by an increase in synthesis and release of thyroid hormones. Graves disease is much more common in women than in men (8:1), and its onset is usually between the ages of 20 and 40 years. It may be accompanied by infiltrative ophthalmopathy (Graves exophthalmos) and, less commonly, by infiltrative dermopathy (pretibial myxedema). The thymus gland is typically enlarged and serum antinuclear antibodies levels are usually elevated, reflecting the underlying autoimmunity. Many patients with Graves disease have a family history of either Graves disease or Hashimoto thyroiditis. Histocompatibility studies have shown an association with group HLA-B8 and HLA-DR3. The pathogenesis of the hyperthyroidism of Graves disease involves the formation of autoantibodies that bind to the TSH receptor in thyroid cell membranes and stimulate the gland to hyperfunction. Such antibodies are called thyroid-stimulating immunoglobulins (TSI) or TSH receptor antibodies (TSHrAb).
Dietary iodine supplementation can trigger Graves disease. An increased incidence of Graves disease occurs in countries that have embarked on national programs to fortify commercial salt with potassium iodide; the increase in Graves disease lasts about 4 years. Similarly, patients being treated with potassium iodide or amiodarone (which contains iodine) have an increased risk of developing Graves disease.
Patients with Graves disease have an increased risk of other systemic autoimmune disorders, including Sjögren syndrome, celiac disease, pernicious anemia, Addison disease, alopecia areata, vitiligo, autoimmune type 1 diabetes mellitus, hypoparathyroidism, myasthenia gravis, and cardiomyopathy.
Autonomous toxic adenomas of the thyroid may be multiple (toxic multinodular goiter) or single (Plummer disease).
These conditions cause thyroid inflammation with release of stored hormone. They all produce a variable triphasic course: variable hyperthyroidism is followed by transient euthyroidism, and progresses to hypothyroidism. Thyroid radioiodine uptake is low during the thyrotoxic phase. Thyroid ultrasound shows a variably heterogenous, hypoechoic gland. All patients are treated with propranolol during the thyrotoxic phase and levothyroxine during the hypothyroid phase. There may be some overlap between these conditions.
Subacute thyroiditis is also known as “de Quervain” or “granulomatous” thyroiditis. It is typically caused by various viral infections. Women are affected four times more frequently than men. Patients typically experience a viral upper respiratory infection and develop an extremely painful thyroid that is tender to touch and typically enlarged to 3–4 times its normal size. There is often dysphagia and pain that can radiate to the jaw or ear. About 50% of affected patients experience a symptomatic thyrotoxic phase that lasts 3–6 weeks. The WBC, erythrocyte sedimentation rate (ESR) and C-reactive protein levels are usually elevated. About 25% have antithyroid antibodies (usually in low titer), so some cases may be autoimmune. An important differential diagnosis is bacterial suppurative thyroiditis. Patients are treated with nonsteroidal anti-inflammatory drugs and corticosteroids for pain. About 10% remain hypothyroid after 1 year. The recurrence rate is 1–4%.
Postpartum thyroiditis refers to Hashimoto thyroiditis that occurs in the first 12 months after delivery. Although this usually occurs after term pregnancies, it can also occur after miscarriages. It is common, occurring in 5% of postpartum women, with an increased incidence in women with preexistent type 1 diabetes mellitus and other immune disorders. About 22% of such women experience hyperthyroidism followed by hypothyroidism, whereas 30% of such women have isolated thyrotoxicosis and 48% have isolated hypothyroidism. The thyrotoxic phase typically occurs 2–6 weeks postpartum and lasts 2–3 months. Affected women are often asymptomatic or experience minor symptoms, such as palpitations, heat intolerance, and irritability. Patients have either no palpable goiter or a small, nontender goiter. Over 80% have antithyroid antibodies. Most women progress to a hypothyroid phase that usually lasts a few months but that is frequently permanent. Affected women experience a recurrence rate of about 70% with subsequent pregnancies.
Silent thyroiditis is also known as subacute lymphocytic thyroiditis or “Hashitoxicosis.” It can occur spontaneously or be triggered by certain medications. Women are affected four times more frequently than men. Patients have either no palpable goiter or a small, nontender goiter. About 50% have antithyroid antibodies and such patients have sometimes had chemotherapeutic agents (such as tyrosine kinase inhibitors, denileukin diftitox, alemtuzumab, interferon-alpha, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide). Graves ophthalmopathy has been caused by ipilimumab. Other drugs can cause silent thyroiditis, including lithium and amiodarone. In those with spontaneous silent thyroiditis, about 10–20% remain hypothyroid after 1 year. There is a recurrence rate of 5–10%; this rate is higher in Japan.
Amiodarone-induced thyrotoxicosis is categorized as type 1 or type 2; about 27% are mixed type 1–2. Type 1 amiodarone-induced thyrotoxicosis is caused by the active production of excessive thyroid hormone. Thyroid color-flow Doppler typically shows an enlarged gland with increased vascularity; scanning with 99mTc-sestamibi shows normal to increased thyroidal uptake. Type 2 amiodarone-induced thyrotoxicosis is caused by thyroiditis with the passive release of stored thyroid hormone. Thyroid color-flow Doppler shows a normal sized gland without increased vascularity; scanning with99mTc-sestamibi scanning shows no thyroidal uptake.
Human chorionic gonadotropin (hCG) can bind to the thyroid’s TSH receptors, so very high serum levels of hCG, particularly during the first 4 months of pregnancy, may cause sufficient receptor activation to cause hyperthyroidism. About 18% of pregnant women have a low serum TSH during pregnancy, but only about 10% of such women have clinical hyperthyroidism that requires treatment. Pregnant women are more likely to have hCG-induced thyrotoxicosis if they have high serum levels of asialo-hCG, a subfraction of hCG that has a greater affinity for TSH receptors. Such women are also more likely to suffer from hyperemesis gravidarum. This condition must be distinguished from true Graves disease in pregnancy, which usually predates conception and may be associated with high serum levels of TSI and antithyroid antibodies or with exophthalmos.
High levels of hCG can also cause thyrotoxicosis in some cases of pregnancies with gestational trophoblastic disease that has manifestations ranging from molar pregnancy to choriocarcinoma. Such molar pregnancies have produced thyrotoxic crisis. Men have developed hyperthyroidism from high serum levels of hCG secreted by a testicular choriocarcinoma.
Thyrotoxicosis factitia is due to intentional or accidental ingestion of excessive amounts of exogenous thyroid hormone. Isolated epidemics of thyrotoxicosis have been caused by consumption of ground beef contaminated with bovine thyroid gland. Struma ovarii refers to thyroid tissue contained in about 3% of ovarian dermoid tumors and teratomas. Such ectopic thyroid tissue may develop thyroid nodules that produce excess thyroid hormone, thereby causing hyperthyroidism. Also, in Graves disease, ectopic thyroid tissue in dermoid tumors can secrete excessive thyroid hormone, along with the normal thyroid. Pituitary TSH hypersecretion by a pituitary thyrotrophe tumor or hyperplasia can rarely cause hyperthyroidism. Serum TSH is elevated or inappropriately normal in the presence of true thyrotoxicosis. Pituitary hyperplasia may be detected on MRI scan as pituitary enlargement without a discrete adenoma being visible. Metastatic functioning thyroid carcinoma can cause hyperthyroidism in patients with a heavy tumor burden. Hyperthyroidism can be induced or aggravated by recombinant human thyroid-stimulating hormone (rhTSH) that is given prior to radioiodine therapy or scanning. (See Thyroid Cancer.)
Thyrotoxicosis due to any cause produces nervousness, restlessness, heat intolerance, increased sweating, pruritus, fatigue, weakness, muscle cramps, frequent bowel movements, or weight change (usually loss). There may be palpitations or angina pectoris. Women frequently report menstrual irregularities.
Signs of thyrotoxicosis also include fine resting finger tremors, moist warm skin, fever, hyperreflexia, fine hair, and onycholysis. Chronic thyrotoxicosis may cause osteoporosis. Clubbing and swelling of the fingers (acropachy) develop in a small number of patients.
In patients with Graves disease, physical examination usually reveals a diffusely enlarged thyroid, frequently asymmetric, often with a bruit. However, some patients have no palpable thyroid enlargement. The thyroid gland in subacute thyroiditis is usually moderately enlarged and tender. In patients with toxic multinodular goiter, the thyroid usually has palpable nodules.
Cardiopulmonary manifestations of thyrotoxicosis commonly include a forceful heartbeat, premature atrial contractions, and sinus tachycardia. Patients often have exertional dyspnea. Atrial fibrillation or atrial tachycardia occurs in about 8% of patients with thyrotoxicosis, more commonly in men, the elderly, and those with ischemic or valvular heart disease. The ventricular response from the atrial fibrillation may be difficult to control. Thyrotoxicosis itself can cause a thyrotoxic cardiomyopathy, and the onset of atrial fibrillation can precipitate heart failure. Echocardiogram reveals pulmonary hypertension in 49% of patients with hyperthyroidism; of these, 71% have pulmonary artery hypertension while 29% have pulmonary venous hypertension. Even “subclinical hyperthyroidism” increases the risk for atrial fibrillation and overall mortality. Hemodynamic abnormalities and pulmonary hypertension are reversible with restoration of euthyroidism.
Graves eye manifestations, which can occur with hyperthyroidism of any etiology, include upper eyelid retraction (Dalrymple sign), lid lag with downward gaze (von Graefe sign), and a staring appearance (Kocher sign). O phthalmopathy is clinically apparent in 20–40% of patients with Graves disease and some cases of amiodarone-induced thyrotoxicosis. It usually consists of conjunctival edema (chemosis), conjunctivitis, and mild exophthalmos (proptosis). About 5–10% of patients experience more severe exophthalmos, with the eye being pushed forward by increased retro-orbital fat and eye muscles that have been thickened by lymphocytic infiltration. Such patients can experience diplopia from extraocular muscle entrapment. There may be weakness of upward gaze (Stellwag sign). The optic nerve may be compressed in severe cases, causing progressive loss of color vision, visual fields, and visual acuity. Corneal drying may occur with inadequate lid closure. Eye changes may sometimes be asymmetric or unilateral. The severity of the eye disease is not closely correlated with the severity of the thyrotoxicosis.
Exophthalmometry should be performed on all patients with Graves disease to document their degree of exophthalmos and detect progression of orbitopathy. The protrusion of the eye beyond the orbital rim is measured with a prism instrument (Hertel exophthalmometer). Maximum normal eye protrusion varies between kindreds and races, being about 22 mm for blacks, 20 mm for whites, and 18 mm for Asians.
The differential diagnosis for Graves ophthalmopathy includes diplopia caused by an orbital lymphoma. Ocular myasthenia gravis is another autoimmune condition that occurs more commonly in Graves disease but is usually mild, often with unilateral eye involvement. Acetylcholinesterase receptor antibody (AChR Ab) levels are elevated in only 36% of such patients, and a thymoma is present in 9%.
Graves dermopathy (pretibial myxedema) occurs in about 3% of patients with Graves disease usually in the pretibial region. It is more common in patients with high levels of serum TSI and severe Graves ophthalmopathy. Glycosaminoglycans accumulation and lymphoid infiltration occur in affected skin, which becomes erythematous with a thickened, rough texture. Elephantiasis of the legs is a rare complication.
Thyroid acropachy is an extreme and unusual manifestation of Graves disease. It presents with digital clubbing, swelling of fingers and toes, and a periosteal reaction of extremity bones. It is ordinarily associated with ophthalmopathy and thyroid dermopathy. Most patients are smokers.
Tetany is a rare presenting feature. In hyperthyroidism, the renal excretion of magnesium is increased and hypomagnesemia is common. Severe magnesium depletion causes hypoparathyroidism that can result in hypocalcemia.
Hyperthyroidism during pregnancy is relatively common, with a prevalence of about 0.2%. Manifestations include many of the features of normal pregnancy: tachycardia, warm skin, heat intolerance, increased sweating, and a palpable thyroid. Pregnancy can have a beneficial effect on the thyrotoxicosis of Graves disease, with decreasing antibody titers and decreasing serum T4 levels as the pregnancy advances; about 30% of affected women experience a remission by late in the second trimester. However, undiagnosed or undertreated hyperthyroidism in pregnancy carries an increased risk of miscarriage, preeclampsia-eclampsia, preterm delivery, abruptio placenta, maternal heart failure, and thyrotoxic crisis (thyroid storm). Such thyrotoxic crisis can be precipitated by trauma, infection, surgery, or delivery and confers a fetal/maternal mortality rate of about 25%.
TSI (TSHrAb) crosses the placenta and if maternal serum TSI levels reach > 500% in the third trimester, the risk of transient neonatal Graves disease in the newborn is increased. Such thyrotoxic newborns have an increased risk of intrauterine growth retardation and prematurity.
Hypokalemic periodic paralysis occurs in about 15% of Asian or Native American men with thyrotoxicosis. It usually presents abruptly with symmetric flaccid paralysis (and few thyrotoxic symptoms), often after intravenous dextrose, oral carbohydrate, or vigorous exercise. Attacks last 7–72 hours.
Serum FT4, T3, FT3, T4, thyroid resin uptake, and FT4 index are all usually increased. Sometimes the FT4 level may be normal but with an elevated serum T3 (T3 toxicosis). Serum T3 can be misleadingly elevated when blood is collected in tubes using a gel barrier, which causes certain immunoassays to report falsely elevated serum total T3 levels in 24% of normal patients. Serum T4 or T3 can be elevated in other nonthyroidal conditions (Table 26–5).
Serum TSH is suppressed in hyperthyroidism (except in the very rare cases of pituitary inappropriate secretion of thyrotropin). Serum TSH may be misleadingly low in other nonthyroidal conditions (Table 26–5). The term “subclinical hyperthyroidism” is used to describe asymptomatic individuals with a low serum TSH but normal serum levels of FT4 and T3; progression to symptomatic thyrotoxicosis occurs at a rate of 1–2% per year in patients without a goiter and at a rate of 5% per year in patients with a multinodular goiter.
Hyperthyroidism can cause other laboratory abnormalities, including hypercalcemia, increased alkaline phosphatase, anemia, and decreased granulocytes. Hypokalemia and hypophosphatemia occur in thyrotoxic periodic paralysis.
Problems of diagnosis occur in patients with acute psychiatric disorders; about 30% of these patients have elevated serum T4 levels without clinical thyrotoxicosis. The TSH is not usually suppressed, distinguishing psychiatric disorder from true hyperthyroidism. T4 levels return to normal gradually.
In Graves disease, serum TSI is usually detectable (65%). Antithyroglobulin or antithyroperoxidase antibodies are usually elevated but are nonspecific. Serum antinuclear antibodies are also usually elevated without any evidence of systemic lupus erythematosus or other rheumatologic disease.
With subacute thyroiditis, patients often have an increased ESR. Serum antithyroid antibodies are usually not present and serum TSI (TSHrAb) levels are normal. Patients with iodine-induced hyperthyroidism also have undetectable serum TSI (or TSHrAb), an absence of serum antithyroperoxidase antibodies, and an elevated urinary iodine concentration. In thyrotoxicosis factitia, serumthyroglobulin levels are low, distinguishing it from other causes of hyperthyroidism.
With hyperthyroidism during pregnancy, women have an elevated serum total T4 and FT4 while the TSH is suppressed. However, about 18% of normal pregnant women have a low serum TSH. An apparent lack of full TSH suppression in hyperthyroidism can be seen due to misidentification of hCG as TSH in certain assays. The serum FT4 assay is difficult in pregnancy. Although the serum T4 is elevated in most pregnant women, values over 20 mcg/dL (257 nmol/L) are encountered only in hyperthyroidism. On treatment, serum total T4 levels during pregnancy should be kept at about 1.5 × the pre-pregnancy level. The T3 resin uptake, which is low in normal pregnancy because of high thyroxine-binding globulin (TBG) concentration, is normal or high in thyrotoxic persons.
Since high levels of T4 and FT4 are normally seen in patients taking amiodarone, a suppressed TSH must be present along with a greatly elevated T4 (> 20 mcg/dL, or > 257 nmol/L) or T3 (> 200 ng/dL, or > 3.1 nmol/L) in order to diagnose hyperthyroidism. In type 1 amiodarone-induced thyrotoxicosis, the presence of proptosis and serum TSI (TSHrAb) is diagnostic. In type 2 amiodarone-induced thyrotoxicosis, serum levels of interleukin-6 (IL-6) are usually quite elevated.
Radioactive iodine (RAI) should never be administered to pregnant women. In others, RAI scanning and uptake may be helpful to determine the cause for hyperthyroidism. RAI uptake and scanning is not necessary for patients with obvious Graves disease who have elevated serum TSI or associated Graves ophthalmopathy. Women with hyperthyroidism due to Graves disease should ideally have the RAI scan extended to include the pelvis in order to screen for concomitant struma ovarii (rare). A high RAI uptake is seen in Graves disease and toxic nodular goiter. Patients with type 1 amiodarone-induced thyrotoxicosis have RAI uptake that is usually detectable. A low RAI uptake is characteristic of subacute thyroiditis and iodine-induced hyperthyroidism. Low RAI uptake is also seen with interleukin-2 therapy and during hyperthyroidism that often follows neck surgery for hyperparathyroidism. In type 2 amiodarone-induced thyrotoxicosis, thyroid RAI uptake is usually below 3%.
Thyroid ultrasound can be helpful in patients with hyperthyroidism, particularly in patients with palpable thyroid nodules. Color flow Doppler sonography is helpful to distinguish type 1 amiodarone-induced thyrotoxicosis (normal to increased blood flow velocity and vascularity) from type 2 amiodarone-induced thyrotoxicosis (reduced vascularity).
99mTc-sestamibi scanning usually shows normal or increased uptake with type 1 amiodarone-induced thyrotoxicosis.
MRI and CT scanning of the orbits are the imaging methods of choice to visualize Graves ophthalmopathy affecting the extraocular muscles. Imaging is required only in severe or unilateral cases or in euthyroid exophthalmos that must be distinguished from orbital pseudotumor, tumors, and other lesions.
True thyrotoxicosis must be distinguished from those conditions that elevate serum T4 and T3 or suppress serum TSH without affecting clinical status (see Table 26–5). Serum TSH is commonly suppressed in early pregnancy and only about 10% of pregnant women with a low TSH have clinical hyperthyroidism.
Some states of hypermetabolism without thyrotoxicosis—notably severe anemia, leukemia, polycythemia, cancer, and pheochromocytoma—rarely cause confusion. Acromegaly may also produce tachycardia, sweating, and thyroid enlargement. Appropriate laboratory tests will easily distinguish these entities.
Cardiac disease (eg, atrial fibrillation, angina) refractory to treatment suggests the possibility of underlying (“apathetic”) hyperthyroidism. Other causes of ophthalmoplegia (eg, myasthenia gravis) and exophthalmos (eg, orbital tumor, pseudotumor) must be considered. Thyrotoxicosis must also be considered in the differential diagnosis of muscle weakness and osteoporosis. Diabetes mellitus and Addison disease may coexist with thyrotoxicosis.
Hypercalcemia, osteoporosis, and nephrocalcinosis may occur in hyperthyroidism. Decreased libido, erectile dysfunction, diminished sperm motility, and gynecomastia may be noted in men. Other complications include cardiac arrhythmias and heart failure, thyroid crisis, ophthalmopathy, dermopathy, and thyrotoxic hypokalemic periodic paralysis (see below.)
The treatment of Graves disease involves a choice of methods rather than a method of choice.
All patients receiving thiourea therapy must be informed of the danger of agranulocytosis or pancytopenia and the need to stop the drug and seek medical attention immediately with the onset of any infection or unusual bleeding. Agranulocytosis (defined as an absolute neutrophil count below 500/mcL) or pancytopenia usually occurs abruptly in about 0.4% of patients taking either methimazole or propylthiouracil. Over 70% of agranulocytosis cases occur within the first 60 days and nearly 85% within 90 days of commencing therapy. But continued long-term vigilance for this side effect is required. About half the cases are discovered because of fever, pharyngitis, or bleeding, but the other cases are discovered with routine complete blood counts. There is a genetic tendency to develop agranulocytosis with thiourea therapy; if a close relative has had this adverse reaction, other therapies should be considered. Agranulocytosis generally remits spontaneously with discontinuation of the thiourea and while patients are treated with antibiotics. Recovery has not been improved by filgrastim (granulocyte colony-stimulating factor [G-CSF]). Surveillance of the WBC can be done when blood is drawn to check thyroid levels during the first few months of treatment. Such surveillance may be helpful, since some cases of agranulocytosis occur gradually and many cases may be discovered while the patient is still asymptomatic.
Other side effects common to thiourea drugs include pruritus, allergic dermatitis, nausea, and dyspepsia. Antihistamines may control mild pruritus without discontinuation of the drug. Since the two thiourea drugs are similar, patients who have a major allergic reaction to one should not be given the other.
The patient may become clinically hypothyroid for 2 weeks or more before TSH levels rise, the pituitary gland having been suppressed by the preceding hyperthyroidism. Therefore, the patient’s changing thyroid status is best monitored clinically and with serum FT4 levels. Rapid growth of the goiter usually occurs if prolonged hypothyroidism is allowed to develop; the goiter may sometimes become massive but usually regresses rapidly with reduction or cessation of thiourea therapy or with thyroid hormone replacement.
Because radiation is harmful to the fetus and children, RAI should not be given to pregnant or lactating women or to mothers who lack childcare. Before starting 131I therapy, all women of reproductive age should have a pregnancy test (serum beta-hCG). Ideally, RAI should not be given to women with Graves disease within about 3 months prior to a planned conception.
Patients may receive 131I while being symptomatically treated with propranolol ER, which is then reduced in dosage as hyperthyroidism resolves. A higher rate of 131I treatment failure has been reported in patients with Graves disease who have been receiving methimazole or propylthiouracil. However, therapy with 131I will usually be effective if the methimazole is discontinued at least 4 days before RAI therapy and if the therapeutic dosage of 131I is adjusted (upward) according to RAI uptake on the pretherapy scan. Prior to 131I therapy, patients are instructed against receiving intravenous iodinated contrast or ingesting large quantities of dietary iodine.
The presence of Graves ophthalmopathy is a relative contraindication to 131I therapy. Following 131I treatment for hyperthyroidism, Graves ophthalmopathy appears or worsens in 15% of patients (23% in smokers and 6% in nonsmokers) and improves in none, whereas during treatment with methimazole, ophthalmopathy worsens in 3% and improves in 2% of patients. Among patients receiving prednisone following 131I treatment, preexistent ophthalmopathy worsens in none and improves in 67%. Therefore, patients with Graves ophthalmopathy who are to be treated with radioiodine should be considered for prophylactic prednisone (20–40 mg/d) for 2 months following administration of 131I, particularly in patients who have severe orbital involvement.
Smoking increases the risk of having a flare in ophthalmopathy following 131I treatment and also reduces the effectiveness of prednisone treatment. Patients who smoke are strongly encouraged to quit prior to RAI treatment. Smokers receiving RAI should be considered for prophylactic prednisone (see above).
FT4 levels may sometimes drop within 2 months after 131I treatment, but then rise again to thyrotoxic levels, at which time thyroid RAI uptake is low. This phenomenon is caused by a release of stored thyroid hormone from injured thyroid cells and does not indicate a treatment failure. In fact, serum FT4 then falls abruptly to hypothyroid levels.
There is a high incidence of hypothyroidism in the months to years after 131I, even when small doses are given. Patients with Graves disease treated with 131I also have an increased lifetime risk of developing hyperparathyroidism, particularly when radioiodine therapy was administered in childhood or adolescence. Lifelong clinical follow-up is mandatory, with measurements of serum TSH, FT4, and calcium when indicated.
The surgical procedure of choice for patients with Graves disease is a total resection of one lobe and a subtotal resection of the other lobe, leaving about 4 g of thyroid tissue (Hartley–Dunhill operation). Subtotal thyroidectomy of both lobes ultimately results in a 9% recurrence rate of hyperthyroidism. Total thyroidectomy of both lobes poses an increased risk of hypoparathyroidism and damage to the recurrent laryngeal nerves.
Patients are ordinarily rendered euthyroid preoperatively with a thiourea drug. Propranolol ER is given orally at initial doses of 60–80 mg twice daily and increased every 2–3 days until the heart rate is < 90 beats per minute. Propranolol is continued until the serum T3 (or free T3) is normal preoperatively. If a patient undergoes surgery while thyrotoxic, larger doses of propranolol are given perioperatively to reduce the likelihood of thyroid crisis. Ipodate sodium or iopanoic acid (500 mg orally twice daily) may be used in addition to a thiourea to accelerate the decline in serum T3. The patient should be euthyroid by the time of surgery.
To reduce thyroid vascularity preoperatively, the patient may be treated for 3 days prior to surgery with oral potassium iodide 25–50 mg (eg, ThyroShield 65 mg/mL, 0.5 mL, or SSKI 1 g/mL, 1 drop) three times daily or iodinated radiocontrast agents (eg, iopanoic acid 500 mg orally twice daily). However, preoperative potassium iodide often increases the volume of the thyroid, so the requirement for preoperative potassium iodide for Graves disease is debatable. Preoperative iodide supplementation is not recommended prior to surgery for multinodular goiter.
Surgical morbidity includes possible damage to the recurrent laryngeal nerve, with resultant vocal cord paralysis. If both recurrent laryngeal nerves are damaged, airway obstruction may develop, and the patient may require intubation and tracheostomy. Hypoparathyroidism also occurs; serum calcium levels must be checked postoperatively. Patients should be admitted for thyroidectomy surgery for at least an overnight observation period. When a competent, experienced neck surgeon performs a thyroidectomy, surgical complications are uncommon.
Toxic solitary thyroid nodules are usually benign but may rarely be malignant. If a nonsurgical therapy is elected, the nodule should be evaluated with a fine-needle aspiration (FNA) biopsy. Hyperthyroidism caused by a single hyperfunctioning thyroid nodule may be treated symptomatically with propranolol ER and methimazole or propylthiouracil, as in Graves disease (see above). Patients who tolerate methimazole well may elect to continue it for long-term therapy. The dose of methimazole should be adjusted to keep the TSH slightly suppressed, so the risk of TSH-stimulated growth of the nodule is reduced. For patients under age 40 years and for healthy older patients, surgery is usually recommended; patients are made euthyroid with a thiourea preoperatively and given several days of iodine, ipodate sodium, or iopanoic acid before surgery (see above). Transient postoperative hypothyroidism resolves spontaneously. Permanent hypothyroidism occurs in about 14% of patients by 6 years after surgery. Patients with a toxic solitary nodule who are over age 40 years or in poor health may be offered 131I therapy. If the patient has been receiving methimazole preparatory to 131I, the TSH should be kept slightly suppressed in order to reduce the uptake of 131I by the normal thyroid. Nevertheless, permanent hypothyroidism occurs in about one-third of patients after 8 years of 131I therapy. The nodule remains palpable in 50% and may grow in 10% of patients after 131I.
Hyperthyroidism caused by a toxic multinodular goiter may also be treated with propranolol ER and methimazole, as in Graves disease. Methimazole does reverse hyperthyroidism, but there is a 95% recurrence rate if it is stopped. Definitive treatment for large multinodular goiters is surgery, prior to which patients are rendered euthyroid. Surgery is particularly indicated to relieve pressure symptoms or for cosmetic indications. Patients with toxic multinodular goiter are prepared for surgery the same as those with Graves disease, except they are not treated preoperatively with potassium iodide. Patients who are to receive 131I treatment are rendered nearly euthyroid with methimazole, which is stopped at least 4 days before RAI treatment. Meanwhile, the patient follows a low-iodine diet; this is done to enhance the thyroid gland’s uptake of RAI, which may be relatively low in this condition (compared to Graves disease). Relatively high doses of 131I are usually required; recurrent thyrotoxicosis and hypothyroidism are common, so patients must be monitored closely. Peculiarly, in about 5% of patients with diffusely nodular toxic goiter, the administration of 131I therapy may induce Graves disease. Also, Graves eye disease has occurred rarely following 131I therapy for multinodular goiter.
Subacute (de Quervain) and lymphocytic (Hashimoto) thyroiditis can cause transient hyperthyroidism from release of stored thyroid hormone from the inflamed thyroid. The condition subsides spontaneously within weeks to months. Thioureas are ineffective, since thyroid hormone production is actually low in this condition. In thyroiditis, RAI uptake is low, distinguishing it from Graves disease. For symptomatic relief, patients are treated with propranolol ER 60–80 mg twice daily and increased every 3 days until the heart rate is < 90 beats per minute for symptomatic relief. Ipodate sodium or iopanoic acid, 500 mg orally daily, promptly corrects elevated T3 levels and is continued for 15–60 days until the serum FT4 level normalizes. Patients are monitored carefully for the development of hypothyroidism and treated as needed. RAI is ineffective, since the thyroid’s iodine uptake is low. With subacute thyroiditis, pain can usually be managed with nonsteroidal anti-inflammatory drugs, but opioid analgesics are sometimes required.
Both men and women with Graves disease who are planning pregnancy should not have radioiodine treatment within about 3 months of conception. Women with Graves disease who are planning to become pregnant are encouraged to consider definitive therapy with RAI or surgery well before conception. Dietary iodine must not be restricted for such women. There is an increased risk of fetal anomalies associated with methimazole in the first trimester. Therefore, women with Graves disease who are being treated with a thiourea should be treated with propylthiouracil through the first trimester and then switched to methimazole. Either thiourea should be given in the smallest dose possible, permitting mild subclinical hyperthyroidism to occur since it is usually well tolerated. About 30% of women with Graves disease experience a remission by the late second trimester.
Both propylthiouracil and methimazole cross the placenta and can induce hypothyroidism, with fetal TSH hypersecretion and goiter. Fetal ultrasound at 20–32 weeks gestation can visualize any fetal goiter, allowing fetal thyroid dysfunction to be diagnosed and treated. Thyroid hormone administration to the mother does not prevent hypothyroidism in the fetus, since T4 and T3 do not freely cross the placenta. Fetal hypothyroidism is rare if the mother’s hyperthyroidism is controlled with small daily doses of propylthiouracil (50–150 mg/d orally) or methimazole (5–15 mg/d orally). Maternal serum TSI levels over 500% at term predict an increased risk of neonatal Graves disease in the infant.
Subtotal thyroidectomy is indicated for pregnant women with Graves disease under the following circumstances: (1) severe adverse reaction to thioureas; (2) high dosage requirement for thioureas (methimazole ≥ 30 mg/d or propylthiouracil ≥ 450 mg/d; (3) uncontrolled hyperthyroidism due to nonadherence to thiourea therapy. Surgery is best performed during the second trimester.
Both methimazole and propylthiouracil are secreted in breast milk, but not in amounts that affect the infant’s thyroid hormone levels. No adverse reactions to these drugs (eg, rash, hepatic dysfunction, leukopenia) have been reported in breast-fed infants. Recommended doses are 20 mg orally daily or less for methimazole and 450 mg orally daily or less for propylthiouracil. It is recommended that the medication be taken just after breastfeeding.
Patients with any type of amiodarone-induced thyrotoxicosis require treatment with propranolol ER for symptomatic relief. Since it is difficult to accurately categorize patients as either type 1 or type 2 amiodarone-induced thyrotoxicosis, it is prudent to treat all patients with methimazole 30 mg orally daily. After two doses of methimazole, iopanoic acid or sodium ipodate may be added to the regimen to further block conversion of T4 to T3; the recommended dosage for each is 500 mg orally twice daily for 3 days, followed by 500 mg once daily until thyrotoxicosis is resolved. If iopanoic acid or sodium ipodate is not available, the alternative is potassium perchlorate; it is given in doses of ≤ 1000 mg daily (in divided doses) for a course not to exceed 30 days in order to avoid the complication of aplastic anemia. Amiodarone may be withdrawn but this does not have a significant therapeutic impact for several months. For patients with type 1 amiodarone-induced thyrotoxicosis, therapy with 131I may be successful, but only for those with sufficient RAI uptake. Patients with clear-cut type 2 amiodarone-induced thyrotoxicosis are usually also treated with prednisone at an initial dose of about 0.5–0.7 mg/kg orally daily; that dose of prednisone is continued for about 2 weeks and then slowly tapered and finally withdrawn after about 3 months. Subtotal thyroidectomy should be considered for patients with amiodarone-induced thyrotoxicosis that is resistant to treatment.
Patients with corticosteroid-resistant acute Graves orbitopathy may also be treated with rituximab. Rituximab may be given by retro-orbital injection, which limits systemic toxicity. The recommended dosing is rituximab 10 mg by retro-orbital injection into the affected eye weekly for 1 month, followed by a 1-month break, then another series of four weekly injections.
Progressive active exophthalmos may be treated with retrobulbar radiation therapy using a supervoltage linear accelerator (4–6 MeV) to deliver 20 Gy over 2 weeks to the extraocular muscles, avoiding the cornea and lens. Prednisone in high doses is given concurrently. Patients who respond well to orbital radiation include those with signs of acute inflammation, recent exophthalmos (< 6 months), or optic nerve compression. Patients with chronic proptosis and orbital muscle restriction respond less well. Retrobulbar radiation does not cause cataracts or tumors; however, it can cause radiation-induced retinopathy (usually subclinical) in about 5% of patients overall, mostly in diabetics.
For severe cases, orbital decompression surgery may save vision, though diplopia often persists postoperatively. General eye protective measures include wearing glasses to protect the protruding eye and taping the lids shut during sleep if corneal drying is a problem. Methylcellulose drops and gels (“artificial tears”) may also help. Tarsorrhaphy or canthoplasty can frequently help protect the cornea and provide improved appearance. Hypothyroidism and hyperthyroidism must be treated promptly.
(1) Digoxin—Digoxin is used to slow a fast ventricular response to thyrotoxic atrial fibrillation; it must be used in larger than normal doses because of increased clearance and an increased number of cardiac cellular sodium pumps requiring inhibition. Digoxin doses are reduced as hyperthyroidism is corrected.
(2) Beta-blockers—Beta-blockers may also reduce the ventricular rate, but they must be used with caution—particularly in patients with cardiomegaly or signs of heart failure—since their negative inotropic effect may precipitate heart failure. Therefore, an initial trial of a short-duration beta-blocker should be considered, such as esmolol intravenously. If a beta-blocker is used, doses of digoxin must be reduced.
(3) Anticoagulants—Anticoagulation is indicated in the following situations: left atrial enlargement on echocardiogram, global left ventricular dysfunction, recent heart failure, hypertension, recurrent atrial fibrillation, or a history of previous thromboembolism. The doses of warfarin required in thyrotoxicosis are smaller than normal because of an accelerated plasma clearance of vitamin K–dependent clotting factors. Higher warfarin doses are usually required as hyperthyroidism subsides.
Heart failure may occur as a result of low-output dilated cardiomyopathy in the setting of hyperthyroidism. It is uncommon and may be caused by an idiosyncratic severe toxic effect of hyperthyroidism upon certain hearts. Cardiomyopathy may occur at any age and without preexisting cardiac disease. Beta-blockers and calcium channel blockers are avoided. Emergency treatment may include afterload reduction, diuretics, digoxin, and other inotropic agents while the patient is being rendered euthyroid. Heart failure usually persists despite correction of hyperthyroidism.
A thiourea drug is given (eg, methimazole, 15–25 mg orally every 6 hours or propylthiouracil, 150–250 mg orally every 6 hours). Ipodate sodium (500 mg/d orally) can be helpful if begun 1 hour after the first dose of thiourea. Iodide is given 1 hour later as Lugol solution (10 drops three times daily orally) or as sodium iodide (1 g intravenously slowly). Propranolol is given (cautiously in the presence of heart failure; see above) in a dosage of 0.5–2 mg intravenously every 4 hours or 20–120 mg orally every 6 hours. Hydrocortisone is usually given in doses of 50 mg orally every 6 hours, with rapid dosage reduction as the clinical situation improves. Aspirin is avoided since it displaces T4 from thyroxine-binding globulin (TBG), raising FT4 serum levels. Definitive treatment with 131I or surgery is delayed until the patient is euthyroid.
Graves disease may rarely subside spontaneously, particularly when it is mild or subclinical. Graves disease that presents in early pregnancy has a 30% chance of spontaneous remission before the third trimester. The ocular, cardiac, and psychological complications can become serious and persistent even after treatment. Permanent hypoparathyroidism and vocal cord palsy are risks of surgical thyroidectomy. Recurrences are common following thiourea therapy but also occur after low-dose 131I therapy or subtotal thyroidectomy. With adequate treatment and long-term follow-up, the results are usually good. However, despite treatment for their hyperthyroidism, women experience an increased long-term risk of death from thyroid disease, cardiovascular disease, stroke, and fracture of the femur. Posttreatment hypothyroidism is common. It may occur within a few months or up to several years after RAI therapy or subtotal thyroidectomy. Malignant exophthalmos has a poor prognosis unless treated aggressively.
Subclinical hyperthyroidism refers to a condition in which asymptomatic individuals have a low serum TSH and normal FT4 and T3. Most such patients do well without treatment. In one series, clinical hyperthyroidism developed in only one of seven patients after 2 years. In most patients, the serum TSH reverts to normal within 2 years. Most such patients do not have accelerated bone loss. However, if a baseline bone density shows significant osteopenia, bone densitometry may be performed periodically. In persons over age 60 years, serum TSH is very low (< 0.1 mU/L) in 3% and mildly low (0.1–0.4 mU/L) in 9%. The chance of developing atrial fibrillation is 2.8% yearly in elderly patients with very low TSH and 1.1% yearly in those with mildly low TSH. Asymptomatic persons with very low TSH are monitored closely but are not treated unless atrial fibrillation or other manifestations of hyperthyroidism develop.
When to Admit
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ESSENTIALS OF DIAGNOSIS
Acute and subacute forms: thyroid gland swelling, sometimes causing pressure symptoms.
Chronic form: thyroid gland may or may not be enlarged with rubbery firmness.
Thyroid function tests variable.
Serum antithyroperoxidase and antithyroglobulin antibody levels usually elevated in Hashimoto thyroiditis.
Thyroiditis may be classified as follows: (1) chronic lymphocytic thyroiditis due to autoimmunity (also called Hashimoto thyroiditis), (2) subacute thyroiditis, (3) suppurative thyroiditis, and (4) Riedel thyroiditis.
Hashimoto thyroiditis, an autoimmune condition, is the most common thyroid disorder in the United States. B-lymphocytes invade the thyroid gland, such that the condition is also known as chronic lymphocytic thyroiditis. Elevated serum levels of antithyroid antibodies (antithyroperoxidase or antithyroglobulin antibodies, or both) are found in 3% of men and 13% of women. Women over the age of 60 years have a 25% incidence of elevated serum levels of antithyroid antibodies, yet only a small subset of such individuals ever develops thyroid dysfunction. However, 1% of the population has serum antithyroid antibody titers > 1:640 and they are at particular risk for thyroid dysfunction. The incidence of Hashimoto thyroiditis varies by kindred, race, and by sex; for example, in persons older than 12 years of age in the United States, elevated levels of antithyroid antibodies are found in 14.3% of whites, 10.9% of Mexican-Americans, and 5.3% of blacks.
Hashimoto thyroiditis is six times more common in women than in men. It is commonly familial. Dietary iodine supplementation increases the incidence of Hashimoto thyroiditis. Childhood or occupational exposure to head–neck external beam radiation increases the lifetime risk of Hashimoto thyroiditis. Women with gonadal dysgenesis (Turner syndrome) have a 15% incidence of thyroiditis by age 40 years. Thyroiditis is also commonly seen in patients with hepatitis C. Subclinical thyroiditis is extremely common; autopsy series have found focal thyroiditis in about 40% of women and 20% of men.
Certain drugs can trigger Hashimoto thyroiditis, including the following: tyrosine kinase inhibitors, denileukin diftitox, alemtuzumab, interferon-alpha, interleukin-2, ipilimumab, tremelimumab, thalidomide, lenalidomide, lithium, and amiodarone.
Hashimoto thyroiditis often progresses to hypothyroidism, which may be linked to thyrotropin receptor–blocking antibodies, detected in 10% of patients with Hashimoto thyroiditis. Hypothyroidism is more likely to develop in smokers than in nonsmokers, possibly due to the thiocyanates in cigarette smoke. High serum levels of thyroid peroxidase antibody also predict progression from subclinical to symptomatic hypothyroidism. Although the hypothyroidism is usually permanent, up to 11% of patients experience a remission after several years. Rarely, the thyroid gland goes on to produce excessivethyroid hormone and autoimmune hyperthyroidism (see Graves disease).
Hashimoto thyroiditis is sometimes associated with other endocrine deficiencies as part of polyglandular autoimmunity (PGA). Adults with type 2 PGA are prone to autoimmune thyroiditis, diabetes mellitus type 1, autoimmune gonadal failure, hypoparathyroidism, and adrenal insufficiency (see Adrenal Insufficiency). Thyroiditis is frequently associated with other autoimmune conditions: pernicious anemia, Sjögren syndrome, vitiligo, inflammatory bowel disease, celiac disease, and gluten sensitivity. It is less commonly associated with alopecia areata, hypophysitis, encephalitis, myocarditis, primary pulmonary hypertension, and membranous nephropathy.
Painless postpartum thyroiditis refers to autoimmune thyroiditis that occurs soon after delivery in 7.2% of women. Women in whom postpartum thyroiditis develops have a 70% chance of recurrence after subsequent pregnancies. It occurs most commonly in women who have high levels of thyroid peroxidase antibody in the first trimester of pregnancy or immediately after delivery. It is also more common in women with other autoimmunity or a family history of Hashimoto thyroiditis.
Painless sporadic thyroiditis is thought to be a subacute form of Hashimoto thyroiditis that is similar to painless postpartum thyroiditis (see above), except that it is not related to pregnancy. It accounts for about 1% of cases of thyrotoxicosis.
Subacute thyroiditis—also called de Quervain thyroiditis, granulomatous thyroiditis, and giant cell thyroiditis—is relatively common. It is believed to be caused by a viral infection and often follows an upper respiratory tract infection. Its incidence peaks in the summer. It accounts for up to 5% of clinical thyroid disease and young and middle-aged women are most commonly affected.
Suppurative thyroiditis refers to a nonviral infection of the thyroid gland. While usually bacterial, mycobacterial, fungal, and parasitic infections can occur, particularly in immunosuppressed individuals. Suppurative thyroiditis is quite rare, since the thyroid is resistant to infection, largely due to its high iodine content. It tends to affect patients with preexistent thyroid disease. Congenital pyriform sinus fistulas are a cause for recurrent suppurative thyroiditis.
Riedel thyroiditis, also called invasive fibrous thyroiditis, Riedel struma, woody thyroiditis, ligneous thyroiditis, and invasive thyroiditis, is the rarest form of thyroiditis. It is found most frequently in middle-aged or elderly women and is usually part of a multifocal systemic fibrosis syndrome. It may occur as a thyroid manifestation of IgG4-related systemic disease (see Chapter 20).
In Hashimoto thyroiditis, the thyroid gland is usually diffusely enlarged, firm, and finely nodular. One thyroid lobe may be asymmetrically enlarged, raising concerns about neoplasm. Although patients may complain of neck tightness, pain and tenderness are not usually present. About 10% of cases are atrophic, the gland being fibrotic, particularly in elderly women.
Symptoms and signs are mostly related to ambient levels of thyroid hormone. However, depression and chronic fatigue are more common in such patients, even after correction of hypothyroidism. About one-third of patients have mild dry mouth (xerostomia) or dry eyes (keratoconjunctivitis sicca) related to Sjögren syndrome. Associated myasthenia gravis is usually of mild severity, mainly affecting the extraocular muscles and having a relatively low incidence of detectable AChR Ab or thymic disease. Associated celiac disease can produce fatigue or depression, often in the absence of gastrointestinal symptoms.
Postpartum thyroiditis is typically manifested by hyperthyroidism that begins 1–6 months after delivery and persists for only 1–2 months. Then, hypothyroidism tends to develop beginning 4–8 months after delivery.
Thyrotoxic symptoms in painless sporadic thyroiditis are usually mild; a small, nontender goiter may be palpated in about 50% of such patients. High serum thyroid peroxidase antibody concentrations are found in only 50%. The course is similar to painless postpartum thyroiditis.
Subacute thyroiditis presents with an acute, usually painful enlargement of the thyroid gland, often with dysphagia. The pain may radiate to the ears. Patients usually have a low-grade fever and fatigue. The manifestations may persist for weeks or months and may be associated with malaise. If there is no pain, it is called silent thyroiditis. Thyrotoxicosis develops in 50% of affected patients and tends to last for several weeks. Subsequently, hypothyroidism develops that lasts 4–6 months. Normal thyroid function typically returns within 12 months, but persistent hypothyroidism develops in 5% of patients.
Patients with suppurative thyroiditis usually are febrile and have severe pain, tenderness, redness, and fluctuation in the region of the thyroid gland. In Riedel thyroiditis, thyroid enlargement is often asymmetric; the gland is stony hard and adherent to the neck structures, causing signs of compression and invasion, including dysphagia, dyspnea, pain, and hoarseness. Related conditions include retroperitoneal fibrosis, fibrosing mediastinitis, sclerosing cervicitis, subretinal fibrosis, and biliary tract sclerosis.
In Hashimoto thyroiditis with clinically evident disease, there are usually increased circulating levels of antithyroid peroxidase (90%) or antithyroglobulin (40%) antibodies. Antithyroid antibodies decline during pregnancy and are often undetectable in the third trimester. Once Hashimoto thyroiditis has been diagnosed, monitoring of these antibody levels is not helpful. The serum TSH level is elevated if thyroid hormone is not elaborated in adequate amounts by the thyroid gland.
Patients with Hashimoto thyroiditis have a 15% incidence of having serum antibodies (IgA tissue transglutaminase [tTG] antibody) associated with celiac disease and at least 5% have clinically significant celiac disease. Seronegative gluten sensitivity is even more common.
In subacute thyroiditis, the ESR is markedly elevated while antithyroid antibody titers are low, distinguishing it from autoimmune thyroiditis. In suppurative thyroiditis, both the leukocyte count and ESR are usually elevated.
With hyperthyroidism due to Hashimoto thyroiditis or subacute thyroiditis, serum FT4 levels tend to be proportionally higher than T3 levels, since the hyperthyroidism is due to the passive release of stored thyroid hormone, which is predominantly T4; this is in contrast to Graves disease and toxic nodular goiter, where T3 is relatively more elevated. Because T4 is less active than T3, the hyperthyroidism seen in thyroiditis is usually less severe. Serum levels of TSH are suppressed in hyperthyroidism due to thyroiditis.
Ultrasound in cases of Hashimoto thyroiditis typically shows a gland with characteristic diffuse heterogeneous density and hypoechogenicity. It helps distinguish thyroiditis from multinodular goiter or thyroid nodules that are suspicious for malignancy. It is also helpful in guiding FNA biopsy of small suspicious thyroid nodules. Color-flow Doppler ultrasonography can help distinguish thyroiditis from Graves disease, since patients with Graves disease have a hypervascular thyroid gland, whereas in thyroiditis there is normal or reduced vascularity.
RAI uptake and scan may be helpful in determining the cause of hyperthyroidism, distinguishing thyroiditis from Graves disease, since patients with subacute thyroiditis exhibit a very low RAI uptake. However, in patients with chronic Hashimoto thyroiditis (euthyroid or hypothyroid), RAI uptake may be normal or high with uneven uptake on the scan; scanning is not useful in diagnosis.
[18F] Fluorodeoxyglucose positron emission tomography (18FDG-PET) scanning frequently shows diffuse thyroid uptake of isotope in cases of thyroiditis. In fact, of all 18FDG-PET scans, about 3% show such uptake. However, discrete thyroid nodules can also be discovered on 18FDG-PET scanning; known as “thyroid PET incidentalomas,” 50% are malignant.
Patients with Hashimoto thyroiditis who have a thyroid nodule should have an ultrasound-guided FNA biopsy, since the risk of papillary thyroid cancer is about 8% in such nodules. When suppurative thyroiditis is suspected, an FNA biopsy with Gram stain and culture is required. FNA biopsy is usually not required for subacute thyroiditis but shows characteristic giant multinucleated cells.
Hashimoto thyroiditis may lead to hypothyroidism or transient thyrotoxicosis. Hyperthyroidism may develop, either due to the emergence of Graves disease or due to the release of stored thyroid hormone, which is caused by inflammation. Variably termed “hashitoxicosis” or “painless sporadic thyroiditis,” it is known as postpartum painless thyroiditis when it occurs in women after delivery. Pregnant women with Hashimoto thyroiditis have an increased risk of spontaneous miscarriage in the first trimester of pregnancy. Perimenopausal women with high serum levels of antithyroperoxidase antibodies have a higher relative risk of depression, independent of ambient thyroid hormone levels.
In the suppurative forms of thyroiditis, any of the complications of infection may occur. Subacute and chronic thyroiditis are complicated by the effects of pressure on the neck structures: dyspnea and, in Riedel struma, vocal cord palsy. Papillary thyroid carcinoma or thyroid lymphoma may rarely be associated with chronic thyroiditis and must be considered in the diagnosis of uneven painless enlargements that continue despite treatment; such patients require FNA biopsy.
Thyroiditis must be considered in the differential diagnosis of all types of goiters, especially if enlargement is rapid. The very low RAI uptake in subacute thyroiditis with elevated T4 and T3 is helpful. Thyroid autoantibody tests have been of help in the diagnosis of Hashimoto thyroiditis, but the tests are not specific (positive in patients with multinodular goiters, malignancy [eg, thyroid carcinoma, lymphoma], and concurrent Graves disease). The subacute and suppurative forms of thyroiditis may resemble any infectious process in or near the neck structures. Chronic thyroiditis, especially if the enlargement is uneven and if there is pressure on surrounding structures, may resemble thyroid carcinoma, and both disorders may be present in the same gland.
If hypothyroidism is present, levothyroxine should be given in the usual replacement doses (0.05–0.2 mg orally daily). In patients with a large goiter and normal or elevated serum TSH, an attempt is made to shrink the goiter by administering levothyroxine in doses sufficient to drive the serum TSH below the reference range while maintaining clinical euthyroidism. Suppressive doses of T4 tend to shrink the goiter an average of 30% over 6 months. If the goiter does not regress, lower replacement doses of levothyroxine may be given. If the thyroid gland is only minimally enlarged and the patient is euthyroid, regular observation is in order, since hypothyroidism may develop subsequently—often years later. (See Hypothyroidism section.)
All treatment is empiric and must be continued for several weeks. Recurrence is common. The drug of choice is aspirin, which relieves pain and inflammation. Thyrotoxic symptoms are treated with propranolol, 10–40 mg every 6 hours. Iodinated contrast agents cause a prompt fall in serum T3 levels and a dramatic improvement in thyrotoxic symptoms. Sodium ipodate (Oragrafin, Bilivist) or iopanoic acid (Telepaque) is given orally in doses of 500 mg orally daily until serum FT4 levels return to normal. Transient hypothyroidism is treated with T4 (0.05–0.1 mg orally daily) if symptomatic.
Treatment is with antibiotics and with surgical drainage when fluctuation is marked.
The treatment of choice is tamoxifen, 20 mg orally twice daily, which must be continued for years. Tamoxifen can induce partial to complete remissions in most patients within 3–6 months. Its mode of action appears to be unrelated to its antiestrogen activity. Short-term corticosteroid treatment may be added for partial alleviation of pain and compression symptoms. Surgical decompression usually fails to permanently alleviate compression symptoms; such surgery is difficult due to dense fibrous adhesions, making surgical complications more likely.
Hashimoto thyroiditis is occasionally associated with other autoimmune disorders (celiac disease, diabetes mellitus, Addison disease, pernicious anemia, etc). In general, however, patients with Hashimoto thyroiditis have an excellent prognosis, since the condition either remains stable for years or progresses slowly to hypothyroidism, which is easily treated. Although 80% of women with postpartum thyroiditis subsequently recover normal thyroid function, permanent hypothyroidism eventually develops in about 50% within 7 years, more commonly in women who are multiparous or who have had a spontaneous abortion. In subacute thyroiditis, spontaneous remissions and exacerbations are common; the disease process may smolder for months. Papillary thyroid carcinoma carries a relatively good prognosis when it occurs in patients with Hashimoto thyroiditis.
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THYROID NODULES & MULTINODULAR GOITER
ESSENTIALS OF DIAGNOSIS
Single or multiple thyroid nodules are commonly found with careful thyroid examinations.
Thyroid function tests mandatory.
Thyroid biopsy for single or dominant nodules or for a history of prior head–neck or chest–shoulder radiation.
Ultrasound examination useful for biopsy and follow-up.
Clinical follow-up required.
Thyroid nodules are extremely common. In Germany, neck ultrasound screening of adults found a 20% incidence of thyroid nodules > 1 cm in diameter. Palpable nodules are found in 5% of women and 1% of men in iodine-sufficient areas of the world; they are even more common in iodine-deficient areas (see Iodine Deficiency Disorder & Endemic Goiter). Each year in the United States, about 275,000 thyroid nodules are detected by palpation, of which 10% are malignant. Palpable thyroid nodules are increasingly prevalent with age. On high-resolution thyroid ultrasound, about 50% of palpable “solitary nodules” are found to be just one nodule in a multinodular goiter.
In recent years, an increased general use of scanning (CT, MRI, ultrasound, PET) has led to an increased rate of incidentally detecting nonpalpable thyroid nodules.
Although 90% of palpable thyroid nodules are benign, the presence of a thyroid nodule ≥ 1 cm diameter warrants follow-up and further testing for function and malignancy. An occasional nodule < 1 cm diameter requires follow-up if it has high-risk characteristics on ultrasound or if the patient has had prior head-neck radiation therapy. Thyroid nodules that are incidentally discovered with increased standard uptake value (SUV) on 18FDG-PET scanning have a 33% risk for being malignant and definitely require biopsy.
Most patients with a thyroid nodule are euthyroid, but there is a high incidence of hypothyroidism or hyperthyroidism. About 90% of thyroid nodules are benign adenoma, colloid nodule, or cyst but may sometimes be a primary thyroid malignancy or (less frequently) metastatic neoplasm. Patients with multiple thyroid nodules have the same overall risk of thyroid cancer as patients with solitary nodules. The risk of a thyroid nodule being malignant is higher among patients with a history of head–neck radiation, total body radiation for bone marrow transplantation, exposure to radioactive fallout as a child or teen, a family history of thyroid cancer or a thyroid cancer syndrome (eg, Cowden syndrome, multiple endocrine neoplasia type 2, familial polyposis, Carney syndrome), or a personal history of another malignancy. The risk of malignancy is also higher if there is hoarseness or vocal fold paralysis, and if the thyroid nodule is large, adherent to the trachea or strap muscles, or associated with lymphadenopathy. The presence of Hashimoto thyroiditis does not reduce the risk of malignancy; a nodule of ≥1 cm in a gland with thyroiditis carries an 8% chance of malignancy.
Table 26–6 illustrates the approach to the evaluation of thyroid nodules based on the index of suspicion for malignancy.
Table 26–6. Clinical evaluation of thyroid nodules.1
Most small thyroid nodules cause no symptoms. They may sometimes be detected only by having the patient swallow during careful inspection and palpation of the thyroid.
A thyroid nodule or multinodular goiter can grow to become visible and of concern to the patient. Particularly large nodular goiters can become a cosmetic embarrassment. Nodules can grow large enough to cause discomfort, hoarseness, or dysphagia. Retrosternal large multinodular goiters can cause dyspnea due to tracheal compression. Large substernal goiters may cause superior vena cava syndrome, manifested by facial erythema and jugular vein distention that progress to cyanosis and facial edema when both arms are kept raised over the head (Pemberton sign).
Depending on their cause, goiters and thyroid nodules may be associated with hypothyroidism (Hashimoto thyroiditis, endemic goiter) or hyperthyroidism (Graves disease, toxic nodular goiter, subacute thyroiditis, and thyroid cancer with metastases).
A serum TSH level should be obtained for all patients with a thyroid nodule. Patients with a subnormal serum TSH must have a radionuclide (123I or 99mTc pertechnetate) thyroid scan to determine whether the nodule is hyperfunctioning; hyperfunctioning nodules are rarely malignant. Tests for antithyroperoxidase antibodies and antithyroglobulin antibodies may also be helpful since very high levels are found in Hashimoto thyroiditis. However, thyroiditis frequently coexists with malignancy, so suspicious nodules should always be biopsied. Serum calcitonin is obtained if a medullary thyroid carcinoma is suspected in a patient with a family history of medullary thyroid carcinoma or MEN type 2.
Neck ultrasonography should be performed to measure the size of a nodule and to determine whether a palpable nodule is part of a multinodular goiter. The following ultrasound characteristics of thyroid nodules increase the likelihood of malignancy: irregular or indistinct margins, heterogenous nodule echogenicity, intranodular vascular images, microcalcifications, complex cyst, or diameter over 1 cm. Ultrasound is also useful for long-term surveillance of thyroid nodules and multinodular goiter. Ultrasonography is generally preferred over CT and MRI because of its accuracy, ease of use, and lower cost. CT scanning is helpful for larger thyroid nodules and multinodular goiter; it can determine the degree of tracheal compression and the degree of extension into the mediastinum.
RAI (123I or 131I) scans have limited usefulness in the evaluation of thyroid nodules. Hypofunctioning (cold) nodules have a somewhat increased risk of being malignant (but most are benign). Hyperfunctioning (hot) nodules are ordinarily benign (but may sometimes be malignant). RAI uptake and scanning is helpful mainly if a patient is hyperthyroid. (See Hyperthyroidism.)
Thyroid nodules are frequently discovered as an incidental finding, with an incidence that depends on the imaging modality: MRI, 50%; CT, 13%; and 18FDG-PET, 2%. When such scanning detects a thyroid nodule, an ultrasound is performed to better determine the nodule’s risk for malignancy and the need for FNA biopsy, and to establish a baseline for ultrasound follow-up. The malignancy risk is about 17% for nodules discovered incidentally on CT or MRI, and 25–50% for nodules discovered incidentally by 18FDG-PET. For incidentally discovered thyroid nodules of borderline concern, follow-up thyroid ultrasound in 3–6 months may be helpful; growing lesions should be biopsied or resected.
FNA biopsy is the best method to assess a thyroid nodule for malignancy. FNA biopsy can be done while patients continue taking anticoagulants or aspirin. For multinodular goiters, the four largest nodules (≥ 1 cm diameter) should be biopsied to minimize the risk of missing a malignancy. For solitary thyroid nodules, FNA biopsy is indicated for: (1) nodules > 5 mm diameter with a suspicious appearance on ultrasound; (2) nodules associated with abnormal cervical lymph nodes; (3) nodules ≥ 1 cm diameter that are solid or have microcalcifications; (4) mixed cystic-solid nodules ≥ 1.5 cm diameter with any suspicious features on ultrasound or ≥ 2 cm diameter with benign features on ultrasound; (5) spongiform nodules ≥ 2 cm diameter. Pure cystic nodules are benign and do not require FNA biopsy. Using ultrasound guidance for FNA biopsy improves the diagnostic accuracy for both palpable and nonpalpable thyroid nodules. The chance of an optimal tissue sampling is also improved by having an experienced clinician perform the FNA biopsy and by having the aspirate interpreted by a skilled cytopathologist.
In one review of thyroid FNA biopsies, about 70% were benign, 5% were malignant, 10% were “suspicious,” and 15% were “nondiagnostic.” Nondiagnostic, bloody, or hypocellular FNA biopsies should be repeated under ultrasound guidance; nodules that continue to have nondiagnostic cytology should be monitored closely; those that are solid or that grow should be resected.
When FNA cytology is “suspicious” for papillary thyroid carcinoma or Hürthle cell neoplasm, the risk of malignancy is 57%. When FNA cytology is a “suspicious” for follicular carcinoma, the overall risk of malignancy is about 20–25%, and higher for patients who are much younger or older than age 50. Most patients with suspicious FNA cytology are advised to have surgery.
Cystic nodules yielding serous fluid are usually benign, but the aspirate should be submitted for cytologic testing. Cystic nodules yielding bloody fluid have a higher chance of being malignant.
False-positive thyroid FNA biopsy results occur at a rate of about 4%. False-negative thyroid FNA biopsy results also occur at an overall rate of about 4%, less commonly when performed under ultrasound guidance and interpreted by cytopathologists. False-negative results delay surgical excision and lead to an increased risk of vascular and capsular invasion by the malignancy. Some false-negative FNA biopsy results may not have actually been inaccurate, since truly benign thyroid nodules can later become malignant.
All thyroid nodules, including those that are benign, need to be monitored by regular periodic palpation and ultrasound about every 6 months initially. After several years of stability, yearly examinations are sufficient. Thyroid nodules should be rebiopsied if growth occurs. A toxic multinodular goiter and hyperthyroidism may develop in patients who have had exposure to large amounts of iodine, either orally (eg, amiodarone) or intravenously (eg, radiographic contrast). Therefore, excessive iodine intake should be minimized. Patients found to have hyperthyroidism may have a RAI uptake and scan, especially if131I is a therapeutic consideration. Patients with toxic multinodular goiters may also be treated with methimazole, propranolol, or surgery (see Hyperthyroidism). Thyroid nodules require careful clinical evaluation and thyroid palpation or ultrasound examinations.
Patients with elevated levels of serum TSH are treated with levothyroxine replacement. Patients with larger nodules (> 2 cm), elevated or normal TSH levels may be considered for TSH suppression with levothyroxine (starting doses of 50 mcg orally daily). Levothyroxine suppression therapy is not recommended for small benign thyroid nodules. Thyroxine suppression therapy is more successful in iodine-deficient areas of the world. Long-term levothyroxine suppression of TSH tends to keep nodules from enlarging, but only 20% shrink more than 50%. Thyroid nodule size increased in 29% of patients treated with levothyroxine versus 56% of patients not receiving levothyroxine. Levothyroxine suppression also reduces the emergency of new nodules: 8% with levothyroxine and 29% without levothyroxine. Levothyroxine suppression therapy is not usually given to patients with cardiac disease, since it increases the risk for angina and atrial fibrillation. Levothyroxine suppression causes a small loss of bone density, particularly in postmenopausal women if the serum TSH is suppressed to < 0.05 mU/L. Such patients are advised to have bone density testing every 3–5 years. For patients with a low baseline TSH level, levothyroxine should not be administered, since that is an indication of autonomous thyroid secretion; levothyroxine will be ineffective and could cause thyrotoxicosis.
Levothyroxine suppression needs to be carefully monitored, since it carries a 17% risk of inducing hyperthyroidism. All patients receiving levothyroxine suppression therapy should have serum TSH levels monitored regularly, with the levothyroxine dose adjusted to keep the serum TSH mildly suppressed (between 0.2 mU/L and 0.8 mU/L). Thyroid nodules require careful clinical evaluation and thyroid palpation or ultrasound examinations about every 6 months initially. After several years of stability, yearly examinations are sufficient.
Total thyroidectomy is required for thyroid nodules that are malignant on FNA biopsy (see Thyroid Cancer). More limited thyroid surgery is indicated for benign nodules with indeterminate or suspicious cytologic test results, compression symptoms, discomfort, or cosmetic embarrassment. Surgery may also be used to remove hyperfunctioning “hot” thyroid adenomas or toxic multinodular goiter causing hyperthyroidism (see Hyperthyroidism).
Thyroid cysts can be aspirated, but cystic fluid recurs in 75% of patients. Percutaneous ethanol injection has been used to shrink pure cysts; the success rate is 80%, although it must often be repeated. Percutaneous ethanol injection can also be used to shrink biopsy-proven benign nodules. While complications occur in about 9%, serious or permanent complications are rare.
Radioactive 131I is a treatment option for hyperthyroid patients with toxic thyroid adenomas, multinodular goiter, or Graves disease (see Hyperthyroidism). It may also be used to shrink benign nontoxic thyroid nodules. Thyroid nodules shrink an average of 40% by 1 year and 59% by 2 years after 131I therapy. Nodules that shrink after 131I therapy generally remain palpable and become firmer; they may develop unusual cytologic characteristics on FNA biopsy. 131I therapy may be used to shrink large multinodular goiter but may rarely induce Graves disease. Hypothyroidism is a risk and may occur years after 131I therapy, so it is advisable to assess thyroid function every 3 months for the first year, every 6 months thereafter, and immediately for symptoms of hypothyroidism or hyperthyroidism.
The great majority of thyroid nodules are benign. Benign thyroid nodules may involute but usually persist or grow slowly. About 90% of thyroid nodules will increase their volume by ≥ 15% over 5 years; cystic nodules are less likely to grow. Cytologically benign nodules that grow are unlikely to be malignant; in one series, only 1 of 78 rebiopsied nodules was found to be malignant. The prognosis for patients with thyroid nodules that prove to be malignant is determined by the histologic type and other factors (see Thyroid Cancer). Multinodular goiters tend to persist or grow slowly, even in iodine-deficient areas where iodine repletion usually does not shrink established goiters. Patients with very small, incidentally discovered, nonpalpable thyroid nodules require follow-up with thyroid ultrasound every 1–2 years but are at low risk for malignancy. Such nodules, if malignant and excised, have only a minor effect on morbidity and mortality.
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ESSENTIALS OF DIAGNOSIS
Painless swelling in region of thyroid.
Thyroid function tests usually normal.
Past history of irradiation to head and neck region may be present.
Positive thyroid FNA biopsy.
The incidence of papillary and follicular (differentiated) thyroid carcinomas increases with age. The overall female:male ratio is 3:1. The yearly incidence of thyroid cancer has been increasing in the United States, with the number of cases diagnosed annually reaching 37,200, probably as a result of the wider use of CT, MRI, PET, and ultrasound that incidentally find small thyroid malignancies. Thyroid cancer mortality has been stable, accounting for about 1500 deaths in the United States annually. In routine autopsy series, thyroid microcarcinoma (≤ 10 mm diameter) is found with the surprising frequency of 35%. Clearly, most thyroid cancers remain microscopic and indolent. However, larger thyroid cancers (palpable or ≥ 1 cm in diameter) are more malignant and require treatment.
Papillary thyroid carcinoma is the most common thyroid malignancy (Table 26–7). Pure papillary (and mixed papillary-follicular) carcinoma comprises about 80% of all thyroid cancers. It usually presents as a single thyroid nodule, but it can arise out of a multinodular goiter. Papillary thyroid carcinoma is commonly multifocal within the gland, with other foci usually arising de novo rather than representing intraglandular metastases. About 10% of cases present with palpable cervical lymph node metastases from a small cancer. Papillary thyroid carcinomas tend to grow slowly and often remain confined to the thyroid and regional lymph nodes for years. However, they may become more aggressive, especially in patients over age 45 years, and most particularly in the elderly. The cancer may invade the trachea and local muscles and may spread to the lungs.
Table 26–7. Some characteristics of thyroid cancer.
Exposure to head and neck radiation therapy poses a particular threat to children who then have an increased lifetime risk of developing thyroid cancer, including papillary carcinoma. These cancers may emerge between 10 and 40 years after exposure, with a peak occurrence 20–25 years later. After an explosion at the Chernobyl Nuclear Plant in the Ukraine in 1986, the risk of developing papillary thyroid carcinoma was highest among children who were under age 5 at the time of exposure to radiation; emergence of more aggressive papillary thyroid carcinoma occurred within 6–7 years after exposure.
Papillary thyroid carcinoma can occur in familial syndromes as an autosomal dominant trait, caused by loss of various tumor suppressor genes. Such syndromes (with associated features) include familial papillary carcinoma (with papillary renal carcinoma), familial nonmedullary thyroid carcinoma, familial polyposis (with large intestine polyps and gastrointestinal tumors), Gardner syndrome (with small and large intestine polyps, fibromas, lipomas, osteomas), Turcot syndrome (with large intestine polyps and brain tumors), and Cowden syndrome (with nodular goiter, benign or malignant breast lesions, macrocephaly, mental retardation, mucocutaneous lesions, benign or malignant uterine neoplasms, or gastrointestinal hamartomas or ganglioneuromas).
Generally speaking, papillary carcinoma is the least aggressive thyroid malignancy. However, the tumor spreads via lymphatics within the thyroid, appearing to be multifocal in 60% of patients and involving both lobes in 30% of patients. About 80% of patients have microscopic metastases to cervical lymph nodes. Unlike other forms of cancer, patients with papillary thyroid carcinoma who have palpable lymph node metastases do not have a particularly increased mortality rate; however, their risk of local recurrence is increased.
Occult metastases to the lung occur in 10–15% of papillary thyroid cancer. About 70% of small lung metastases resolve following 131I therapy; however, larger pulmonary metastases have only a 10% remission rate.
Microscopic “micropapillary” carcinoma (≤ 1 mm and invisible even on thyroid ultrasound) is a variant of normal, being found in 24% of thyroidectomies performed for benign thyroid disease when 2-mm sections were carefully examined. It thus appears that the overwhelming majority of these microscopic foci never become clinically significant. The surgical pathology report of such a tiny papillary carcinoma that is otherwise benign does not justify aggressive follow-up or treatment because a cancer diagnosis is unwarranted and harmful. All that may be required is yearly follow-up with palpation of the neck and mild TSH suppression by thyroxine.
Follicular thyroid carcinoma and its variants (eg, Hürthle cell carcinoma) account for about 14% of thyroid malignancies; follicular thyroid carcinoma is generally more aggressive than papillary carcinoma. Rarely, some follicular carcinomas secrete enough T4 to cause thyrotoxicosis if the tumor load becomes significant. Metastases commonly are found in neck nodes, bones, and lungs. Most follicular thyroid carcinomas avidly absorb iodine, making possible diagnostic scanning and treatment with 131I after total thyroidectomy. The follicular histopathologic features that are associated with a high risk of metastasis and recurrence are poorly differentiated and Hürthle cell (oncocytic) variants. The latter variants do not take up RAI.
Follicular thyroid carcinoma and adenomas develop in patients with Cowden disease, a rare autosomal dominant familial syndrome caused by loss of a tumor suppressor gene; such patients tend to have macrocephaly, multiple hamartomas, early-onset breast cancer, intestinal polyps, facial papules, and other skin and mucosal lesions.
Medullary thyroid carcinoma represents about 3% of thyroid cancers. About one-third of cases are sporadic, one-third are familial, and one-third are associated with MEN type 2. Medullary thyroid carcinoma is often caused by an activating mutation of the ret protooncogene (RET) on chromosome 10. Mutation analysis of the ret protooncogene exons 10, 11, 13, and 14 detects 95% of the mutations causing MEN 2A and 90% of the mutations causing familial medullary thyroid carcinoma. Patients with MEN 2B have activating mutations in exon 16 of the ret protooncogene. These germline mutations can be detected by DNA analysis of peripheral WBCs. Therefore, discovery of a medullary thyroid carcinoma makes genetic analysis mandatory. If a gene defect is discovered, related family members must have genetic screening for that specific gene defect. When a family member with MEN 2A or familial medullary thyroid carcinoma does not have an identifiable ret protooncogene mutation, gene carriers may still be identified using family linkage analysis. Even when no gene defect is detectable, family members should have thyroid surveillance every 6 months. Somatic mutations of the ret protooncogene can be identified in the tumors of 30% of patients with sporadic (nonfamilial) medullary thyroid carcinoma. (See Multiple Endocrine Neoplasia.)
Medullary thyroid carcinoma arises from parafollicular thyroid cells that can secrete calcitonin, prostaglandins, serotonin, ACTH, corticotropin-releasing hormone (CRH), and other peptides. These peptides can cause symptoms and can be used as tumor markers. Early local metastases are usually present, usually to adjacent muscle and trachea as well as to local and mediastinal lymph nodes. Eventually, late metastases may appear in the bones, lungs, adrenals, or liver. Medullary thyroid carcinoma does not concentrate iodine.
Anaplastic thyroid carcinoma represents about 2% of thyroid cancers. It usually presents in an older patient as a rapidly enlarging mass in a multinodular goiter. It is the most aggressive thyroid carcinoma and metastasizes early to surrounding nodes and distant sites. Local pressure symptoms include dysphagia or vocal cord paralysis. This tumor does not concentrate iodine.
Other thyroid malignancies together represent about 3% of thyroid cancers. Lymphoma of the thyroid is more common in older women. Thyroid lymphomas are most commonly B cell lymphomas (50%) or mucosa-associated lymphoid tissue (MALT; 23%); other types include follicular, small lymphocytic, and Burkitt lymphoma and Hodgkin disease. Thyroidectomy is rarely required. Other cancersmay sometimes metastasize to the thyroid, particularly bronchogenic, breast, and renal carcinomas and malignant melanoma.
Thyroid carcinoma usually presents as a palpable, firm, nontender nodule in the thyroid. Most thyroid carcinomas are asymptomatic, but large thyroid cancers can cause neck discomfort, dysphagia, or hoarseness (due to pressure on the recurrent laryngeal nerve). About 3% of thyroid malignancies present with a metastasis, usually to local lymph nodes but sometimes to distant sites such as bone or lung. Palpable lymph node involvement is present in 15% of adults and 60% of youths. Metastatic functioning differentiated thyroid carcinoma can sometimes secrete enough thyroid hormone to produce thyrotoxicosis. Anaplastic thyroid carcinoma is more apt to be advanced at the time of diagnosis, presenting with dysphagia, hoarseness, dyspnea, and metastases to the lungs. Occasionally, such carcinomas may be discovered while they are still relatively small and localized.
Medullary thyroid carcinoma frequently causes flushing and persistent diarrhea (30%), which may be the initial clinical feature. Patients with metastases often experience fatigue as well as other symptoms. Cushing syndrome develops in about 5% of patients from secretion of ACTH or CRH. Signs of pressure or invasion of surrounding tissues are present in anaplastic or large tumors; recurrent laryngeal nerve palsy can occur.
Lymphoma usually presents as a rapidly enlarging, painful mass arising out of a multinodular or diffuse goiter affected by autoimmune thyroiditis, with which it may be confused microscopically. About 20% of cases have concomitant hypothyroidism.
Thyroid function tests are generally normal unless there is concomitant thyroiditis. Follicular carcinoma may secrete enough T4 to suppress TSH and cause clinical hyperthyroidism. (FNA biopsy is discussed above in Thyroid Nodules.)
Serum thyroglobulin is high in most metastatic papillary and follicular tumors, making this a useful marker for recurrent or metastatic disease. Caution must be exercised for the following reasons: (1) Circulating antithyroglobulin antibodies can cause erroneous thyroglobulin determinations. However, declining levels of antithyroglobulin antibodies are a good prognostic sign after treatment for differentiated thyroid carcinoma. (2) Thyroglobulin levels may be misleadingly elevated in thyroiditis, which often coexists with carcinoma. (3) Certain thyroglobulin assays falsely report the continued presence of thyroglobulin after total thyroidectomy and tumor resection, causing undue concern about possible metastases. Therefore, unexpected thyroglobulin levels should prompt a repeat assay in another reference laboratory.
Serum calcitonin levels are usually elevated in medullary thyroid carcinoma, making this a marker for metastatic disease. However, serum calcitonin may be elevated in many other conditions, such as thyroiditis; pregnancy; azotemia; hypercalcemia; and other malignancies, including pheochromocytomas, carcinoid tumors, and carcinomas of the lung, pancreas, breast, and colon.
In patients with medullary thyroid carcinoma, serum calcitonin and carcinoembryonic antigen (CEA) determinations should be obtained before surgery, then regularly in postoperative follow-up: every 4 months for 5 years, then every 6 months for life. In patients with extensive metastases, serum calcitonin should be measured in the laboratory with serial dilutions. Calcitonin levels remain elevated in patients with persistent tumor but also in some patients with apparent cure or indolent disease. Therefore, serum calcitonin levels > 250 ng/L (> 73 pmol/L) or rising levels of calcitonin are the best indication for recurrence or metastatic disease. Serum CEA levels are usually elevated with medullary carcinoma, making this a useful second marker; however, it is not specific for this carcinoma.
RAI uptake occurs in many normal tissues and can be mistaken for metastatic differentiated thyroid carcinoma, leading to unnecessary radioiodine therapy. Negative RAI scans are common in early metastatic differentiated thyroid carcinoma. Unfortunately, negative RAI scans also occur frequently with more advanced metastatic thyroid carcinoma, making it more difficult to detect and to distinguish from nonthyroidal neoplasms. An elevated serum thyroglobulin in patients with a clear RAI scan should arouse suspicion for metastases that are not avid for radioiodine.
The complications vary with the type of carcinoma. Differentiated thyroid carcinomas may have local or distant metastases, and hyperthyroidism can develop in patients with a heavy tumor burden. One-third of medullary thyroid carcinomas secrete serotonin and prostaglandins, producing flushing and diarrhea. The management of patients with medullary carcinomas may be complicated by the coexistence of pheochromocytomas or hyperparathyroidism.
Treatment of Differentiated Thyroid Carcinoma
Surgical removal is the treatment of choice for thyroid carcinomas. Neck ultrasound is obtained preoperatively, since suspicious cervical lymphadenoapathy is detected in about 25%. Intraoperative thyroid ultrasound by the surgeon also helps assess the extent of the tumor and lymph node involvement, altering surgical treatment in many cases. For differentiated papillary and follicular carcinoma > 1 cm diameter, total thyroidectomy is performed with limited removal of cervical lymph nodes. For medullary thyroid carcinoma, repeated neck dissections are often required.
Surgery consists of a thyroid lobectomy for an indeterminate “follicular lesion” that is ≤ 4 cm diameter. If malignancy is diagnosed on pathology, a completion thyroidectomy is performed. For indeterminate follicular lesions > 4 cm diameter that are at higher risk for being malignant, a bilateral thyroidectomy is performed as the initial surgery. Higher risk lesions include those with a FNA biopsy that shows marked atypia or that are suspicious for papillary carcinoma and those that occur in patients with a history of radiation exposure or a family history of thyroid carcinoma.
For biopsies that are diagnostic of malignancy, surgery involves lobectomy alone for papillary thyroid carcinomas < 1 cm diameter in patients under age 45 years who have no history of head and neck irradiation and no evidence of lymph node metastasis on ultrasonography. Other patients should have a total or near total thyroidectomy. The advantage of near-total thyroidectomy for differentiated thyroid carcinoma is that multicentric foci of carcinoma are more apt to be resected. Also, there is less normal thyroid tissue to compete with cancer for 131I administered later for scans or treatment. A central neck lymph node dissection is performed at the time of thyroidectomy for patients with nodal metastases that are clinically evident. A lateral neck dissection is performed for patients with biopsy-proven lateral cervical lymphadenopathy. Neck muscle resections are usually avoided for differentiated thyroid carcinoma. However, patients with the Hürthle cell variant of follicular carcinoma may benefit from a modified radical neck dissection. Metastases to the brain are best treated surgically, since treatment with radiation or RAI is ineffective. Levothyroxine is prescribed in doses of 0.05–0.1 mg orally daily immediately postoperatively (see Thyroxine Suppression and Chemotherapy, below). About 2–4 months after surgery, patients require reevaluation and often require therapy with 131I (see below).
Permanent injury to one recurrent laryngeal nerve occurs in between 1–2% and 7% of patients, depending on the experience of the surgeon. Bilateral nerve palsies are rare. Temporary recurrent laryngeal nerve palsies occur in another 5% but often resolve within 6 months. After total thyroidectomy, temporary hypoparathyroidism occurs in 20% and becomes permanent in about 2%. The incidence of hypoparathyroidism may be reduced if accidentally resected parathyroids are immediately autotransplanted into the neck muscles. Thyroidectomy requires at least an overnight hospital admission, since late bleeding, airway problems, and tetany can occur. Ambulatory thyroidectomy is potentially dangerous and should not be done. Following surgery, staging (Table 26–8) should be done to help determine prognosis and to plan therapy and follow-up.
Table 26–8. Pathologic tumor-node-metastasis (pTNM) staging and tumor-related approximate survival rates for adults with appropriately treated differentiated (papillary) thyroid carcinoma based upon patient age, primary tumor size and invasiveness (T), lymph node involvement (N), and distant metastases (M).1
In pregnant women with thyroid cancer, surgery is usually delayed until after delivery, except for fast-growing tumors that may be resected after 24 weeks gestation; there has been no difference in survival or tumor recurrence rates in women who underwent surgery during or after their pregnancy. Differentiated thyroid carcinoma does not behave more aggressively during pregnancy. But there is a higher risk of complications in pregnant women undergoing thyroid surgery, compared to nonpregnant women.
Patients who have had a thyroidectomy for differentiated thyroid cancer must take thyroxine replacement for life. Oral thyroxine should be given in doses that suppress serum TSH without causing clinical thyrotoxicosis. Serum TSH should be suppressed below 0.1 mU/L for patients with stage II disease and below 0.05 mU/L for patients with stage III–IV disease. (See Table 26–8.) Although patients receiving thyroxine suppression therapy (TSH < 0.05 mU/L) are at risk for a lower bone density than age-matched controls, the adverse effect upon bone density and fracture risk is relatively minor for patients who remain clinically euthyroid. Nevertheless, patients receiving thyroxine suppression therapy are advised to have periodic bone densitometry.
Differentiated thyroid cancers variably retain the normal thyroid’s ability to respond to TSH, secrete thyroglobulin, and concentrate iodine. There are two reasons to treat patients with 131I after thyroidectomy: (1) thyroid remnant ablation and (2) treatment of known or suspected thyroid cancer. 131I is usually administered 2–4 months after surgery. Treatment with 131I is repeated 9–12 months later if surveillance RAI scanning shows evidence of metastatic disease. (See Surveillance, below.)
Before starting 131I therapy, patients should follow a low iodine diet for at least 2 weeks. The low iodine diet consists of avoiding the following: iodized table salt, sea salt, fish, shellfish, seaweed, commercial bread, dairy products, processed meats, canned or dried fruit, canned fruit juices, highly salted soups and snack foods, black tea, instant coffee, food coloring with Red Dye #3, egg yolks, multivitamins with iodine, or topical iodine. Patients must not be given amiodarone or intravenous radiologic contrast dyes containing iodine. Radioiodine administration is contraindicated in women who are nursing or pregnant. In all women of reproductive age, pregnancy must be excluded prior to radioiodine scanning or therapy.
Staging with RAI scanning or 18FDG-PET/CT scanning assists with determining the activity of 131I to be administered. Treatment protocols vary among institutions. Generally, patients with higher-risk stage 1 cancer or stage 2 cancer are treated with 131I activities of 50–100 mCi (1.8–3.7 GBq). Patients with stage 3–4 cancers typically receive 131I activities of 100–150 mCi (3.7–5.5 GBq). Repeated treatments may be required for persistent radioiodine-avid metastatic disease. Patients with differentiated thyroid carcinoma who have little or no uptake of RAI into metastases (about 35% of cases) should not be treated with 131I. Patients with asymptomatic, stable, radioiodine-resistant metastases should receive levothyroxine to suppress serum TSH and should be carefully monitored for tumor progression.
Some patients have elevated serum thyroglobulin levels but a negative whole-body radioiodine scan and a negative neck ultrasound. In such patients, an 18F-FDG PET/CT scan is obtained. If all scans are negative, the patient has a good prognosis and empiric therapy with 131I is not useful.
Activities of 131I over 100 mCi (3.7 GBq) can cause gastritis, temporary oligospermia, sialadenitis, and xerostomia. Therapy with 131I can cause neurologic decompensation in patients with brain metastases; such patients are treated with prednisone 30–40 mg orally daily for several days before and after 131I therapy. Cumulative doses of 131I over 500 mCi (18.5 GBq) can cause infertility, pancytopenia (4%), and leukemia (0.3%). Pulmonary fibrosis can occur in patients with diffuse lung metastases after receiving cumulative 131I activities over 600 mCi (22 GBq). The kidneys excrete RAI, so patients receiving dialysis require only 20% of the usual 131I activity.
Thyrogen should not be administered to patients with an intact thyroid gland because it can cause severe thyroid swelling and hyperthyroidism. Hyperthyroidism can also occur in patients with significant metastases or residual normal thyroid. Other side effects include nausea (11%) and headache (7%). Thyrotropin has caused neurologic deterioration in 7% of patients with central nervous system metastases.
Women must not receive RAI therapy if they are pregnant, lactating, or lack childcare. Women are advised to avoid pregnancy for at least 4 months following 131I therapy. Men have been found to have abnormal spermatozoa for up to 6 months following 131I therapy and are advised to use contraceptive methods during that time.
Patients who have osteolytic metastases to bone from differentiated thyroid carcinoma can be treated with zoledronic acid. For patients with asymptomatic osseous metastases, the dose is zoledronic acid 4 mg intravenously every 6 months; for those with symptomatic osseous metastases, the dose is zoledronic acid 4 mg intravenously every 3 months for the first year and then every 6 months.
Patients with aggressive differentiated thyroid carcinoma may have metastases that are not avid for radioiodine or are refractory to 131I therapy. Recurrence in the neck may be treated with surgical debulking and external beam radiation therapy. Such malignancies are usually also resistant to most chemotherapy regimens. However, certain tyrosine kinase inhibitors have achieved objective responses: pazopanib (49%), sunitinib (31%), and axitinib (30%).
Treatment of Other Thyroid Malignancies
Patients with anaplastic thyroid carcinoma are treated with local resection and radiation. Lovastatin has been demonstrated to cause differentiation and apoptosis of anaplastic thyroid carcinoma cells in vitro, but clinical studies have not been performed. Anaplastic thyroid carcinoma does not respond to 131I therapy and is resistant to chemotherapy.
Patients with thyroid MALT lymphomas have a low risk of recurrence after simple thyroidectomy. Patients with other thyroid lymphomas are best treated with external radiation therapy; chemotherapy is added for extensive lymphoma.
Patients with a ret protooncogene mutation should have a prophylactic total thyroidectomy, ideally by age 6 years (MEN 2A) or at age 6 months (MEN 2B). Medullary thyroid carcinoma is best treated with surgery for the primary tumor and metastases. It does not respond to 131I therapy and is generally resistant to chemotherapy. In one study, vandetanib (100 mg orally once daily) produced a partial remission in 16% and stable disease in 53% of patients with locally advanced or metastatic medullary thyroid carcinoma. Vandetanib has reversed Cushing syndrome caused by ectopic ACTH secretion.
External beam radiation therapy may be delivered to bone metastases, especially those that are without radioiodine uptake or are RAI-refractory. Local neck radiation therapy may also be given to patients with anaplastic thyroid carcinoma. Brain metastases can be treated with gamma knife radiosurgery.
Most differentiated thyroid carcinoma recurs within the first 5–10 years after thyroidectomy. While lifetime monitoring is recommended, the follow-up protocol can be tailored to the staging and aggressiveness of the malignancy. All patients require at least a yearly thyroid ultrasound and serum thyroglobulin level (while taking levothyroxine). Patients at higher risk have traditionally required at least two annual consecutively negative stimulated serum thyroglobulin determinations < 1 ng/mL and normal RAI scans (if done) and neck ultrasound before they are considered to be in remission. The first surveillance occurs with stimulated postoperative serum thyroglobulin, 131I therapy, and post-therapy scanning about 2–4 months after surgery. (See Treatment.) At 9–12 months postoperatively, patients may receive another stimulated serum thyroglobulin and radioiodine scan. Patients need not have repeated 131I therapies if persistent RAI uptake is confined to the thyroid bed and if neck ultrasounds appear normal and stimulated serum thyroglobulin levels remain < 2 ng/mL. Patients with differentiated thyroid carcinoma must be monitored long-term for recurrent or metastatic disease. Further radioiodine or other scans may be required for patients with more aggressive differentiated thyroid cancer, prior metastases, rising serum thyroglobulin levels, or other evidence of metastases.
Detectable thyroglobulin levels do not necessarily indicate the presence of residual or metastatic thyroid cancer. Conversely, baseline serum thyroglobulin levels are insensitive markers for disease recurrence. However, baseline or stimulated serum thyroglobulin levels ≥ 2 ng/mL indicate the need for a repeat neck ultrasound and further scanning with RAI or 18FDG-PET. If serum thyroglobulin levels remain ≥ 2 ng/mL in the presence of normal scanning, it is prudent to repeat the serum thyroglobulin in a national reference laboratory. In one series of patients with differentiated thyroid cancer following thyroidectomy, there was a 21% incidence of metastases in patients with serum thyroglobulin < 1 ng/mL (while receiving thyroxine for TSH suppression). Therefore, baseline serum thyroglobulin levels are inadequately sensitive and stimulated serum thyroglobulin measurements should be used and always with neck ultrasound. The usefulness of routinely doing a radioiodine scan (see below) in low-risk patients is controversial but continues to be done in many centers during stimulation following either rhTSH or thyroid hormone withdrawal, according to described protocols.
The 131I radioisotope may be used in scanning activities provided it is given < 2 weeks before scheduled 131I treatment to avoid “stunning” metastases such that they take up less of the RAI therapy activity. Alternatively, the 123I radioisotope may also be used and does not stun tumors; it allows single-photon emission computed tomography (SPECT) to better localize metastases. Initial RAI scanning is typically performed about 2–4 months following surgery for differentiated thyroid carcinoma. Whole-body scanning should be performed for at least 30 minutes for at least 140,000 counts and spot views of the neck should be obtained for at least 35,000 counts.
About 65% of metastases are detectable by RAI scanning, but only after optimal preparation: Patients should ideally have a total or near-total thyroidectomy, since any residual normal thyroid competes for RAI with metastases, which are less avid for iodine. It is reasonable to perform a rhTSH-stimulated scan and thyroglobulin level 2–3 months after the initial neck surgery; if the scan is negative and the serum thyroglobulin is < 2 ng/mL, low-risk patients may not require further scanning but should continue to be monitored with neck ultrasound and serum thyroglobulin levels every 6–12 months. For higher-risk patients, the rhTSH-stimulated thyroglobulin and RAI scan may be repeated about 1 year after surgery and then again if warranted. Serum thyroglobulin and radioiodine scanning are stimulated by either rhTSH or thyroid hormone withdrawal according to the protocols described above for 131I treatment.
The combination of rhTSH-stimulated scanning and thyroglobulin levels detects a thyroid remnant or cancer with a sensitivity of 84%. However, the presence of antithyroglobulin antibodies renders the serum thyroglobulin determination uninterpretable. In about 21% of low-risk patients, rhTSH stimulates serum thyroglobulin to above 2 ng/mL; such patients have a 23% risk of local neck metastases and a 13% risk of distant metastases. The rhTSH-stimulated radioiodine neck and whole-body scan detects only about half of these metastases because they are small or not avid for iodine. Some patients have persistent radioiodine uptake in the neck on diagnostic scanning but have no visible tumor on neck ultrasound; such patients do not require additional radioiodine therapy, especially if the serum thyroglobulin level is very low.
18FDG-PET scanning predicts survival better than standard staging; the number, location, and SUVmax of metastases are all significant prognostic factors. (See Prognosis.) 18FDG-PET scanning is particularly sensitive for detecting medullary thyroid carcinoma metastases, and prescan thyrotropin does not improve the PET scan sensitivity for medullary thyroid carcinoma.
Papillary thyroid cancer staging and survival data are shown in Table 26–8. 18FDG-PET scanning independently predicts survival, with patients having few PET-avid metastases and low SUVmax (highest image-pixel standardized uptake value) having a better prognosis. There is generally a good prognosis, particularly for adults under age 45 years, despite the fact that up to 40% of these patients are found to harbor lymph node metastases when extensive lymph node dissections are performed. The following characteristics imply a worse prognosis: age over 45 years, male sex, bone or brain metastases, macronodular (> 1 cm) pulmonary metastases, and lack of 131I uptake into metastases. Younger patients with pulmonary metastases tend to respond better to 131I therapy than do older adults. Certain papillary histologic types are associated with a higher risk of recurrence and reduced survival: tall cell, columnar cell, and diffuse sclerosing types. Brain metastases are detected in 1%; they reduce median survival to 12 months, but the patient’s prognosis is improved by surgical resection. Patients with a follicular variant of papillary carcinoma have a prognosis somewhere between that of papillary and follicular thyroid carcinoma.
Patients with follicular carcinoma have a cancer mortality rate that is 3.4 times higher than patients with papillary carcinoma. The Hürthle cell variant of follicular carcinoma is even more aggressive. Both follicular carcinoma and its Hürthle cell variant tend to present at a more advanced stage than papillary carcinoma. However, at a given stage, the different types of differentiated thyroid carcinoma have a similar prognosis. Patients with primary tumors > 1 cm in diameter who undergo limited thyroid surgery (subtotal thyroidectomy or lobectomy) have a 2.2-fold increased mortality over those having total or near-total thyroidectomies. Patients who have not received 131I ablation have mortality rates that are increased twofold by 10 years and threefold by 25 years (over those who have received ablation). The risk of cancer recurrence is twofold higher in men than in women and 1.7-fold higher in multifocal than in unifocal tumors.
Patients with a normal 18FDG-PET scan have a 98% 5-year survival, while those having > 10 metastases have a 20% 5-year survival. Those with a SUVmax of 0.1-4.6 have a 5-year survival of 85%, while those with a SUVmax > 13.3 have a 5-year survival of 20%. Patients with only local metastases have a 5-year survival of 95%, while those with regional (supraclavicular, mediastinal) metastases have a 5-year survival of 70%, and those with distant metastases have a 5-year survival of 35%.
Medullary thyroid carcinoma is more aggressive than differentiated thyroid cancer but is typically fairly indolent. The overall 10-year survival rate is 90% when the tumor is confined to the thyroid, 70% for those with metastases to cervical lymph nodes, and 20% for those with distant metastases. Patients with sporadic disease usually have lymph node involvement noted at the time of diagnosis, whereas distal metastases may not be noted for years. For patients with medullary thyroid carcinoma who have metastases to lymph nodes, modified radical neck dissection is recommended. Familial cases or those associated with MEN 2A tend to be less aggressive; the 10-year survival rate is higher, in part due to earlier detection.
Medullary thyroid carcinoma that is seen in MEN 2B is more aggressive, arises earlier in life, and carries a worse overall prognosis, especially when associated with a germline M918T mutation. The elderly tend to have more aggressive medullary thyroid carcinomas. Women with medullary thyroid carcinoma who are under age 40 years have a better prognosis. A better prognosis is also obtained in patients undergoing total thyroidectomy and neck dissection; radiation therapy reduces recurrence in patients with metastases to neck nodes. The mortality rate is increased 4.5-fold when primary or metastatic tumor tissue stains heavily for myelomonocytic antigen M-1. Conversely, tumors with heavy immunoperoxidase staining for calcitonin are associated with prolonged survival even in the presence of significant metastases.
Anaplastic thyroid carcinoma carries a 1-year survival rate of about 10% and a 5-year survival rate of about 5%. Patients with fully localized tumors on MRI have a better prognosis.
Localized lymphoma carries a 5-year survival of nearly 100%. Those with disease outside the thyroid have a 63% 5-year survival. However, the prognosis is better for those with MALT lymphomas. Patients presenting with stridor, pain, laryngeal nerve palsy, or mediastinal extension tend to fare worse.
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IODINE DEFICIENCY DISORDER & ENDEMIC GOITER
ESSENTIALS OF DIAGNOSIS
Common in regions with low-iodine diets.
High rate of congenital hypothyroidism and cretinism.
Goiters may become multinodular and enlarge.
Most adults with endemic goiter are found to be euthyroid; however, some are hypothyroid or hyperthyroid.
About 1 billion people are iodine deficient, having no access to iodized salt and living in areas with iodine-depleted soil. Severe iodine deficiency increases the risk of miscarriage and stillbirth. Cretinism occurs in about 0.5% of live births in iodine-deficient areas. Moderate iodine deficiency during gestation and infancy causes other manifestations of congenital hypothyroidism, such as deafness and short stature and permanently lowers a child’s IQ by 10–15 points.
Although iodine deficiency is the most common cause of endemic goiter, there are other natural goitrogens, including certain foods (eg, sorghum, millet, maize, cassava), mineral deficiencies (selenium, iron, zinc), and water pollutants, which can themselves cause goiter or aggravate a goiter proclivity caused by iodine deficiency. In iodine-deficient patients, smoking can induce goiter growth. Pregnancy aggravates iodine deficiency and is associated with an increase in size of thyroid nodules and the emergence of new nodules. Some individuals are particularly susceptible to goiter owing to congenital partial defects in thyroid enzyme activity.
Endemic goiters may become multinodular and very large. Growth often occurs during pregnancy and may cause compressive symptoms.
Substernal goiters are usually asymptomatic but can cause tracheal compression, respiratory distress and failure, dysphagia, superior vena cava syndrome, gastrointestinal bleeding from esophageal varices, palsies of the phrenic or recurrent laryngeal nerves, or Horner syndrome. Cerebral ischemia and stroke can result from arterial compression or thyrocervical steal syndrome. Substernal goiters can rarely cause pleural or pericardial effusions. The incidence of significant malignancy is < 1%.
Some patients with endemic goiter may become hypothyroid. Others may become thyrotoxic as the goiter grows and becomes more autonomous, especially if iodine is added to the diet.
The serum T4 and TSH are generally normal. TSH falls in the presence of hyperthyroidism if a multinodular goiter has become autonomous in the presence of sufficient amounts of iodine for thyroid hormone synthesis. TSH rises with hypothyroidism. Thyroid RAI uptake is usually elevated, but it may be normal if iodine intake has improved. Serum levels of antithyroid antibodies are usually either undetectable or in low titers. Serum thyroglobulin is often elevated.
Endemic goiter must be distinguished from all other forms of nodular goiter that may coexist in an endemic region.
Adding iodine to commercial salt prevents iodine deficiency. In the United States, potassium iodide is used. Some tropical countries use potassium iodate, since it is more stable than potassium iodide in hot and humid climates. Iodized salt contains iodine at about 20 mg per kg salt. The minimum dietary requirement for iodine is about 50 mcg daily, with optimal iodine intake being 150–300 mcg daily. Iodine sufficiency is assessed by measurement of urinary iodide excretion, the target being more than 10 mcg/dL. Initiating iodine supplementation in an iodine-deficient area greatly reduces the emergence of new goiters but causes an increased frequency of hyperthyroidism during the first year.
The addition of potassium iodide to table salt greatly reduces the prevalence of endemic goiter and cretinism but is less effective in shrinking established goiter. One iodine-depleted area was Pescopagano, Italy, where 46% of adults had goiters. Hyperthyroidism (present or past) occurred in 2.9%, twice the rate seen in iodine-sufficient areas, mostly due to toxic nodular goiter. Hypothyroidism was overt in 0.2% and subclinical in 3.8%. Salt was iodized (30 mg of potassium iodate per kg salt) and made available in 1985. After 15 years, the incidence of goiter declined to 23%. However, the prevalence of Hashimoto thyroiditis rose from 3.5% to 14.5% after 15 years of iodine supplementation.
Iodine supplementation has not proven effective for treating adults with large multinodular goiter and actually increases their risk of developing thyrotoxicosis. Thyroidectomy may be required for cosmesis, compressive symptoms, or thyrotoxicosis. There is a high goiter recurrence rate in iodine-deficient geographic areas, so near-total thyroidectomy is preferred when surgery is indicated. Certain patients may be treated with 131I for large compressive goiters.
Dietary iodine supplementation increases the risk of autoimmune thyroid dysfunction, which may cause hypothyroidism or hyperthyroidism. Excessive iodine supplementation increases the risk of goiter. Suppression of TSH by administering thyroxine carries the risk of inducing hyperthyroidism, particularly in patients with autonomous multinodular goiters; therefore, thyroxine suppression should not be started in patients with a low TSH level. Treating patients with 131I for large multinodular goiter may shrink the gland; however, Graves disease develops in some patients 3–10 months following therapy.
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DISEASES OF THE PARATHYROIDS
Parathyroid hormone (PTH) increases osteoclastic activity in bone, increases the renal tubular reabsorption of calcium, and stimulates the synthesis of 1,25-dihydroxycholecalciferol by the kidney. Meanwhile, PTH inhibits the absorption of phosphate and bicarbonate by the renal tubule. All of these actions cause a net increase in serum calcium).
HYPOPARATHYROIDISM & PSEUDOHYPOPARATHYROIDISM
ESSENTIALS OF DIAGNOSIS
Tetany, carpopedal spasms, tingling of lips and hands, muscle and abdominal cramps, psychological changes.
Positive Chvostek sign and Trousseau phenomenon.
Serum calcium low; serum phosphate high; alkaline phosphatase normal; urine calcium excretion reduced.
Low or low-normal serum PTH in presence of hypocalcemia.
Serum magnesium may be low.
Acquired hypoparathyroidism occurs in 10% of patients after thyroidectomy, but it is usually transient, with permanent hypoparathyroidism developing in less than half of such patients. It may also occur after multiple parathyroidectomies. Hypoparathyroidism may occur after surgical removal of a parathyroid adenoma for primary hyperparathyroidism due to suppression of the remaining normal parathyroids and accelerated remineralization of the skeleton. This is known as “hungry bone syndrome.” In such cases, hypocalcemia can be quite severe, particularly in patients with preoperative hyperparathyroid bone disease and vitamin D or magnesium deficiency. Neck irradiation may rarely cause hypoparathyroidism.
Autoimmune hypoparathyroidism may be isolated or combined with other endocrine deficiencies in polyglandular autoimmunity (PGA), which is also known asautoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). PGA type 1 presents in childhood with at least two of the following manifestations: candidiasis, hypoparathyroidism, or Addison disease. Cataracts, uveitis, alopecia, vitiligo, or autoimmune thyroid disease may also develop. Fat malabsorption occurs in 20% of patients with PGA-1 and may present as weight loss; diarrhea; or malabsorption of vitamin D, a fat-soluble vitamin used to treat the hypoparathyroidism. Hypoparathyroidism can also occur in systemic lupus erythematosus, caused by antiparathyroid antibodies.
Parathyroid deficiency may also be the result of damage from heavy metals such as copper (Wilson disease) or iron (hemochromatosis, transfusion hemosiderosis), granulomas, Riedel thyroiditis, tumors, or infection.
Functional hypoparathyroidism may also occur as a result of magnesium deficiency (malabsorption, chronic alcoholism), which prevents the secretion of PTH. Correction of hypomagnesemia results in rapid disappearance of the condition. Hypermagnesemia can also suppress PTH secretion; it may occur in patients with kidney disease who take magnesium supplements, laxatives, or antacids.
Congenital hypoparathyroidism causes hypocalcemia beginning in infancy. However, it may not be diagnosed for many years. Hypoparathyroidism may also be seen in DiGeorge syndrome, along with congenital cardiac and facial anomalies; hypocalcemia usually presents with tetany in infancy, but some cases are not detected until adulthood.
Acute hypoparathyroidism and hypocalcemia can occur spontaneously or may be precipitated when a patient with untreated hypoparathyroidism receives a proton pump inhibitor. Manifestations of hypocalcemia include tetany, muscle cramps, carpopedal spasm, irritability, altered mental status, convulsions, and stridor; tingling of the circumoral area, hands, and feet is almost always present. Symptoms of the chronic disease are lethargy, personality changes, anxiety state, blurring of vision due to premature cataracts, Parkinsonism, and mental retardation. Some patients with chronic hypocalcemia are asymptomatic, even with very low levels of serum calcium.
Chvostek sign (facial muscle contraction on tapping the facial nerve in front of the ear) is positive, and Trousseau phenomenon (carpal spasm after application of a sphygmomanometer cuff) is present. Cataracts may occur; the nails may be thin and brittle; the skin is dry and scaly, at times with fungus infection (candidiasis), and there may be loss of eyebrows; and deep tendon reflexes may be hyperactive. Papilledema and elevated CSF pressure are occasionally seen. Teeth may be defective if the onset of the disease occurs in childhood.
Serum calcium is low, serum phosphate high, urinary calcium low, and alkaline phosphatase normal. Serum calcium is largely bound to albumin. In patients with hypoalbuminemia, the serum ionized calcium may be determined, but it has had surprisingly poor clinical utility. Alternatively, the serum calcium level can be corrected for serum albumin level as follows:
Radiographs or CT scans of the skull may show basal ganglia calcifications; the bones may be denser than normal. Cutaneous calcification may occur.
Slit-lamp examination may show early posterior lenticular cataract formation. The electrocardiogram (ECG) shows prolonged QT intervals and T wave abnormalities. Patients with chronic hypoparathyroidism tend to have increased bone mineral density, particularly in the lumbar spine.
Acute tetany with stridor, especially if associated with vocal cord palsy, may lead to respiratory obstruction requiring tracheostomy. Pseudotumor cerebri has been reported. Heart failure may rarely occur. The complications of chronic hypoparathyroidism largely depend on the duration of the disease. There may be associated autoimmunity causing celiac disease, pernicious anemia, or Addison disease. In long-standing cases, cataract formation and calcification of the basal ganglia are seen. Occasionally, parkinsonian symptoms or choreoathetosis develop. Ossification of the paravertebral ligaments may occur with nerve root compression; surgical decompression may be required. Seizures are common in untreated patients. Overtreatment with vitamin D and calcium may produce nephrocalcinosis and impairment of kidney function. Chronic hypocalcemia can cause heart failure.
Paresthesias, muscle cramps, or tetany due to respiratory alkalosis, in which the serum calcium is normal, can be confused with hypocalcemia. In fact, hyperventilation tends to accentuate hypocalcemic symptoms.
At times hypoparathyroidism is misdiagnosed as idiopathic epilepsy, choreoathetosis, or brain tumor (on the basis of brain calcifications, convulsions, choked disks) or, more rarely, as “asthma” (on the basis of stridor and dyspnea). In patients with hypoalbuminemia, serum levels of ionized calcium are normal.
Hypocalcemia may also be due to malabsorption of calcium, magnesium, or vitamin D; patients do not always have diarrhea. Hypocalcemia may also be caused by certain drugs: loop diuretics, plicamycin, phenytoin, alendronate, and foscarnet. In addition, hypocalcemia may be seen in cases of rapid intravascular volume expansion or due to chelation from transfusions of large volumes of citrated blood. It is also observed in patients with acute pancreatitis. Hypocalcemia may develop in some patients with certain osteoblastic metastatic carcinomas (especially breast, prostate) instead of the expected hypercalcemia. Hypocalcemia with hyperphosphatemia (simulating hypoparathyroidism) is seen in azotemia but may also be caused by large doses of intravenous, oral, or rectal phosphate preparations and by chemotherapy of responsive lymphomas or leukemias.
Hypocalcemia with hypercalciuria may be due to a familial syndrome involving a mutation in the calcium-sensing receptor; such patients have levels of serum PTH that are in the normal range, distinguishing it from hypoparathyroidism. It is transmitted as an autosomal dominant disorder. Such patients are hypercalciuric; treatment with calcium and vitamin D may cause nephrocalcinosis.
Congenital pseudohypoparathyroidism is a group of disorders characterized by resistance to PTH. There are several subtypes caused by different mutations involving the PTH receptor or its G protein or adenylyl cyclase. Renal tubular resistance to PTH causes hypercalciuria with resultant hypocalcemia. PTH levels are high and the PTH receptors in bone are typically not involved, such that bony changes of hyperparathyroidism may be evident. In pseudohypoparathyroidism type 1a, patients have hypocalcemia and hyperphosphatemia with additional features known as Albright hereditary osteodystrophy: mental retardation, short stature, obesity, round face, short fourth metacarpals, ectopic bone formation, hypothyroidism, and hypogonadism. Patients without hypocalcemia but sharing the phenotypic abnormalities are said to have “pseudopseudohypoparathyroidism.”
This usually occurs after surgery and requires immediate treatment.
Table 26–9. Vitamin D preparations used in the treatment of hypoparathyroidism.
The goal should be to maintain the serum calcium in a slightly low but asymptomatic range of 8–8.6 mg/dL (2–2.15 mmol/L). This will minimize the hypercalciuria that would otherwise occur and provides a margin of safety against overdosage and hypercalcemia, which may produce permanent damage to kidney function. Patients with mild, asymptomatic hypocalcemia require no therapy. For others, calcium supplementation (1 g/d) is given, along with a vitamin D preparation.
Patients with chronic hypoparathyroidism must usually be treated with some type of vitamin D (Table 26–9). Monitoring of serum calcium at regular intervals (at least every 3 months) is mandatory.Calcitriol, a short-acting preparation, is given in doses that range from 0.25 mcg/d to 2.0 mcg orally daily. Ergocalciferol (vitamin D2) is derived from plants and is commercially available. The usual dose ranges from 25,000 to 150,000 units/d. It is a slow-acting preparation that is stored in fat, giving it a long duration of action. If toxicity develops, hypercalcemia—treatable with hydration and prednisone—may persist for weeks after it is discontinued. Despite this risk, ergocalciferol usually produces a more stable serum calcium level than do the shorter-acting preparations.
Teriparatide (Forteo) is a recombinant preparation of human PTH 1-34. Teriparatide is effective in treating patients with hypoparathyroidism when given by subcutaneous injection at an initial dose of 0.4 mcg/kg twice daily. The dose is adjusted to produce normal serum calcium levels. The disadvantages of teriparatide therapy include its extremely high cost and the necessity for injections. The US Food and Drug Administration (FDA) has not approved teriparatide for this indication, since prolonged high-dose exposure has caused osteosarcoma in rats. Therefore, teriparatide therapy is reserved for patients with severe hypoparathyroidism that fails to respond to vitamin D.
Target serum calcium levels (albumin-corrected) should be 8.0–8.5 mg/dL (2–2.13 mmol/L); these levels are mildly low to avoid hypercalciuria. It is prudent to monitor urine calcium with “spot” urine determinations and keep the level below 30 mg/dL (7.5 mmol/L), if possible. Hypercalciuria may respond to oral hydrochlorothiazide, usually given with a potassium supplement.
Caution: Phenothiazine drugs should be administered with caution, since they may precipitate extrapyramidal symptoms in hypocalcemic patients. Furosemide should be avoided, since it may worsen hypocalcemia.
The outlook is good if the diagnosis is made promptly and treatment instituted. Any dental changes, cataracts, and brain calcifications are permanent. Periodic blood chemical evaluation is required, since changes in calcium levels may call for modification of the treatment schedule. Hypercalcemia that develops in patients with seemingly stable, treated hypoparathyroidism may be a presenting sign of Addison disease.
Despite optimal therapy, patients with hypoparathyroidism have been reported to have an overall reduced quality of life. Affected patients have a high risk of having mood and psychiatric disorders along with a reduced overall sense of well being.
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ESSENTIALS OF DIAGNOSIS
Frequently detected incidentally by routine blood testing.
Renal calculi, polyuria, hypertension, constipation, fatigue, mental changes.
Bone pain; rarely, cystic lesions and pathologic fractures.
Serum and urine calcium elevated; urine phosphate high with low to normal serum phosphate; alkaline phosphatase normal to elevated.
Primary hyperparathyroidism is the most common cause of hypercalcemia, with a prevalence of 1–4 cases per 1000 persons. It occurs at all ages but most commonly in the seventh decade and in women (74%). Before age 45, the prevalence is similar in men and women.
Parathyroid glands vary in number and location and ectopic parathyroid glands have been found within the thyroid gland, high in the neck or carotid sheath, in the retroesophageal space, and within the thymus or mediastinum. Hyperparathyroidism is caused by hypersecretion of PTH, usually by a single parathyroid adenoma (80%), and less commonly by hyperplasia by two or more parathyroid glands (20%), or carcinoma (≤ 1%). However, when hyperparathyroidism presents before age 30 years, there is a higher incidence of multiglandular disease (36%) and parathyroid carcinoma (5%). The size of the parathyroid adenoma correlates with the serum PTH level.
Hyperparathyroidism is familial in about 10% of cases. Parathyroid hyperplasia may arise in MEN types 1, 2A, and 2B. In MEN 1, multiglandular hyperparathyroidism is usually the initial manifestation and ultimately occurs in 90% of affected individuals. Hyperparathyroidism in MEN 2A is less frequent that in MEN 1 and is usually milder. Familial hyperparathyroidism can also occur in the hyperparathyroidism-jaw tumor syndrome, a rare autosomal dominant familial condition in which parathyroid cystic adenomas or carcinomas are associated with ossifying fibromas of the mandible and maxilla as well as renal lesions (cysts, hamartomas, Wilms tumors). Affected individuals usually present with severe hypercalcemia as teenagers or young adults; the pathology is usually a single parathyroid adenoma. (See Table 26–17.)
Hyperparathyroidism results in the excessive excretion of calcium and phosphate by the kidneys. PTH stimulates renal tubular reabsorption of calcium; however, hyperparathyroidism causes hypercalcemia and an increase in calcium in the glomerular filtrate that overwhelms tubular reabsorption capacity, resulting in hypercalciuria. At least 5% of renal calculi are associated with this disease. Diffuse parenchymal calcification (nephrocalcinosis) is seen less commonly. Excessive PTH can cause cortical demineralization that is particularly evident at the wrist and hip; trabecular bone is usually spared as evidenced by relatively higher spinal bone density compared to the wrist. Severe, chronic hyperparathyroidism can cause diffuse demineralization, pathologic fractures, and cystic bone lesions throughout the skeleton, a condition known as osteitis fibrosa cystica.
Parathyroid carcinoma is a rare cause of hyperparathyroidism but is more common in patients with serum calcium levels ≥ 14.0 mcg/dL (≥ 3.5 mmol/L). About 50% of parathyroid carcinomas are palpable.
Secondary and tertiary hyperparathyroidism usually occurs in patients with chronic kidney disease, in which hyperphosphatemia and decreased renal production of 1,25-dihydroxycholecalciferol (1,25[OH]2D3) initially produce a decrease in ionized calcium. The parathyroid glands are stimulated (secondary hyperparathyroidism) and may enlarge, becoming autonomous (tertiary hyperparathyroidism). The bone disease seen in this setting is known as renal osteodystrophy. Parathyroid hyperplasia in uremia can result in extremely high serum PTH levels that are associated with uremic vascular calcification. Hypercalcemia often occurs after kidney transplant. Secondary hyperparathyroidism predictably develops in patients with a deficiency in vitamin D. Serum calcium levels are typically in the normal range, but may rise to become borderline elevated with time, with tertiary hyperparathyroidism due to parathyroid glandular hyperplasia. (See Osteomalacia.)
In the developed world, hypercalcemia is typically discovered incidentally by routine chemistry panels. Many patients are asymptomatic or have mild symptoms that may be elicited only upon questioning. Parathyroid adenomas are usually so small and deeply located in the neck that they are almost never palpable; when a mass is palpated, it usually turns out to be an incidental thyroid nodule.
Symptomatic patients are said to have problems with “bones, stones, abdominal groans, psychic moans, with fatigue overtones.” The manifestations are categorized as skeletal and those associated with hypercalcemia.
The hallmark of primary hyperparathyroidism is hypercalcemia, with the serum adjusted total calcium > 10.5 mg/dL (> 10.6 mmol/L) (Figure 26–1). The adjusted total calcium = measured serum calcium in mg/dL + [0.8 × (4.0 – patient’s serum albumin in g/dL)]. Serum ionized calcium determinations have not proven very helpful clinically, except in hyperproteinemic states (such as hyperalbuminemia,Waldenström macroglobulinemia, myeloma, or thrombocytosis); in such patients with hyperparathyroidism, the serum ionized calcium is usually > 5.4 mg/dL (1.4 mmol/L).
Figure 26–1. Parathyroid hormone and calcium nomogram. Relationship between serum intact parathyroid hormone (PTH) and serum calcium levels in patients with hypoparathyroidism, pseudohypoparathyroidism, nonparathyroid hypercalcemia, primary hyperparathyroidism (HPT), and secondary hyperparathyroidism. (Used with permission from GJ Strewler, MD.)
Note: A multivariate model that adds clinical and demographic information may perform better than the nomogram alone. (See O’Neill SS et al. Multivariate analysis of clinical, demographic, and laboratory data for classification of disorders of calcium homeostasis. Am J Clin Pathol. 2011 Jan;135(1):100–7. [PMID: 21173131])
The urine calcium excretion may be high or normal (averaging 250 mg/g creatinine) but it is usually low for the degree of hypercalcemia. The serum phosphate is often < 2.5 mg/dL (< 0.8 mmol/L). There is an excessive loss of phosphate in the urine in the presence of hypophosphatemia (25% of cases), whereas in secondary hyperparathyroidism due to kidney disease, the serum phosphate may be high. The alkaline phosphatase is elevated only if bone disease is present. The plasma chloride and uric acid levels may be elevated. Vitamin D deficiency is common in patients with hyperparathyroidism, and it is prudent to screen for vitamin D deficiency with a serum 25-OH vitamin D determination. Serum 25-OH vitamin D levels < 20 mcg/L (< 50 nmol/L) can aggravate hyperparathyroidism and its bone manifestations; vitamin D replacement may be helpful in treating such patients with hyperparathyroidism.
Elevated serum levels of intact PTH (immunoradiometric assay) confirm the diagnosis of hyperparathyroidism. Patients with apparent hyperparathyroidism should be screened for familial benign hypocalciuric hypercalcemia with a 24-hour urine for calcium and creatinine. Patients should discontinue thiazide diuretics prior to this test. Calcium excretion of < 50 mg/24 hours (< 12.5 mmol/24 hours) or < 5 mg/dL (< 1.25 mmol/L) on a random urine is not typical for primary hyperparathyroidism and indicates possible familial benign hypocalciuric hypercalcemia.
Patients with low bone density who have an elevated serum PTH but a normal serum calcium must be evaluated for causes of secondary hyperparathyroidism (eg, vitamin D or calcium deficiency, hyperphosphatemia, renal failure). In the absence of secondary hyperparathyroidism, patients with an elevated serum PTH but normal serum calcium are determined to have normocalcemic hyperparathyroidism. Such individuals require monitoring, since hypercalcemia develops in about 19% of patients over 3 years of follow-up.
Preoperative parathyroid imaging is performed for most patients prior to parathyroid surgery and is particularly important for patients who have had prior neck surgery. Imaging is not necessary for the diagnosis of hyperparathyroidism, which depends on serum parathyroid and calcium levels. But there is occasional diagnostic difficulty and the visualization of an apparent parathyroid adenoma helps secure the diagnosis and often allows for minimally invasive surgery.
Ultrasound of the neck should be performed with a high-resolution transducer (5–15 MHz) and should scan the neck from the mandible to the superior mediastinum in an effort to locate ectopic parathyroid adenomas. Ultrasound has a sensitivity of 79% for single adenomas but only 35% for multiglandular disease. Enlarged parathyroids appear as ovoid, homogeneous, hypoechoic structures that are 0.8–1.5 cm in length and less compressible than surrounding tissue. Doppler imaging assists in distinguishing parathyroid adenomas from other structures.
Sestamibi scintigraphy with (99mTc)-sestamibi can be useful for localizing parathyroid adenomas. However, false-positive scans are common, caused by thyroid nodules, thyroiditis, or cervical lymphadenopathy. Therefore, three-dimensional single-photon emission computed tomography (SPECT) is most useful. Sestamibi-SPECT imaging improves sensitivity to 98% for single parathyroid adenomas. Dual-phase imaging at 10–15 minutes, in addition to the usual imaging at 90–180 minutes, can identify the occasional parathyroid adenoma with rapid sestamibi washout that is not visible with later imaging.
Preoperative sestamibi-iodine subtraction scanning and neck ultrasonography can locate parathyroid adenomas preoperatively in an effort to improve the outcome and limit the invasiveness of neck surgery. Therefore, preoperative imaging has been used mainly to improve the outcome for limited neck exploration, with only modest success. (See Surgery.) Small benign thyroid nodules are discovered incidentally in nearly 50% of patients with hyperparathyroidism who have imaging with ultrasound or MRI.
Axial imaging is not usually required prior to a first neck surgery for hyperparathyroidism. Conventional CT and MRI are generally inferior to ultrasound and sestamibi imaging. However, a CT imaging technique has been developed, known as four-dimensional CT (4D-CT), with the fourth dimension referring to time. It captures the rapid uptake and washout of contrast from parathyroid adenomas and is particularly useful for preoperative imaging for patients who have had prior neck surgery and for those with ectopic glands. In such patients, 4D-CT has a sensitivity of 88%, versus 54% for sestamibi SPECT and 21% for ultrasound. However, 4D-CT delivers more radiation to the thyroid and is used mostly for older patients. MRI may also be useful for repeat neck operations and when ectopic parathyroid glands are suspected. MRI has the advantages of delivering no radiation and showing better soft tissue contrast than CT.
Patients with hyperparathyroidism have a high risk of calcium nephrolithiasis. Therefore, it has been suggested that all patients with hyperparathyroidism have noncontrast-enhanced CT scanning of the kidneys to determine whether calcium-containing stones are present. For patients with apparently asymptomatic hyperparathyroidism, the presence or absence of calcium nephrolithiasis can be a deciding factor about whether to have parathyroidectomy surgery.
Bone density measurements by dual energy x-ray absorptiometry (DXA) are helpful in determining the amount of bone loss in patients with hyperparathyroidism. Bone loss occurs mostly in long bones, and DXA should ideally include three areas: lumbar spine, hip, and distal radius.
Bone radiographs are usually normal and are not required to make the diagnosis of hyperparathyroidism. There may be demineralization, subperiosteal resorption of bone (especially in the radial aspects of the fingers), or loss of the lamina dura of the teeth. There may be cysts throughout the skeleton, mottling of the skull (“salt-and-pepper appearance”), or pathologic fractures. Articular cartilage calcification (chondrocalcinosis) is sometimes found.
Patients with renal osteodystrophy may have ectopic calcifications around joints or in soft tissue. Such patients may exhibit radiographic changes of osteopenia, osteitis fibrositis cystica, or osteosclerosis, alone or in combination. Osteosclerosis of the vertebral bodies is known as “rugger jersey spine.”
Pathologic long bone fractures are more common in patients with hyperparathyroidism than in the general population. Urinary tract infection due to stone and obstruction may lead to kidney disease and uremia. If the serum calcium level rises rapidly, clouding of sensorium, kidney disease, and rapid precipitation of calcium throughout the soft tissues may occur. Peptic ulcer and pancreatitis may be intractable before surgery. Insulinomas or gastrinomas may be associated, as well as pituitary tumors (MEN type 1). Pseudogout may complicate hyperparathyroidism both before and after surgical removal of tumors. Hypercalcemia during gestation produces neonatal hypocalcemia.
In tertiary hyperparathyroidism due to chronic kidney disease, high serum calcium and phosphate levels may cause disseminated calcification in the skin, soft tissues, and arteries (calciphylaxis); this can result in painful ischemic necrosis of skin and gangrene, cardiac arrhythmias, and respiratory failure. The actual serum levels of calcium and phosphate have not correlated well with calciphylaxis, but a calcium (mg/dL) × phosphate (mg/dL) product over 70 is usually present.
A report of hypercalcemia may be due to laboratory error or excess tourniquet time and should always be repeated. Hypercalcemia may be due to high serum protein concentrations; in the presence of very high or low serum albumin concentrations, an adjusted serum calcium or a serum ionized calcium is more dependable than the total serum calcium concentration. Hypercalcemia may also be seen with dehydration; spurious elevations in serum calcium have been reported with severe hypertriglyceridemia, when the calcium assay uses spectrophotometry.
Many malignant tumors (breast, lung, pancreas, uterus, renal cell carcinoma, paraganglioma, etc) can produce hypercalcemia. In some cases (breast carcinoma especially), bony metastases are present. In others, no metastases to bone can be demonstrated. Most of these tumors secrete PTH-related protein (PTHrP), which has tertiary structural homologies to PTH and causes bone resorption and hypercalcemia similar to those of PTH. Serum phosphate is often low. Other tumors can secrete excessive 1,25 (OH)2 vitamin D3, particularly lymphoproliferative and ovarian malignancies. The clinical features of the hypercalcemia of cancer can closely simulate hyperparathyroidism. However, serum PTH levels are usually low. Serum PTHrP or 1,25 (OH)2 vitamin D3 may be elevated.
Multiple myeloma is a common cause of hypercalcemia in the older population. Many other hematologic cancers, such as monocytic leukemia, T cell leukemia and lymphoma, and Burkitt lymphoma, have also been associated with hypercalcemia.
Macrophages and perhaps other cells present in granulomatous tissue have the ability to synthesize 1,25(OH)2D3. Hypercalcemia has been reported in patients with sarcoidosis, tuberculosis, berylliosis, histoplasmosis, coccidioidomycosis, leprosy, and even foreign-body granuloma. Increased intestinal calcium absorption and hypercalciuria are more common than hypercalcemia. Serum levels of 1,25(OH)2D3 are elevated. Sarcoid granulomas can also secrete PTHrP.
Ingestion of large amounts of calcium or vitamin D can cause hypercalcemia, especially in patients who concurrently take thiazide diuretics, which reduce urinary calcium loss. Hypercalcemia is reversible following withdrawal of calcium and vitamin D supplements. If hypercalcemia persists, the possibility of associated hyperparathyroidism should be strongly considered.
In vitamin D intoxication, patients may be taking large amounts of vitamin D for unclear reasons, so a thorough review of all medications is important. Hypercalcemia may persist for several weeks. Serum levels of 25-hydroxycholecalciferol (25[OH]D3) are helpful to confirm the diagnosis. A brief course of corticosteroid therapy may be necessary if hypercalcemia is severe.
Familial benign hypocalciuric hypercalcemia can be easily mistaken for mild hyperparathyroidism. It is a common autosomal dominant inherited disorder (prevalence: 1 in 16,000) caused by a loss-of-function mutation in the gene encoding the calcium sensing receptor (CaSR). CaSRs are found on the surface of the parathyroid glands and allow the parathyroid glands to vary PTH secretion according to serum calcium levels. Reduced function of the CaSR causes the parathyroid glands to falsely “sense” hypocalcemia and inappropriately release slightly excessive amounts of PTH. The renal tubule CaSRs are also affected, causing hypocalciuria. Familial benign hypocalciuric hypercalcemia is characterized by hypercalcemia, hypocalciuria (usually < 50 mg/24 h), variable hypermagnesemia, and normal or minimally elevated serum levels of PTH. These patients do not normalize their hypercalcemia after subtotal parathyroid removal and should not be subjected to surgery. The condition has an excellent prognosis and is easily diagnosed with a family history and urinary calcium determination.
Hypercalcemia is common in untreated Addison disease. This is partly due to disinhibition of calcium uptake by the renal tubule and gut. Additionally, Addison disease can cause dehydration and hyperproteinemia, resulting in higher levels of nonionized calcium.
Prolonged immobilization at bed rest commonly causes hypercalcemia, particularly in adolescents, critically ill patients, and patients with extensive Paget disease of bone. Hypercalcemia develops in about one-third of acutely ill patients being treated in intensive care units, particularly patients with acute kidney injury. Serum calcium elevations are typically mild but may reach 15 mg/dL (3.75 mmol/L). Serum PTH levels are usually slightly elevated, consistent with mild hyperparathyroidism, but may be suppressed or normal.
Other causes of hypercalcemia are shown in Table 21–8. Modest hypercalcemia is occasionally seen in patients taking thiazide diuretics or lithium; such patients may have an inappropriately nonsuppressed PTH level with hypercalcemia.
Hyperthyroidism causes increased turnover of bone and occasional hypercalcemia. Bisphosphonates can increase serum calcium in 20% and serum PTH becomes high in 10%, mimicking hyperparathyroidism.
Patients with mild hyperparathyroidism should only be considered “asymptomatic” after very close questioning. Many patients may not realize they have manifestations, such as cognitive slowing, having become accustomed to such symptoms over years. Truly asymptomatic patients may be closely monitored and advised to keep active, avoid immobilization, and drink adequate fluids. For postmenopausal women with hyperparathyroidism, estrogen replacement therapy reduces serum calcium by an average of 0.75 mg/dL (0.19 mmol/L) and slightly improves bone density.
Affected patients should avoid thiazide diuretics, large doses of vitamin A, and calcium-containing antacids or supplements. Serum calcium and albumin are checked about twice yearly, kidney function and urine calcium once yearly, and three-site bone density (distal radius, hip, and spine) every 2 years. Rising serum calcium should prompt further evaluation and determination of PTH levels.
Parathyroidectomy is recommended for patients with hyperparathyroidism who are symptomatic or pregnant or who have nephrolithiasis or bone disease.
Some patients with seemingly asymptomatic hyperparathyroidism may be surgical candidates for other reasons such as (1) serum calcium 1 mg/dL (0.25 mmol/L) above the upper limit of normal with urine calcium excretion > 50 mg/24 h (off thiazide diuretics), (2) urine calcium excretion over 400 mg/24 h, (3) creatinine clearance < 60 mL/min, (4) cortical bone density (wrist, hip) ≥ 2.5 SD below normal or previous fragility bone fracture, (5) relative youth (under age 50–60 years), (6) difficulty ensuring medical follow-up, or (7) pregnancy. During pregnancy, parathyroidectomy is performed in the second trimester. Surgery for patients with “asymptomatic” hyperparathyroidism may improve bone mineral density and confer modest benefits in social and emotional function, with improvements in anxiety and phobias being reported in comparison to similar patients who are monitored without surgery.
Preoperative parathyroid imaging has been used in an attempt to allow unilateral minimally invasive neck surgery. The reported success rates vary considerably. Even in patients with concordant sestamibi and ultrasound scans, and an intraoperative PTH drop of > 50%, hyperparathyroidism may persist postoperatively in up to 15% of patients.
Without preoperative localization studies, bilateral neck exploration is usually advisable for the following: (1) patients with a family history of hyperparathyroidism, (2) patients with a personal or family history of MEN, and (3) patients wanting an optimal chance of success with a single surgery. Patients undergoing unilateral neck exploration can have the incision widened for bilateral neck exploration if two abnormal glands are found or if the serum quick PTH falls by < 63% within 10 minutes of the parathyroid resection. Parathyroid glands are not uncommonly supernumerary (five or more) or ectopic (eg, intrathyroidal, carotid sheath, mediastinum). The optimal surgical management for patients with MEN type 1 is subtotal parathyroidectomy that usually results in a cure, although recurrent hyperparathyroidism develops in 18% and the rate of postoperative hypoparathyroidism is high.
Parathyroid hyperplasia is commonly seen with secondary or tertiary hyperparathyroidism associated with uremia. Cinacalcet is an alternative to surgery. When surgery is performed, a subtotal parathyroidectomy is optimal; three and one-half glands are usually removed, and a metal clip is left to mark the location of residual parathyroid tissue.
Parathyroid carcinoma can cause severe hypercalcemia associated with very high serum levels of PTH. Preoperative localizing studies usually detect a large invasive tumor. Therapy consists of en bloc resection of the tumor and the ipsilateral thyroid lobe. Metastases to local and to distant sites occur in about 50% of patients. Reoperation for neck recurrence is usually necessary. Adjuvant treatment includes radiation therapy. Cinacalcet is administered initially in doses of 30 mg twice daily and increased as needed up to 90 mg four times daily. Intravenous bisphosphonate (zoledronic acid) is used as needed.
Complications—Serum PTH levels fall below normal in 70% of patients within hours after successful surgery, commonly causing hypocalcemic paresthesias or even tetany. Hypocalcemia tends to occur the evening after surgery or on the next day. Therefore, frequent postoperative monitoring of serum calcium (or serum calcium plus albumin) is advisable beginning the evening after surgery. Once hypercalcemia has resolved, liquid or chewable calcium carbonate is given orally to reduce the likelihood of hypocalcemia. Symptomatic hypocalcemia is treated with larger doses of calcium; calcitriol (0.25–1 mcg daily orally) may be added, with the dosage depending on symptom severity. Magnesium salts are sometimes required postoperatively, since adequate magnesium is required for functional recovery of the remaining suppressed parathyroid glands.
In about 12% of patients having successful parathyroid surgery, PTH levels rise above normal (while serum calcium is normal or low) by 1 week postoperatively. This secondary hyperparathyroidism is probably due to “hungry bones” and is treated with calcium and vitamin D preparations. Such therapy is usually needed only for 3–6 months but is required long-term by some patients.
Hyperthyroidism commonly occurs immediately following parathyroid surgery. It is caused by release of stored thyroid hormone during surgical manipulation of the thyroid. In symptomatic patients, short-term treatment with propranolol may be required for several days.
The vitamin D analogs paricalcitol and doxercalciferol suppress PTH secretion and cause less hypercalcemia than calcitriol; however, they are very expensive. The doses are adjusted to keep serum PTH levels in the range of 150–300 pg/mL (15–30 pmol/L). Paricalcitol (Zemplar) is administered intravenously during dialysis three times weekly in starting doses of 0.04–0.1 mcg/kg to a maximum dose of 0.24 mcg/kg three times weekly. Alternatively, paricalcitol may be administered orally at doses of 1–2 mcg daily for serum PTH levels < 500 pg/mL (<50 pmol/L) or 2–4 mcg daily for serum PTH levels > 500 pg/mL (>50 pmol/L). Dialysis patients receiving paricalcitol have improved survival compared with patients receiving calcitriol. Doxercalciferol (Hectorol) is administered intravenously three times weekly during hemodialysis to patients with azotemic secondary hyperparathyroidism in starting doses of 4 mcg three times weekly to a maximum dose of 18 mcg three times weekly. Alternatively, doxercalciferol may be administered orally three times weekly at dialysis, starting with 10 mcg three times weekly at dialysis to a maximum of 60 mcg/wk.
Renal osteodystrophy is caused by secondary or tertiary hyperparathyroidism during kidney disease. It can be prevented or delayed by reducing hyperphosphatemia with phosphate binding medication and dietary phosphate restriction.
Patients with symptomatic hyperparathyroidism usually experience worsening disease (eg, nephrolithiasis) unless they have treatment. Conversely, the majority of completely asymptomatic patients with a serum calcium < 11.0 mg/dL (< 2.75 mmol/L) remain stable with follow-up. However, worsening hypercalcemia, hypercalciuria, and reductions in cortical bone mineral density develop in about one-third of asymptomatic patients. Therefore, asymptomatic patients must be monitored carefully and treated with oral hydration and mobilization.
Surgical removal of apparently single sporadic parathyroid adenomas is successful in 94%. Patients with MEN 1 undergoing subtotal parathyroidectomy may experience long remissions, but hyperparathyroidism frequently recurs. Despite treatment for hyperparathyroidism, patients remain at increased risk for all-cause mortality, cardiovascular disease, kidney stones, and renal failure. These increased risks are likely the residuals of pretreatment hypertension and nephrolithiasis.
Spontaneous cure due to necrosis of the tumor has been reported but is exceedingly rare. The bones, in spite of severe cyst formation, deformity, and fracture, will heal if a parathyroid tumor is successfully removed. The presence of pancreatitis increases the mortality rate. Acute pancreatitis usually resolves with correction of hypercalcemia, whereas subacute or chronic pancreatitis tends to persist. Significant renal damage may progress even after removal of an adenoma.
Parathyroid carcinoma tends to invade local structures and may sometimes metastasize; repeat surgical resections and radiation therapy can prolong life. Aggressive surgical and medical management of parathyroid carcinoma can result in a median overall survival of 14.3 years (range 10.5–25.7 years) from the date of diagnosis. Factors associated with a worsened mortality rate include lymph node or distant metastases, high number of recurrences, and higher serum calcium levels at recurrence.
When to Refer
Refer to parathyroid surgeon for parathyroidectomy.
When to Admit
Patients with severe hypercalcemia for intravenous hydration.
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METABOLIC BONE DISEASE
The term “metabolic bone disease” denotes those conditions producing diffusely decreased bone density and diminished bone strength. It is categorized by histologic appearance: osteoporosis (bone matrix and mineral both decreased) and osteomalacia (bone matrix intact, mineral decreased). Osteoporosis and osteomalacia often coexist in the same patient.
ESSENTIALS OF DIAGNOSIS
Fracture propensity of spine, hip, pelvis, and wrist from demineralization.
Serum PTH, calcium, phosphorus, and alkaline phosphatase usually normal.
Serum 25-hydroxyvitamin D levels often low as a comorbid condition.
Osteoporosis is a skeletal disorder characterized by a loss of bone osteoid that reduces bone integrity, resulting in an increased risk of fractures. In the United States, osteoporosis causes about 2 million fractures annually, including 547,000 vertebral fractures, 300,000 hip fractures, and 135,000 pelvic fractures. White women have a 40% lifetime risk of sustaining one or more osteoporotic fractures. The morbidity and indirect mortality rates are very high. The rate of bone formation is often normal, whereas the rate of bone resorption is increased.
Osteoporosis can be caused by a variety of factors, which are listed in Table 26–10. The most common causes include aging, high-dose corticosteroid administration, alcoholism, smoking, and sex hormone deficiency. Hypogonadal men frequently develop osteoporosis. Anti-androgen therapy for prostate cancer can cause osteoporosis and such men should monitored with bone densitometry.
Table 26–10. Causes of osteoporosis.1
Osteogenesis imperfecta is caused by a major mutation in the gene encoding for type I collagen, the major collagen constituent of bone. This causes severe osteoporosis; spontaneous fractures occur in utero or during childhood. Blue sclerae may be present. Certain polymorphisms in the genes encoding type I collagen are common, particularly in whites, resulting in collagen disarray and predisposing to hypogonadal (eg, menopausal) or idiopathic osteoporosis.
Osteoporosis is usually asymptomatic until fractures occur. It may present as backache of varying degrees of severity or as a spontaneous fracture or collapse of a vertebra. Loss of height is common. Once osteoporosis is identified, a carefully directed history and physical examination must be performed to determine its cause (Table 26–10).
Serum calcium, phosphate, and PTH are normal. The alkaline phosphatase is usually normal but may be slightly elevated, especially following a fracture. Vitamin D deficiency is very common and serum determination of 25-hydroxyvitamin D should be obtained for every individual with low bone density. Serum 25-hydroxyvitamin D levels < 20 ng/mL (< 50 nmol/L) are considered frank vitamin D deficiency. Lesser degrees of vitamin D deficiency (serum 25-hydroxyvitamin D levels in the range of 20–30 ng/mL (50–75 nmol/L) may also increase the risk for hip fracture. (See Osteomalacia.) Testing for thyrotoxicosis and hypogonadism may be required. Celiac disease may be screened for with serum immunoglobulin A (IgA) endomysial antibody and tissue transglutaminase antibody determinations.
DXA is used to determine the bone density of the lumbar spine and hip. Bone densitometry should be performed on all patients who are at risk for osteoporosis or osteomalacia or have pathologic fractures or radiographic evidence of diminished bone density. This test delivers negligible radiation, and the measurements are quite accurate. However, bone densitometry cannot distinguish osteoporosis from osteomalacia; in fact, both are often present. Also, the bone mineral density does not directly measure bone quality and is only fairly successful at predicting fractures. Vertebral bone mineral density may be misleadingly high in compressed vertebrae and in patients with extensive arthritis. DXA also overestimates the bone mineral density of taller persons and underestimates the bone mineral density of smaller persons. Quantitative CT delivers more radiation but is more accurate in the latter situations.
Bone mineral density is typically expressed in g/cm2, for which there are different normal ranges for each bone and for each type of DXA-measuring machine. The “T score” is a simplified way of reporting bone density in which the patient’s bone mineral density is compared to the young normal mean and expressed as a standard deviation score. The World Health Organization has established criteria for defining osteoporosis in postmenopausal white women, based on T score:
T score ≥ –1.0: Normal.
T score –1.0 to –2.5: Osteopenia (“low bone density”).
T score < –2.5: Osteoporosis.
T score < –2.5 with a fracture: Severe osteoporosis.
This classification is somewhat arbitrary and there really is no bone mineral density fracture threshold; instead, the fracture risk increases about twofold for each standard deviation drop in bone mineral density. In fact, most women with fragility fractures have bone densities above –2.5. Surveillance DXA bone densitometry is recommended for postmenopausal women with a frequency according to their T scores: obtain DXA every 5 years for T scores –1.0 to –1.5, every 3–5 years for scores –1.5 to –2.0, and every 1–2 years for scores under –2.0.
The “Z score” is used to express bone density in premenopausal women, younger men, and children, The Z score is a statistical term that is used for expressing an individual’s bone density as standard deviation from age-matched, race-matched, and sex-matched means.
Osteopenia and fractures can be caused by osteomalacia (see below) and bone marrow neoplasia such as myeloma or metastatic bone disease. These conditions coexist in many patients.
For prevention and treatment of osteoporosis, the diet should be adequate in protein, total calories, calcium, and vitamin D. Pharmacologic corticosteroid doses should be reduced or discontinued if possible. Thiazides may be useful if hypercalciuria is present. High-impact physical activity (eg, jogging) significantly increases bone density in men and women. Stair-climbing increases bone density in women. Patients who cannot exercise vigorously should be encouraged to engage in other exercise regularly, thereby increasing strength and reducing the risk of falling. Weight training is helpful to increase muscle strength as well as bone density. Measures should be taken to avoid falls at home (eg, adequate lighting, handrails on stairs, handholds in bathrooms). Patients who have weakness or balance problems must use a cane or a walker; rolling walkers should have a brake mechanism. Balance exercises can reduce the risk of falls. Patients should be kept active; bedridden patients should be given active or passive exercises. The spine may be adequately supported (though braces or corsets are usually not well tolerated), but rigid or excessive immobilization must be avoided. Alcohol and smoking should be avoided.
Several treatment options are available, so a regimen is tailored to each patient. Generally, treatment is indicated for all women with osteoporosis (T scores below –2.5) and for all patients who have had fragility fractures. Prophylactic treatment should also be considered for patients with advanced osteopenia (T scores between –2.0 and –2.5).
Calcium supplementation does not reduce the fracture risk in otherwise healthy patients with a dietary calcium intake of over 1000 mg daily. One meta-analysis concluded that calcium supplementation is associated with a 27% increased risk of myocardial infarction; however, methodological shortcomings in that study have raised doubts about its validity. Conversely, the Women’s Health Initiative found that myocardial infarction rates were not significantly higher among postmenopausal women taking calcium. Calcium supplements may increase the risk of calcium-containing kidney stones, unless taken with meals. Some patients experience gastrointestinal upset with calcium supplements. Therefore, calcium supplementation should probably be given only to those patients whose diets are low in calcium. More important is the assurance of adequate vitamin D through sun exposure or oral vitamin D supplementation. If calcium supplementation is given, it should include vitamin D. Calcium supplementation may be given as calcium citrate (0.4–0.7 g elemental calcium per day) or calcium carbonate (1–1.5 g elemental calcium per day).
Bisphosphonates may be given orally once weekly or monthly. Alendronate is administered orally once weekly as either a 70-mg standard tablet or a 70-mg effervescent tablet (Binosto). The effervescent tablet must be dissolved in 4 oz plain water over at least 5 minutes and stirred 10 seconds before drinking; it is easier to swallow for some patients and may reduce esophageal injury, but there have been no studies comparing it to standard alendronate tablets. Risedronate is given as one 35-mg tablet orally once weekly. Both these medications reduce the risk of both vertebral and nonvertebral fractures. Alendronate appears to be superior to risedronate in preventing nonvertebral fractures. Another bisphosphonate, ibandronate sodium, is taken once monthly in a dose of 150 mg orally. Once-monthly ibandronate is convenient and reduces the risk of vertebral fractures but not nonvertebral fractures; its effectiveness has not been directly compared with other bisphosphonates. Oral bisphosphonates can cause nausea, chest pain, and hoarseness. Erosive esophagus can occur, particularly in patients with hiatal hernia and gastroesophageal reflux.
For patients who cannot tolerate oral bisphosphonates or for whom oral bisphosphonates are contraindicated, intravenous bisphosphonates are available. Zoledronic acid (Zometa, Reclast) is a third-generation bisphosphonate and a potent osteoclast inhibitor. It can be given every 12 months in doses of 2–5 mg intravenously over at least 15–30 minutes. Pamidronate (Aredia) can be given in doses of 30–60 mg by slow intravenous infusion in normal saline solution every 3–6 months.
Bisphosphonate therapy can cause several side effects that are collectively known as the acute-phase response. Such a response occurs in 42% of patients following the first infusion of zoledronic acid and usually starts within the first few days following the infusion. Among patients receiving their first infusion of zoledronic acid, these adverse side effects have included fever, chills, or flushing (20%); musculoskeletal pain (20%); nausea, vomiting, or diarrhea (8%); nonspecific symptoms, such as fatigue, dyspnea, edema, headache, or dizziness (22%); and eye inflammation (0.6%). Intravenous zoledronic acid has caused seizures that may be idiosyncratic or due to hypocalcemia. The acute-phase response is most commonly seen after the first dose of bisphosphonate (particularly zoledronic acid) and tends to diminish with time. Symptoms are transient, lasting several days and usually resolving spontaneously but typically recurring with subsequent doses. For patients experiencing a severe acute-phase response with zoledronic acid, intravenous pamidronate can substitute for zoledronic acid for subsequent treatment. Additionally, patients who experience an especially severe acute-phase response can be given prophylactic corticosteroids and ondansetron prior to subsequent bisphosphonate infusions.
Osteonecrosis of the jaw is a rare complication of bisphosphonate therapy for osteoporosis. A painful, necrotic, nonhealing lesion of the jaw occurs, particularly after tooth extraction. About 95% of jaw osteonecrosis cases have occurred with high-dose therapy with zoledronic acid or pamidronate for patients with myeloma or solid tumor osteolytic metastases. Only about 5% of cases have occurred in patients receiving oral (or, less frequently, intravenous) bisphosphonate doses for osteoporosis. The incidence of osteonecrosis is estimated to be about 1:100,000 patients treated for osteoporosis and 1:100 patients being treated for cancer. In a prospective 3-year trial of 7714 women who received intravenous zoledronic acid 5 mg/year, there were no cases of osteonecrosis. For patients with painful osteonecrotic exposed bone, treatment is 90% effective (without resolution of the exposed bone) using antibiotics along with 0.12% chlorohexidine antiseptic mouthwash. Patients receiving bisphosphonates must receive regular dental care and try to avoid dental extraction.
Atypical “chalkstick” fractures of the femur occur rarely in patients taking bisphosphonates. Bisphosphonate use for more than 5 years is associated with 2.7-fold risk in subtrochanteric or shaft fractures; but the absolute risk is low at about 1 fracture per 1000 bisphosphonate users yearly. In one study, atypical femoral fractures developed in 4 of 327 patients after receiving at least 24 intravenous bisphosphonate infusions for bone metastases. Atypical fractures are subtrochanteric or diaphyseal, occur with little trauma, and are usually transverse as opposed to the more typical comminuted or spiral femoral shaft fractures. Bilateral femoral fractures occur in 27%. About 70% of affected patients have had prodromal thigh pain prior to the fracture. The risk for atypical femoral fractures is particularly increased among patients concurrently taking high-dose corticosteroids and those receiving treatment for more than 5 years. Teriparatide may be helpful to promote healing of such fractures. Despite this rare complication, the overall risk of hip fracture is reduced among patients taking bisphosphonates for up to 5 years.
Patients taking oral bisphosphonates have an increased risk of developing esophageal cancer. In North America and Europe, the incidence of esophageal cancer at age 60–79 is about 1 per 1000 population over 5 years; this risk is estimated to increase to about 2 per 1000 with administration of oral bisphosphonates for 5 years or longer.
In patients taking bisphosphonates, hypercalcemia is seen in 20% and serum PTH levels increase above normal in 10%, mimicking primary hyperparathyroidism. Hypocalcemia occurs frequently, resulting in secondary hyperparathyroidism; therefore, patients taking bisphosphonates are frequently prescribed prophylactic oral calcium supplements (500–1000 mg/d) with vitamin D3 (1000 units/d).
The half-life of alendronate in bone is 10 years. Therefore, bisphosphonates may be discontinued after a 5-year course of therapy. Repeat bone densitometry may be obtained after 3 years of bisphosphonate therapy. Bone density falls in 18% of patients during their first year of treatment with bisphosphonates, but 80% of such patients have gain in bone density with continued bisphosphonate treatment.
Hypogonadal men are at risk for developing osteoporosis that can be prevented with testosterone administration. (See Male Hypogonadism.)
Raloxifene increases the risk for thromboembolism and should not be used by women with such a history. Leg cramps can also occur.
Teriparatide should not be used for patients with hypercalcemia. Similarly, teriparatide should be used with caution in patients if they are also taking corticosteroids and thiazide diuretics along with oral calcium supplementation because hypercalcemia may develop.
Following a course of teriparatide, a course of bisphosphonates should be considered in order to retain the improved bone density.
Bone mineral density densitometries can detect whether progressive osteopenia or frank osteoporosis is developing. Osteoporosis should ideally be prevented, since it can be only be partially reversed. Measures noted above are reasonably effective in preventing and treating osteoporosis and reducing fracture risk.
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ESSENTIALS OF DIAGNOSIS
Painful proximal muscle weakness (especially pelvic girdle); bone pain and tenderness.
Decreased bone density from defective mineralization.
Laboratory abnormalities may include increased alkaline phosphatase, decreased 25-hydroxy-vitamin D, hypocalcemia, hypocalciuria, hypophosphatemia, secondary hyperparathyroidism.
Classic radiologic features may be present.
Defective mineralization of the growing skeleton in childhood causes permanent bone deformities (rickets). Defective skeletal mineralization in adults is known as osteomalacia. It is caused by any condition that results in inadequate calcium or phosphate mineralization of bone osteoid.
Etiology (Table 26–11)
Table 26–11. Causes of osteomalacia.1
Vitamin D is predominantly synthesized in the skin during exposure to ultraviolet B light. Vitamin D is also consumed in the diet from plants (ergocalciferol, D2) or animals/fish (cholecalciferol, D3). Both forms of vitamin D are converted in the liver to 25-hydroxyvitamin D (25OHD); 25OHD is subsequently converted in various tissues (mainly kidney) to 1,25-dihydroxyvitamin D (1,25[OH]2D), the active hormone whose production is regulated by serum calcium, phosphorus, and PTH. 1,25(OH)2D binds to cytoplasmic vitamin D receptors, increasing the absorption of dietary calcium from the intestine and increasing the reabsorption of calcium in the renal tubule, thereby reducing calcium loss in the urine. 1,25(OH)2D also stimulates bone osteoblasts to release RANKL that stimulates osteoclasts, which release calcium from bone.
Vitamin D deficiency is the most common cause of osteomalacia and its incidence is increasing throughout the world as a result of diminished exposure to sunlight caused by urbanization, automobile and public transportation, modest clothing, and sunscreen use. Significant vitamin D deficiency (serum 25OHD < 50 nmol/L or < 20 ng/mL) was found in 24.3% of postmenopausal women from 25 countries. The incidence varied: < 1% in Southeast Asia, 29% in the United States, and 36% in Italy. Patients in whom clinically severe osteomalacia develops typically have had chronic severe vitamin D deficiency (serum 25OHD < 25 nmol/L or < 10 ng/mL). The prevalence of severe vitamin D deficiency is 3.5% in the United States and 12.5% in Italy. Among US men over age 65 years, 25% have serum 25OHD levels below 20 ng/mL; men over age 75 with such low vitamin D levels have particularly accelerated bone loss. Vitamin D deficiency is particularly common in the institutionalized elderly, with the incidence exceeding 60% in some groups not receiving vitamin D supplementation. Deficiency of vitamin D may arise from insufficient sun exposure, malnutrition, or malabsorption (due to pancreatic insufficiency, cholestatic liver disease, celiac disease, inflammatory bowel disease, jejunoileal bypass, Billroth type II gastrectomy). Orlistat is a weight-loss medication that causes fat malabsorption and reduced serum 25OHD levels. Cholestyramine binds bile acids necessary for vitamin D absorption. Patients with severe nephrotic syndrome lose large amounts of vitamin D–binding protein in the urine, and osteomalacia may also develop.
Anticonvulsants (eg, phenytoin, carbamazepine, valproate, phenobarbital) inhibit the hepatic production of 25OHD and sometimes cause osteomalacia. Phenytoin can also directly inhibit bone mineralization. Serum levels of 1,25(OH)2D are usually normal.
Vitamin D–dependent rickets type I is caused by a rare autosomal recessive disorder with a defect in the renal enzyme 1-alpha-hydroxylase leading to defective synthesis of 1,25(OH)2D. It presents in childhood with rickets and alopecia; osteomalacia develops in adults with this condition unless treated with oral calcitriol in doses of 0.5–1 mcg daily.
Vitamin D–dependent rickets type II (better known as hereditary 1,25[OH]2D-resistant rickets) is caused by a genetic defect in the 1,25(OH)2D receptor. Patients have hypocalcemia with childhood rickets and adult osteomalacia. Alopecia is common. These patients respond variably to oral calcitriol in very large doses (2–6 mcg daily).
The total daily consumption of calcium should be at least 1000 mg daily. Patients who have deficient calcium intake develop rickets (childhood) or osteomalacia (adulthood) despite sufficient vitamin D. A nutritional deficiency of calcium can occur in any severely malnourished patient. Some degree of calcium deficiency is common in the elderly, since intestinal calcium absorption declines with age. Ingestion of excessive wheat bran also causes calcium malabsorption.
Hypophosphatemia can cause severe major muscle weakness, dysphagia, diplopia, cardiomyopathy, and respiratory muscle weakness. Patients may have impaired cognition. Chronic hypophosphatemia can cause bone pain and affect bone integrity. Phosphate deficiency in childhood causes classic rickets, whereas phosphate deficiency in adulthood causes osteomalacia.
Sodium-phosphate cotransporters (NPT2a or NPT2c) reabsorb phosphate from the proximal renal tubule. Mutations in the genes encoding them or in NHERF1 cause hypophosphatemia, bone mineral depletion, and calcium-phosphate kidney stones.
Bone mineralization is inhibited by aluminum. Osteomalacia may occur in patients receiving long-term renal hemodialysis with tap water dialysate or from aluminum-containing antacids used to reduce phosphate levels. Osteomalacia may develop in patients being maintained on long-term total parenteral nutrition if the casein hydrolysate used for amino acids contains high levels of aluminum.
Hypophosphatasia, a deficiency of bone alkaline phosphatase effect, is a rare genetic cause of osteomalacia that is commonly misdiagnosed as osteoporosis. The incidence in the United States is about 1 in 100,000 live births; about 1 in 300 adults is a carrier. Many different mutations in the gene (designated ALPL) encoding bone alkaline phosphatase have been described, and transmission can be either autosomal recessive or autosomal dominant. The phenotypic presentation of hypophosphatasia is extremely variable. At its mildest, hypophosphatasia can present in middle age with premature loss of teeth, foot pain (due to metatarsal stress fractures), thigh pain (due to femoral pseudofractures), or arthritis (due to chondrocalcinosis). Serum alkaline phosphatase (collected in a non-EDTA tube) is low for age in patients with hypophosphatasia. To confirm the diagnosis, a 24-hour urine should be assayed for phosphoethanolamine, a substrate for tissue-nonspecific alkaline phosphatase, whose excretion is always elevated in patients with hypophosphatasia. Prenatal genetic testing, by way of chorionic villus biopsy, is available for the infantile form of hypophosphatasia. There is no proven therapy for hypophosphatasia, except for supportive care. Teriparatide, a useful therapy for osteoporosis, has been administered to some patients with hypophosphatasia, but its long-term efficacy is unknown.
This rare condition sporadically affects middle-aged patients, who present with progressive bone pain and pathologic fractures. Bones have a dense “fishnet” appearance on radiographs. Serum alkaline phosphatase levels are elevated. Some patients have a monoclonal gammopathy, indicating a possible plasma cell dyscrasia causing an impairment in osteoblast function and collagen disarray. Remission has been reported after repeated courses of melphalan, corticosteroids, and vitamin D analog over 3 years.
The clinical manifestations of defective bone mineralization depend on the age at onset and the severity. In adults, osteomalacia is typically asymptomatic at first. Eventually, bone pain occurs, along with muscle weakness due to calcium deficiency. Pathologic fractures may occur with little or no trauma. Vitamin D deficiency has also been associated with a possible increased risk of multiple sclerosis, rheumatoid arthritis, diabetes mellitus (types 1 and 2), and other conditions, but the causal relationship is uncertain.
Serum is obtained for calcium, albumin, phosphate, alkaline phosphatase, PTH, and 25[OH]D3 determinations. Bone densitometry helps document the degree of osteopenia. Radiographs may show diagnostic features.
In one series of biopsy-proved osteomalacia, alkaline phosphatase was elevated in 94% of patients; the calcium or phosphorus was low in 47% of patients; 25(OH)D3 was low in 29% of patients; pseudofractures were seen in 18% of patients; and urinary calcium was low in 18% of patients. 1,25(OH)2D3 may be low even when 25(OH)D2 levels are normal.
Bone biopsy is not usually necessary but is diagnostic of osteomalacia if there is significant unmineralized osteoid.
Osteomalacia is often seen together with osteoporosis, and its presence can be inferred by finding low serum levels of 25(OH) vitamin D, low serum calcium, or low serum phosphate. A high serum alkaline phosphatase may be present in severe osteomalacia but not osteoporosis. The relative contribution of the two entities to diminished bone density may not be apparent until treatment, since a dramatic rise in bone density is often seen with therapy for osteomalacia. Phosphate deficiency must be distinguished from hypophosphatemia seen in hyperparathyroidism.
Prevention & Treatment
To obtain adequate sunshine vitamin D, the face, arms, hands, or back must have sun exposure without sunscreen for 15 minutes at least twice weekly. The main natural food source of vitamin D is fish, particularly salmon, mackerel, cod liver oil, and sardines or tuna canned in oil. Most commercial cow’s milk is fortified with vitamin D at about 400 international units per quart; however, skim milk and other dairy products contain much less vitamin D.
Many vitamin supplements contain plant-derived vitamin D2, which has less biologic availability than once believed. Over-the-counter multivitamin/mineral supplements contain variable amounts of vitamin D, and vitamin D toxicity has occurred from two different multivitamins sold in the United States. Therefore, it is prudent to recommend that patients take a dedicated vitamin D supplement from a reliable manufacturer.
In sunlight-deprived individuals (eg, veiled women, confined patients, or residents of higher latitudes during winter), the recommended daily allowance should be vitamin D3 1000 international units daily. In such individuals, vitamin D3 supplements should be given prophylactically. Patients receiving long-term phenytoin therapy may be treated prophylactically with vitamin D, 50,000 international units orally every 2–4 weeks.
Frank vitamin D deficiency is treated with ergocalciferol (D2), 50,000 international units orally once weekly for 8 weeks. Following that, vitamin D3 (cholecalciferol) supplementation is used at a dose of 2000 international units daily. Vitamin D3 is more effective than vitamin D2 in raising serum levels of 25(OH)D. Some patients require long-term supplementation with ergocalciferol of up to 50,000 international units weekly. In patients with intestinal malabsorption, oral doses of 25,000–100,000 international units of vitamin D3 daily may be required. Some patients with steatorrhea respond better to oral 25(OH)D3 (calcifediol), 50–100 mcg/d. Serum levels of 25(OH)D should be monitored and the dosage of vitamin D adjusted to maintain serum 25(OH)D levels above 30 ng/mL. During treatment with high-dose vitamin D, serum calcium should also be monitored to avoid hypercalcemia.
Beyond increasing the intestinal absorption of calcium, vitamin D supplementation may have additional effects. Vitamin D supplementation has been associated with improved muscle strength and a reduced fall risk, factors that reduce the risk of bone fracture.
The addition of calcium supplements to vitamin D is probably not necessary for the prevention of osteomalacia in the majority of otherwise well-nourished patients. However, patients with malabsorption or poor nutrition should receive calcium supplementation. Recommended doses of calcium are as follows: calcium citrate (eg, Citracal), 0.4–0.6 g elemental calcium per day, or calcium carbonate (eg, OsCal, Tums), 1–1.5 g elemental calcium per day. Calcium supplements are best administered with meals.
In hypophosphatemic osteomalacia, nutritional deficiencies are corrected, aluminum-containing antacids are discontinued, and patients with renal tubular acidosis are given bicarbonate therapy. In patients with sporadic adult-onset hypophosphatemia, hyperphosphaturia, and low serum 1,25(OH)2D levels, a search is conducted for occult tumors that may be resected; whole-body MRI scanning may be required.
For those with X-linked or idiopathic hypophosphatemia and hyperphosphaturia, oral phosphate supplements must be given long-term. Calcitriol, 0.25–0.5 mcg/d, is given also to improve the impaired calcium absorption caused by the oral phosphate. If necessary, rhGH may be added to the above regimen to reduce phosphaturia.
Patients with hypophosphatasia have been treated with teriparatide with improvement in bone pain and fracture healing.
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PAGET DISEASE OF BONE (Osteitis Deformans)
ESSENTIALS OF DIAGNOSIS
Bone pain may be the first symptom.
Kyphosis, bowed tibias, large head, deafness, and frequent fractures.
Serum calcium and phosphate normal; alkaline phosphatase elevated; urinary hydroxyproline elevated.
Dense, expanded bones on radiographs.
Paget disease is manifested by one or more bony lesions having high bone turnover and disorganized osteoid formation. The involved bone has increased osteoclast activity, causing lytic lesions in bone that may progress at about 1 cm/yr. Involved bones become vascular, weak, and deformed.
The prevalence of Paget disease has declined by about 36% over that past 20 years. However, it remains a common disease in certain countries, with striking geographic variation in prevalence. It is most common in the United Kingdom and in areas of European migration, particularly New Zealand, Australia, the United States, South Africa, Quebec, and Brazil. Interestingly, the disease appears equally common among different races in these countries. Paget disease occurs in 1–2% of the population of the United States, and its prevalence increases with age. It is uncommon in Africa, Asia, and Scandinavia. Usually diagnosed in patients over age 40 years, its prevalence doubles with each decade thereafter, reaching an incidence of about 10% after age 80. It is most often discovered incidentally during radiology imaging or because of incidentally discovered elevations in serum alkaline phosphatase.
The cause of Paget disease is unknown. However, there is believed to be a genetic component, since about 30% of affected patients have a first-degree relative with the disease. Mutations in the SQSTM1gene have been discovered in 25–50% of cases with familial Paget disease and in 5–10% of patients with apparently sporadic Paget disease.
Paget disease is often mild and asymptomatic. Only 27% of affected individuals are symptomatic at the time of diagnosis. Paget disease involves multiple bones (polyostotic) in 72% and only a single bone (monostotic) in 28%. It occurs most commonly in the pelvis, vertebrae, femur, humerus, and skull. The affected bones are typically involved right away and the disease tends not to involve additional bones during its course. Pain is the usual first symptom. It may occur in the involved bone or in an adjacent joint, which can be involved with degenerative arthritis. The bones can become soft, leading to bowed tibias, kyphosis, and frequent “chalkstick” fractures with slight trauma. If the skull is involved, the patient may report headaches and an increased hat size. Deafness may occur. Increased vascularity over the involved bones causes increased warmth and can cause vascular “steal” syndromes.
Serum alkaline phosphatase is usually markedly elevated. However, some patients with limited monostotic involvement may have serum alkaline phosphatase levels within the normal range. A serum bone-specific alkaline phosphatase is usually high and is useful for patients with a normal serum total alkaline phosphatase and to distinguish the source of an elevated serum alkaline phosphatase as being from bone (rather than liver). Other markers of bone turnover are also usually elevated, particularly serum procollagen type-I N-terminal propeptide (PINP) and urine N-telopeptide of type 1I collagen cross-links (NTx). Serum calcium may be elevated, particularly if the patient is at bed rest. A serum 25-OH vitamin D determination should be obtained to screen for vitamin D deficiency, which can also present with an increased serum alkaline phosphatase and bone pain. Also, any vitamin D deficiency should be corrected before prescribing a bisphosphonate.
On radiographs, the initial lesions are typically osteolytic, with focal radiolucencies (“osteoporosis circumscripta”) in the skull or advancing flame-shaped lytic lesions in long bones. Bone lesions may subsequently become sclerotic and have a mixed lytic and sclerotic appearance. The affected bones eventually become thickened and deformed. Technetium pyrophosphate bone scans are helpful in delineating activity of bone lesions even before any radiologic changes are apparent.
Certain rare familial types of sclerosing bone dysplasias share phenotypic homologies with Paget disease of bone. Familial expansile osteolysis, familial early-onset Paget disease, and familial skeletal hyperphosphatasia are autosomal dominant disorders caused by different tandem duplications of the gene encoding RANK, resulting in its constitutive activation. The differential diagnosis also includes myelofibrosis, intramedullary osteosclerosis, Erdheim-Chester disease, Langerhans cell histiocytosis, and sickle cell disease.
Paget disease must be differentiated from primary bone lesions such as osteogenic sarcoma, multiple myeloma, and fibrous dysplasia and from secondary bone lesions such as osteitis fibrosa cystica and metastatic carcinoma to bone. Fibrogenesis imperfecta ossium is a rare symmetric disorder that can mimic the features of Paget disease; serum alkaline phosphatase is likewise elevated. This condition may be associated with paraproteinemias.
If immobilization occurs, hypercalcemia and renal calculi may develop. The increased vascularity may give rise to high-output cardiac failure. Arthritis frequently develops in joints adjacent to involved bone.
Extensive skull involvement may cause cranial nerve palsies from impingement of the neural foramina. Involvement of the petrous temporal bone frequently causes hearing loss (mixed sensorineural and conductive) and occasionally tinnitus or vertigo. Skull involvement can also cause a vascular steal syndrome with somnolence or ischemic neurologic events; the optic nerve may be affected, resulting in loss of vision. Jaw involvement can cause the teeth to spread intraorally and become misaligned. Vertebral collapse can cause compression of spinal cord or spinal nerves, resulting in radiculopathy or paralysis. Vertebral involvement can also cause a vascular steal syndrome with paralysis. Surgery for fractured long bones is often complicated by excessive blood loss from these vascular lytic lesions.
Osteosarcoma may develop in long-standing lesions but is rare (< 1%). Sarcomatous change is suggested by a marked increase in bone pain, sudden rise in alkaline phosphatase, and appearance of a new lytic lesion.
Asymptomatic patients may require only clinical surveillance and no treatment. However, treatment should be considered for asymptomatic patients who have extensive involvement of the skull, long bones, or vertebrae. Patients must be monitored carefully before, during, and after treatment with clinical examinations and serial serum alkaline phosphatase determinations.
Bisphosphonates are used to treat patients with Paget disease. Zoledronic acid is the treatment of choice. Administered intravenously as a single 5 mg dose, it normalizes serum alkaline phosphatase in 89% of patients by 6 months and in 98% by 2 years. Oral bisphosphonate regimens include risedronate 30 mg/d for 2 months or alendronate 40 mg/d for 6 months. However, 2 years after a course of oral risedronate, only 57% of patients maintain a normal serum alkaline phosphatase. Therefore, with oral bisphosphonates, repeated courses of treatment are often necessary.
Patients frequently experience a paradoxical increase in pain at sites of disease soon after commencing bisphosphonate therapy; this is the “first dose effect” and the pain usually subsides with further treatment. Flu-like symptoms occur fairly frequently. Following intravenous zoledronic acid, patients frequently experience fever, fatigue, myalgia, bone pain, and ocular problems. Serious side effects are rare but include seizures, uveitis, and acute kidney disease. Hypocalcemia is common and may be severe, especially if intravenous bisphosphonates are given along with loop diuretics. Therefore, it is advisable to administer calcium and vitamin D supplements, especially during the first 2 weeks following treatment. Asthma may occur in aspirin-sensitive patients. To prevent esophageal complications, oral bisphosphonates should be taken with 8 oz of plain water only; they are relatively contraindicated in patients with a history of esophagitis, esophageal stricture, dysphagia, hiatal hernia, or achalasia.
The prognosis in general is good, but relapse can occur after an initial successful treatment with bisphosphonate. By 6.5 years after initial therapy, the recurrence rate is 12.5% after treatment with zolendronic acid and 62% after risedronate. Therefore, patients must be monitored long-term, measuring serum alkaline phosphatase at least yearly. In general, the prognosis is worse the earlier in life the disease starts. Fractures usually heal well. In the severe forms, marked deformity, intractable pain, and cardiac failure are found. These complications should become rare with prompt bisphosphonate treatment. Osteosarcoma that arises at sites of Paget disease results in a 2-year survival of only 25%.
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DISEASES OF THE ADRENAL CORTEX
ACUTE ADRENOCORTICAL INSUFFICIENCY (Adrenal Crisis)
ESSENTIALS OF DIAGNOSIS
Weakness, abdominal pain, fever, confusion, nausea, vomiting, and diarrhea.
Low blood pressure, dehydration; skin pigmentation may be increased.
Serum potassium high, sodium low, BUN high.
Cosyntropin (ACTH1–24) unable to stimulate an increase in serum cortisol to ≥ 20 mcg/dL.
Acute adrenal insufficiency is an emergency caused by insufficient cortisol. Crisis may occur in the course of treatment of chronic insufficiency, or it may be the presenting manifestation of adrenal insufficiency. Acute adrenal crisis is more commonly seen in primary adrenal insufficiency (Addison disease) than in disorders of the pituitary gland causing secondary adrenocortical hypofunction.
Adrenal crisis may occur in the following situations: (1) during stress, (eg, trauma, surgery, infection, hyperthyroidism, or prolonged fasting) in a patient with latent or treated adrenal insufficiency; (2) following sudden withdrawal of adrenocortical hormone in a patient with chronic insufficiency or in a patient with temporary insufficiency due to suppression by exogenous corticosteroids or megestrol; (3) following bilateral adrenalectomy or removal of a functioning adrenal tumor that had suppressed the other adrenal; (4) following sudden destruction of the pituitary gland (pituitary necrosis), or when thyroid hormone is given to a patient with hypoadrenalism; and (5) following injury to both adrenals by trauma, hemorrhage, anticoagulant therapy, thrombosis, infection or, rarely, metastatic carcinoma; (6) following administration of etomidate, which is used intravenously for rapid anesthesia induction or intubation.
The patient complains of headache, lassitude, nausea and vomiting, abdominal pain, and often diarrhea. Confusion or coma may be present. Fever may be 40.6 °C or more. The blood pressure is low. Recurrent hypoglycemia and reduced insulin requirements may present in patients with preexisting type 1 diabetes mellitus. Other signs may include cyanosis, dehydration, skin hyperpigmentation, and sparse axillary hair (if hypogonadism is also present). Meningococcemia may be associated with purpura and adrenal insufficiency secondary to adrenal infarction (Waterhouse–Friderichsen syndrome).
The eosinophil count may be high. Hyponatremia or hyperkalemia (or both) are usually present. Hypoglycemia is frequent. Hypercalcemia may be present. Blood, sputum, or urine culture may be positive if bacterial infection is the precipitating cause of the crisis.
The diagnosis is made by a simplified cosyntropin stimulation test, which is performed as follows: (1) Synthetic ACTH1–24 (cosyntropin), 0.25 mg, is given intramuscularly. (2) Serum is obtained for cortisol between 30 and 60 minutes after cosyntropin is administered. Normally, serum cortisol rises to at least 20 mcg/dL. For patients receiving corticosteroid treatment, hydrocortisone must not be given for at least 8 hours before the test. Other corticosteroids (eg, prednisone, dexamethasone) do not interfere with specific assays for cortisol.
If the patient has primary adrenal insufficiency, the plasma ACTH is markedly elevated, generally > 200 pg/mL (> 44 pmol/L).
Acute adrenal insufficiency must be distinguished from other causes of shock (eg, septic, hemorrhagic, cardiogenic). Hyperkalemia is also seen with gastrointestinal bleeding, rhabdomyolysis, hyperkalemic paralysis, and certain drugs (eg, angiotensin-converting enzyme [ACE] inhibitors, spironolactone). Hyponatremia is seen in many other conditions (eg, hypothyroidism, diuretic use, heart failure, cirrhosis, vomiting, diarrhea, severe illness, or major surgery). Acute adrenal insufficiency must be distinguished from an acute abdomen in which neutrophilia is the rule, whereas adrenal insufficiency is characterized by a relative lymphocytosis and eosinophilia.
More than 90% of serum cortisol is protein bound and low serum levels of binding proteins result in misleadingly low serum cortisol determinations by most assays. Nearly 40% of critically ill patients, with serum albumin < 2.5 g/dL (< 25 g/L), have low serum total cortisol levels but normal serum free cortisol or salivary cortisol levels and normal adrenal function.
If the diagnosis is suspected, draw a blood sample for cortisol determination and treat with hydrocortisone, 100–300 mg intravenously, and saline immediately, without waiting for the results. Thereafter, give hydrocortisone phosphate or hydrocortisone sodium succinate, 100 mg intravenously immediately, and continue intravenous infusions of 50–100 mg every 6 hours for the first day. Give the same amount every 8 hours on the second day and then adjust the dosage in view of the clinical picture.
Since bacterial infection frequently precipitates acute adrenal crisis, broad-spectrum antibiotics should be administered empirically while waiting for the results of initial cultures. The patient must be treated for electrolyte abnormalities, hypoglycemia, and dehydration.
When the patient is able to take food by mouth, give oral hydrocortisone, 10–20 mg every 6 hours, and reduce dosage to maintenance levels as needed. Most patients ultimately require hydrocortisone twice daily (am, 10–20 mg; pm, 5–10 mg). Mineralocorticoid therapy is not needed when large amounts of hydrocortisone are being given, but as the dose is reduced it is usually necessary to add fludrocortisone acetate, 0.05–0.2 mg orally daily. Some patients never require fludrocortisone or become edematous at doses of more than 0.05 mg once or twice weekly. Once the crisis has passed, the patient must be evaluated to assess the degree of permanent adrenal insufficiency and to establish the cause if possible.
Rapid treatment will usually be lifesaving. However, acute adrenal insufficiency is frequently unrecognized and untreated since its manifestations mimic more common conditions; lack of treatment leads to shock that is unresponsive to volume replacement and vasopressors, resulting in death.
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CHRONIC ADRENOCORTICAL INSUFFICIENCY (Addison Disease)
ESSENTIALS OF DIAGNOSIS
Weakness, fatigability, anorexia, weight loss; nausea and vomiting, diarrhea; abdominal pain, muscle and joint pains; amenorrhea.
Sparse axillary hair; increased skin pigmentation, especially of creases, pressure areas, and nipples.
Hypotension, small heart.
Serum sodium may be low; potassium, calcium, and BUN may be elevated; neutropenia, mild anemia, eosinophilia, and relative lymphocytosis may be present.
Plasma cortisol levels are low or fail to rise after administration of corticotropin.
Plasma ACTH level is elevated.
Addison disease refers to primary adrenal insufficiency caused by dysfunction or absence of the adrenal cortices. It is distinct from secondary adrenal insufficiency caused by deficient secretion of ACTH. (See Anterior Hypopituitarism.)
Addison disease is an uncommon disorder with a prevalence of about 140 per million and an annual incidence of about 4 per million in the United States. Addison disease is characterized by a chronic deficiency of cortisol. Serum ACTH levels are consequently elevated, causing pigmentation that ranges from none to strikingly dark. Patients with destruction of the adrenal cortices or with classic 21-hydroxylase deficiency also have mineralocorticoid deficiency with hyponatremia, volume depletion, and hyperkalemia. In contrast, mineralocorticoid deficiency is not present in patients with familial glucocorticoid deficiency and Allgrove syndrome (see below).
Autoimmune destruction of the adrenals is the most common cause of Addison disease in the United States (accounting for about 80% of spontaneous cases). With such autoimmunity, adrenal function decreases over several years as it progresses to overt adrenal insufficiency. It may occur alone or as part of a polyglandular autoimmune (PGA) syndrome. Type 1 PGA is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome and is caused by a defect in T cell-mediated immunity inherited as an autosomal recessive trait. Type 1 PGA usually presents in early childhood with mucocutaneous candidiasis, followed by hypoparathyroidism and dystrophy of the teeth and nails; Addison disease usually appears by age 15 years. Partial or late expression of the syndrome is common. A varied spectrum of associated diseases may be seen in adulthood, including hypogonadism, hypothyroidism, pernicious anemia, alopecia, vitiligo, hepatitis, malabsorption, and Sjögren syndrome.
Type 2 PGA usually presents in young adults age 20–40 years, usually women (female:male ratio is 3:1). The following conditions may be presentations of type 2 PGA: autoimmune adrenal insufficiency, type 1 diabetes mellitus, or autoimmune thyroid disease (usually hypothyroidism, sometimes hyperthyroidism). The combination of Addison disease and hypothyroidism is known as Schmidt syndrome. Patients may also have vitiligo, alopecia areata, Sjögren syndrome, or celiac disease. Type 2 PGA is also associated with autoimmune primary ovarian failure; testicular failure (5%); pernicious anemia (4%); and, rarely, autoimmune hypophysitis, encephalitis, or hypoparathyroidism (late-onset).
Tuberculosis as a leading cause of Addison disease is relatively rare in the United States but common where tuberculosis is more prevalent.
Bilateral adrenal hemorrhage may occur during sepsis, heparin-associated thrombocytopenia or anticoagulation, or with antiphospholipid antibody syndrome. It may occur in association with major surgery or trauma, presenting about 1 week later with pain, fever, and shock. It may also occur spontaneously and present with flank pain; MRI may show adrenal enlargement with increased T2-weighted imaging.
Adrenoleukodystrophy is an X-linked peroxisomal disorder causing accumulation of very long-chain fatty acids in the adrenal cortex, testes, brain, and spinal cord. It may present at any age and accounts for one-third of cases of Addison disease in boys. Aldosterone deficiency occurs in 9%. Hypogonadism is common. Psychiatric symptoms often include mania, psychosis, or cognitive impairment. Neurologic deterioration may be severe or mild (particularly in heterozygote women), mimics symptoms of multiple sclerosis, and can occur years after the onset of adrenal insufficiency.
Rare causes of adrenal insufficiency include lymphoma, metastatic carcinoma, coccidioidomycosis, histoplasmosis, cytomegalovirus infection (more frequent in patients with AIDS), syphilitic gummas, scleroderma, amyloidosis, and hemochromatosis.
Congenital adrenal insufficiency occurs in several conditions. Familial glucocorticoid deficiency is an autosomal recessive disease that is caused by mutations in the adrenal ACTH receptor (melanocortin 2 receptor, MC2R). It is characterized by isolated cortisol deficiency and ACTH resistance and may present with neonatal hypoglycemia, frequent infections, and dark skin pigmentation.Triple A (Allgrove) syndrome is caused by a mutation in the AAAS gene that encodes a protein known as ALADIN (alachrima, achalasia, adrenal insufficiency, neurologic disorder). It is characterized by variable expression of the following: adrenal ACTH resistance with cortisol deficiency, achalasia, alacrima, nasal voice, autonomic dysfunction, and neuromuscular disease of varying severity (hyperreflexia to spastic paraplegia). Cortisol deficiency usually presents in infancy but may not occur until the third decade of life. Congenital adrenal hypoplasia causes adrenal insufficiency due to absence of the adrenal cortex; patients may also have hypogonadotropic hypogonadism, myopathy, and high-frequency hearing loss.
Patients with hereditary defects in adrenal enzymes for cortisol synthesis develop congenital adrenal hyperplasia due to ACTH stimulation. The most common enzyme defect is P450c21 (21-hydroxylase deficiency). Patients with severely defective P450c21 enzymes (classic congenital adrenal hyperplasia) manifest a deficiency of mineralocorticoids (salt wasting) in addition to deficient cortisol and excessive androgens. Hypertension develops in about 60% of adult patients with classic congenital adrenal hyperplasia. Testicular adrenal rests can be found in 44% of men with the condition. Women with milder enzyme defects have adequate cortisol but develop hirsutism in adolescence or adulthood and are said to have “late-onset” congenital adrenal hyperplasia. (See Hirsutism section.) Patients with deficient P450c17 (17-hydroxylase deficiency) have varying degrees of adrenocortical deficiency with associated hypertension, hypokalemia, and primary hypogonadism.
Drugs that cause primary adrenal insufficiency include mitotane (for adrenocortical carcinoma) and abiraterone acetate (Zytiga), a P450c17 inhibitor used for prostate cancer.
Symptoms of adrenal insufficiency may include muscle weakness, fatigue, fever, anorexia, nausea, vomiting, weight loss, anxiety, and mental irritability. Patients usually have significant pain: arthralgias, myalgias, chest pain, abdominal pain, back pain, leg pain, or headache. Psychiatric symptoms include irritability and depression. Cerebral edema can cause headache, vomiting, gait disturbance, and intellectual dysfunction that may progress to coma. Hypotension, salt craving, dehydration, orthostasis and syncope can occur. Women may develop scant axillary and pubic hair and experience a lack of libido. Changes in skin pigmentation vary from none at all to dark diffuse tanning over nonexposed as well as exposed areas; hyperpigmentation is especially prominent over the knuckles, elbows, knees, posterior neck, palmar creases, and gingival mucosa. Nail beds may develop longitudinal pigmented bands. Nipples and areolas tend to darken. The skin in pressure areas such as the belt or brassiere lines and the buttocks also darkens. New scars are pigmented. Hypoglycemia may worsen the patient’s weakness and mental functioning, rarely leading to coma. Patients tend to be hypotensive and orthostatic; about 90% have systolic blood pressures under 110 mm Hg; blood pressure over 130 mm Hg is rare. Other findings may include a small heart, hyperplasia of lymphoid tissues. Some patients have associated vitiligo (10%). Manifestations of other autoimmune disease (see above) may be present.
Patients with adult-onset adrenoleukodystrophy may present with neuropsychiatric symptoms, sometimes without adrenal insufficiency.
The WBC count usually shows moderate neutropenia, lymphocytosis, and a total eosinophil count over 300/mcL. Among patients with chronic Addison disease, the serum sodium is usually low (90%) while the potassium is usually elevated (65%). Patients with diarrhea may not be hyperkalemic. Fasting blood glucose may be low. Hypercalcemia may be present. Young men with idiopathic Addison disease are screened for adrenoleukodystrophy by determining plasma very long-chain fatty acid levels; affected patients have high levels.
A plasma cortisol < 3 mcg/dL (< 83 nmol/L) at 8 am is diagnostic, especially if accompanied by simultaneous elevation of the plasma ACTH level > 200 pg/mL (> 44 pmol/L). The diagnosis is confirmed by a simplified cosyntropin stimulation test, which is performed as follows: (1) Synthetic ACTH1–24 (cosyntropin), 0.25 mg, is given intramuscularly. (2) Serum cortisol is obtained 45 minutes after cosyntropin is administered. Normally, serum cortisol rises to at least 20 mcg/dL. For patients receiving corticosteroid treatment, hydrocortisone must not be given for at least 8 hours before the test. Other corticosteroids (eg, prednisone, dexamethasone) do not interfere with specific assays for cortisol.
Serum DHEA levels are < 1000 ng/mL (< 350 nmol/L) in 100% of patients with Addison disease and a serum DHEA above 1000 ng/mL excludes the diagnosis. However, serum DHEA levels below 1000 ng/mL (< 350 nmol/L) are not helpful, since about 15% of the general population have such low DHEA levels, particularly children and elderly individuals.
Anti-adrenal antibodies are found in the serum in about 50% of cases of autoimmune Addison disease. The presence of serum antibodies to 21-hydroxylase help secure the diagnosis of autoimmune adrenal insufficiency. Antibodies to thyroid (45%) and other tissues may be present.
Salt-wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency is usually diagnosed at birth in females due to ambiguous genitalia. Males and patients with milder enzyme defects may present later. The diagnosis of adrenal insufficiency is made as above. The specific diagnosis requires elevated serum levels of 17-OH progesterone.
Elevated plasma renin activity (PRA) indicates the presence of depleted intravascular volume and the need for higher doses of fludrocortisone replacement. Serum epinephrine levels are low in patients with adrenal insufficiency, since these patients do not have the high local concentrations of cortisol that are required to induce the enzyme PNMT in adrenal medulla for the synthesis of epinephrine from norepinephrine.
When Addison disease is not clearly autoimmune, a chest radiograph is obtained to look for tuberculosis, fungal infection, or cancer as possible causes. CT scan of the abdomen will show small noncalcified adrenals in autoimmune Addison disease. The adrenals are enlarged in about 85% of cases due to metastatic or granulomatous disease. Calcification is noted in about 50% of cases of tuberculous Addison disease but is also seen with hemorrhage, fungal infection, pheochromocytoma, and melanoma.
Patients with secondary adrenal insufficiency (hypopituitarism) lack ACTH and have normal skin pigmentation, in contrast to patients with Addison disease who have elevated levels of ACTH that can increase skin pigmentation. Patients with ACTH deficiency have normal mineralocorticoid production and do not develop hyperkalemia. Addison disease should be considered in any patient with unexplained hypotension, but shock is usually caused by more common conditions such as gastrointestinal bleeding or sepsis. Hyponatremia or hyperkalemia may be seen in numerous other conditions (seeChapter 21). Drospirenone, the progestin component in certain oral contraceptives, may cause hyperkalemia.
Unexplained weight loss, weakness, and anorexia may be mistaken for occult cancer. Nausea, vomiting, diarrhea, and abdominal pain may be misdiagnosed as intrinsic gastrointestinal disease. The hyperpigmentation may be confused with that due to ethnic or racial factors. Weight loss may simulate anorexia nervosa or emotional stress. The neurologic manifestations of Allgrove syndrome and adrenoleukodystrophy (especially in women) may mimic multiple sclerosis. Hemochromatosis also enters the differential diagnosis of skin hyperpigmentation, but may truly be a cause of Addison disease. About 17% of patients with AIDS have symptoms of cortisol resistance. AIDS can also cause frank adrenal insufficiency.
Hyperkalemia can be caused by isolated hypoaldosteronism and is seen in various conditions. Hyporeninemic hypoaldosteronism can be caused by renal tubular acidosis type IV and is commonly seen with diabetic nephropathy, hypertensive nephrosclerosis, tubulointerstitial diseases, and AIDS (see Chapter 21). Hyperreninemic hypoaldosteronism can be seen in patients with myotonic dystrophy, aldosterone synthase deficiency, and congenital adrenal hyperplasia. Hyperkalemia, hypertension, and hypogonadism may present as delayed adolescence or in adulthood in some patients with congenital adrenal hyperplasia (CYP17 deficiency); cortisol deficiency is also usually present but may not be clinically evident.
Any of the complications of the underlying disease (eg, tuberculosis) are more likely to occur, and the patient is susceptible to intercurrent infections that may precipitate crisis. Associated autoimmune diseases are common (see above).
Patients with Addison disease must be thoroughly informed about their condition. All infections should be treated immediately and vigorously, with the dose of hydrocortisone increased appropriately (see below). Patients are advised to wear a medical alert bracelet or medal reading, “Adrenal insufficiency—takes hydrocortisone.”
Replacement therapy should include a combination of corticosteroids and mineralocorticoids. In mild cases, hydrocortisone alone may be adequate.
Hydrocortisone is the drug of choice. Most addisonian patients are well maintained on 15–30 mg of hydrocortisone orally daily in two divided doses, two-thirds in the morning and one-third in the late afternoon or early evening. Some patients respond better to prednisone in a dosage of about 2–4 mg orally in the morning and 1–2 mg in the evening. Adjustments in dosage are made according to the clinical response. A proper dose usually results in a normal WBC count differential.
The dose of corticosteroid should be raised in case of infection, trauma, surgery, stressful diagnostic procedures, or other forms of stress. The maximum hydrocortisone dose for severe stress is 50 mg intravenously or intramuscularly every 6 hours. Lower doses, oral or parenteral, are used for less severe stress. The dose is reduced back to normal as the stress subsides.
Fludrocortisone acetate has a potent sodium-retaining effect. The dosage is 0.05–0.3 mg orally daily or every other day. In the presence of postural hypotension, hyponatremia, or hyperkalemia, the dosage is increased. Similarly, in patients with fatigue, elevated PRA indicates the need for a higher replacement dose of fludrocortisone. If edema, hypokalemia, or hypertension ensues, the dose is decreased.
DHEA is given to some patients with adrenal insufficiency. In a double-blind clinical trial, patients taking DHEA 50 mg orally each morning experienced an improved sense of well-being, increased muscle mass, and a reversal in bone loss at the femoral neck. DHEA replacement did not improve fatigue, cognitive problems, or sexual dysfunction; however, its placebo effect may be significant in that regard. Older women who receive DHEA should be monitored for androgenic effects. Because over-the-counter preparations of DHEA have variable potencies, it is best to have the pharmacy formulate this with pharmaceutical-grade micronized DHEA.
The life expectancy of patients with Addison disease has been considered reasonably normal, as long as they are very compliant with taking their medications and are knowledgeable about their condition. However, a retrospective Swedish study of 1675 patients with Addison disease found an unexpected increase in all-cause mortality, mostly from cardiovascular disease, malignancy, and infectious causes. Associated conditions can pose additional health risks. For example, patients with adrenoleukodystrophy or Allgrove syndrome may suffer from neurologic disease. Patients with adrenal tuberculosis may have a serious systemic infection that requires treatment. Adrenal crisis can occur in patients who stop their medication or who experience stress such as infection, trauma, or surgery without appropriately higher doses of corticosteroids. Patients who take excessive doses of corticosteroid replacement can develop Cushing syndrome, which imposes its own risks.
Many patients with treated Addison disease complain of chronic low-grade fatigue.
Many patients with Addison disease do not feel entirely normal, despite glucocorticoid and mineralocorticoid replacement. This may be due, in part, to the inadequacy of oral replacement to duplicate cortisol’s normal circadian rhythm. Also, patients with Addison disease are deficient in epinephrine, but replacement epinephrine is not available. Fatigue may also be an indication of suboptimal dosing of medication, electrolyte imbalance, or concurrent problems such as hypothyroidism or diabetes mellitus. However, most patients with Addison disease are able to live fully active lives.
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CUSHING SYNDROME (Hypercortisolism)
ESSENTIALS OF DIAGNOSIS
Central obesity, muscle wasting, thin skin, hirsutism, purple striae.
Osteoporosis, hypertension, poor wound healing.
Hyperglycemia, glycosuria, leukocytosis, lymphocytopenia, hypokalemia.
Elevated serum cortisol and urinary free cortisol. Lack of normal suppression by dexamethasone.
The term Cushing “syndrome” refers to the manifestations of excessive corticosteroids, commonly due to supraphysiologic doses of corticosteroid drugs and rarely due to spontaneous production of excessive corticosteroids by the adrenal cortex. Cases of spontaneous Cushing syndrome are rare (2.6 new cases yearly per million population) and have several possible causes.
About 40% of cases are due to Cushing “disease,” by which is meant the manifestations of hypercortisolism due to ACTH hypersecretion by the pituitary. Cushing disease is caused by a benign pituitary adenoma that is typically very small (< 5 mm) and usually located in the anterior pituitary (98%) or in the posterior pituitary (2%). It is at least three times more frequent in women than men. Excessive ingestion of gamma-hydroxybutyric acid (GHB, Xyrem) can also induce ACTH-dependent Cushing syndrome that resolves after the drug is stopped.
About 10% of cases are due to nonpituitary ACTH-secreting neoplasms (eg, small cell lung carcinoma), which produce excessive amounts of ectopic ACTH. Hypokalemia and hyperpigmentation are commonly found in this group.
About 15% of cases are due to ACTH from a source that cannot be initially located.
About 30% of cases are due to excessive autonomous secretion of cortisol by the adrenals—independently of ACTH, serum levels of which are usually low. Most such cases are due to a unilateral adrenal tumor. Benign adrenal adenomas are generally small and produce mostly cortisol; adrenocortical carcinomas are usually large when discovered and can produce excessive cortisol as well as androgens, with resultant hirsutism and virilization. ACTH-independent macronodular adrenal hyperplasia can also produce hypercortisolism due to the adrenal cortex cells’ abnormal stimulation by hormones such as catecholamines, arginine vasopressin, serotonin, hCG/LH, or gastric inhibitory polypeptide; in the latter case, hypercortisolism may be intermittent and food dependent and serum ACTH may not be completely suppressed. Pigmented bilateral adrenal macronodular adrenal hyperplasia is a rare cause of Cushing syndrome in children and young adults; it may be an isolated condition or part of the Carney complex.
Patients with Cushing syndrome usually have central obesity with a plethoric “moon face,” “buffalo hump,” supraclavicular fat pads, protuberant abdomen, and thin extremities. Muscle atrophy causes weakness, with difficulty standing up from a seated position or climbing stairs. Patients may also experience oligomenorrhea or amenorrhea (or erectile dysfunction in the male), backache, headache, hypertension, osteoporosis, avascular necrosis of bone, acne, and superficial skin infections. Patients may have thirst and polyuria (with or without glycosuria), renal calculi, glaucoma, purple striae (especially around the thighs, breasts, and abdomen), and easy bruisability. Unusual bacterial or fungal infections are common. Wound healing is impaired. Mental symptoms may range from diminished ability to concentrate to increased lability of mood to frank psychosis. Patients are susceptible to opportunistic infections.
Glucose tolerance is impaired as a result of insulin resistance. Polyuria is present as a result of increased free water clearance; diabetes mellitus with glycosuria may worsen it. Patients with Cushing syndrome often have leukocytosis with relative granulocytosis and lymphopenia. Hypokalemia may be present, particularly in cases of ectopic ACTH secretion.
Tests for Hypercortisolism
The easiest screening test for Cushing syndrome is the dexamethasone suppression test: dexamethasone 1 mg is given orally at 11 pm and serum is collected for cortisol determination at about 8 am the next morning; a cortisol level < 5 mcg/dL (< 135 nmol/L, fluorometric assay) or < 1.8 mcg/dL (< 49 nmol/L, high-performance liquid chromatography [HPLC] assay) excludes Cushing syndrome with some certainty. However, 8% of established patients with pituitary Cushing disease have dexamethasone-suppressed cortisol levels < 2 mcg/dL. Therefore, when other clinical criteria suggest hypercortisolism, further evaluation is warranted even in the face of normal dexamethasone-suppressed serum cortisol. Antiseizure drugs (eg, phenytoin, phenobarbital, primidone) and rifampin accelerate the metabolism of dexamethasone, causing a lack of cortisol suppression by dexamethasone. Estrogens—during pregnancy or as oral contraceptives or ERT—may also cause lack of dexamethasone suppressibility.
Patients with an abnormal dexamethasone suppression test require further investigation, which includes a 24-hour urine collection for free cortisol and creatinine. An abnormally high 24-hour urine free cortisol (or free cortisol to creatinine ratio of > 95 mcg cortisol/g creatinine) helps confirm hypercortisolism. A misleadingly high urine free cortisol excretion occurs with high fluid intake. In pregnancy, urine free cortisol is increased, while 17-hydroxycorticosteroids remain normal and diurnal variability of serum cortisol is normal. Carbamazepine and fenofibrate cause false elevations of urine free cortisol when determined by HPLC.
A midnight serum cortisol level > 7.5 mcg/dL is indicative of Cushing syndrome and distinguishes it from other conditions associated with a high urine free cortisol (pseudo-Cushing states). Requirements for this test include being in the same time zone for at least 3 days, being without food for at least 3 hours, and having an indwelling intravenous line established in advance for the blood draw.
Late-night salivary cortisol assays are useful due to the inconvenience of obtaining a midnight blood specimen for serum cortisol. Assays are available that use liquid chromatography-tandem mass spectrometry. Midnight salivary cortisol levels are normally < 0.15 mcg/dL (4.0 nmol/L). Midnight salivary cortisol levels that are consistently > 0.25 mcg/dL (7.0 nmol/L) are considered very abnormal. The late-night salivary cortisol test has a high sensitivity and specificity for Cushing syndrome, but false-positive and false-negative tests have occurred.
Interestingly, hypercortisolism without Cushing syndrome can occur in several conditions, such as severe depression, anorexia nervosa, alcoholism, and familial cortisol resistance.
Finding the Cause of Hypercortisolism
Once hypercortisolism is confirmed, a plasma or serum ACTH is obtained. It must be collected properly in a plastic tube on ice and processed quickly by a laboratory with a reliable, sensitive assay. A level of ACTH below 20 pg/mL (< 4.4 pmol/L) indicates a probable adrenal tumor, whereas higher levels are produced by pituitary or ectopic ACTH-secreting tumors.
In ACTH-independent Cushing syndrome, CT of the adrenals usually detects a mass lesion. Most such lesions are benign adrenal adenomas, but an adrenal carcinoma is suspected in the following circumstances: (1) diameter ≥ 4 cm; (2) nodule growth; or (3) atypical imaging: density on noncontrast CT > 10 Hounsfield units (HU) or CT contrast washout ≥ 60% or relative contrast washout ≥ 40% at 15 minutes after intravenous administration.
In ACTH-dependent Cushing syndrome, MRI of the pituitary demonstrates a pituitary lesion in about 50% of cases. Premature cerebral atrophy is often noted. When the pituitary MRI is normal or shows a tiny (< 5 mm diameter) irregularity that may be incidental, selective catheterization of the inferior petrosal sinus veins draining the pituitary is performed. ACTH levels in the inferior petrosal sinus that are more than twice the simultaneous peripheral venous ACTH levels are indicative of pituitary Cushing disease. Inferior petrosal sinus sampling is also done during CRH administration, which ordinarily causes the ACTH levels in the inferior petrosal sinus to be over three times the peripheral ACTH level when the pituitary is the source of ACTH.
When inferior petrosal sinus ACTH concentrations are not above the requisite levels, a search for an ectopic source of ACTH is undertaken. Location of ectopic sources of ACTH commences with CT scanning of the chest and abdomen, with special attention to the lungs (for carcinoid or small cell carcinomas), the thymus, the pancreas, and the adrenals. In patients with ACTH-dependent Cushing syndrome, chest masses should not be assumed to be the source of ACTH, since opportunistic infections are common, so it is prudent to biopsy a chest mass to confirm the pathologic diagnosis prior to resection.
CT scanning fails to detect the source of ACTH in about 40% of patients with ectopic ACTH secretion.111 In-octreotide (OCT, somatostatin receptor scintigraphy) scanning is also useful in detecting occult tumors. A low-dose scan with 6 mCi OCT is used first; a high-dose scan with 12 mCi OCT may be used if the low-dose scan gives equivocal results. 18FDG-PET scanning is not usually helpful. Some ectopic ACTH-secreting tumors elude discovery, necessitating bilateral adrenalectomy. The ectopic source of ACTH should continue to be sought, since it may become detectable by OCT or CT scanning at a later date.
In non-ACTH-dependent Cushing syndrome, a CT scan of the adrenals can localize the adrenal tumor in most cases.
Alcoholic patients can have hypercortisolism and many clinical manifestations of Cushing syndrome. Pregnant women have elevated serum ACTH levels, increased urine free cortisol, and high serum cortisol levels due to high serum levels of cortisol-binding globulin. Critically ill patients frequently have hypercortisolism, usually with suppression of serum ACTH. Regular use of the “party drug” gamma hydroxybutyrate (GHB, sodium oxybate) has been reported to cause reversible ACTH-dependent Cushing syndrome. Depressed patients also have hypercortisolism that can be nearly impossible to distinguish biochemically from Cushing syndrome but without clinical signs of Cushing syndrome. Cushing syndrome can be misdiagnosed as anorexia nervosa (and vice versa) owing to the muscle wasting and extraordinarily high urine free cortisol levels found in anorexia. Patients with severe obesity frequently have an abnormal dexamethasone suppression test, but the urine free cortisol is usually normal, as is diurnal variation of serum cortisol. Patients with familial cortisol resistance have hyperandrogenism, hypertension, and hypercortisolism without actual Cushing syndrome.
Some adolescents develop violaceous striae on the abdomen, back, and breasts; these are known as “striae distensae” and are not indicative of Cushing syndrome. Patients with familial partial lipodystrophy type I develop central obesity and moon facies, along with thin extremities due to atrophy of subcutaneous fat. However, these patients’ muscles are strong and may be hypertrophic, distinguishing this condition from Cushing syndrome. Patients receiving antiretroviral therapy for HIV-1 infection frequently develop partial lipodystrophy with thin extremities and central obesity with a dorsocervical fat pad (“buffalo hump”) that may mimic Cushing syndrome.
Adrenal nodules are discovered incidentally on up to 4% of abdominal CT or MRI scans obtained for other reasons; they have been dubbed “adrenal incidentalomas.” It is always necessary to determine whether such masses are malignant or secretory. Although the overwhelming majority of adrenal incidentalomas are benign adrenal adenomas, the differential diagnosis includes adrenal carcinoma, pheochromocytoma, metastases, lymphoma, myelolipoma, infection, and cysts. When an adrenal incidentaloma > 4 cm in diameter is detected in a patient without a history of malignancy, it should be resected, unless it is an unmistakably benign myelolipoma, hemorrhage, or adrenal cyst. Masses 3–4 cm in diameter may be resected if they appear suspicious. Smaller adrenal incidentalomas are usually observed. A noncontrast CT scan can determine the density of the mass; adrenal incidentalomas with a density < 10 Hounsfield units (HU) on CT are unlikely to be a pheochromocytoma or metastasis. An adrenal intravenous contrast “washout” CT scan is obtained; the density of the adrenal incidentaloma in HU is calculated 60 seconds after contrast and again 15 minutes after contrast; a reduction (washout) of ≥ 40% is consistent with a benign adrenal adenoma. However, such testing is never absolutely accurate; so if the adrenal incidentaloma is not resected, a follow-up CT of the adrenals in 6–12 months is recommended to look for growth.
All patients with an adrenal nodule require a clinical assessment for Cushing syndrome and hyperaldosteronism. In particular, patients with hypertension or any manifestations of Cushing syndrome require an appropriate biochemical evaluation. All (even normotensive) patients with an adrenal incidentaloma require testing for pheochromocytoma with plasma fractionated free metanephrines (see Pheochromocytoma).
Cushing disease is best treated by transsphenoidal selective resection of the pituitary adenoma. With an experienced pituitary neurosurgeon, reported remission rates range from 65% to 90%. After successful pituitary surgery, the rest of the pituitary usually returns to normal function; however, the pituitary corticotrophs remain suppressed and require 6–36 months to recover normal function. Hydrocortisone or prednisone replacement therapy is necessary in the meantime. When Cushing disease persists or recurs after pituitary surgery, bilateral laparoscopic adrenalectomy is usually the best treatment option.
Radiation therapy is an option for patients with ACTH-secreting pituitary tumors that persist or recur after pituitary surgery. Stereotactic pituitary radiosurgery (gamma knife or cyberknife), normalizes urine free cortisol in two-thirds of patients within 12 months compared with a 23% cure rate with conventional radiation therapy. Pituitary radiosurgery can also be used to treat Nelson syndrome, the progressive enlargement of ACTH-secreting pituitary tumors following bilateral adrenalectomy.
Medical therapy is not usually the best option for patients with persistent or recurrent Cushing disease and must be used indefinitely. Cabergoline, 0.5–3.5 mg orally twice weekly, was successful in 40% of patients in one small study. Pasireotide, a multireceptor-targeting somatostatin analog, is another potential treatment for refractory ACTH-secreting pituitary tumors causing Cushing disease or Nelson syndrome. Pasireotide (600–900 mcg subcutaneously twice daily) normalizes the urine free cortisol in at least 17% of patients with Cushing disease. Ketoconazole inhibits adrenal steroidogenesis and is another treatment option when given in doses of about 200 mg orally every 6 hours; however, it is marginally effective and can cause liver toxicity. Mifepristone is a glucocorticoid receptor antagonist that is given orally in doses of 300–1200 mg daily. Side effects are frequent and include nausea, headache, fatigue, hypokalemia, abortion, and adrenal insufficiency.
Benign adrenal adenomas may be resected laparoscopically if they are < 6 cm diameter. Postoperatively, the contralateral adrenal’s cortisol secretion is deficient due to ACTH suppression, so postoperative corticosteroid replacement is required until recovery occurs.
Adrenocortical carcinomas can usually be distinguished from benign adrenal adenomas since they are usually larger (average 11 cm diameter) and many have metastases that are visible on preoperative scans. However, some adrenal carcinomas are smaller and the histopathologic diagnosis can be difficult. Some adrenal carcinomas have microscopic metastases that can only be inferred from the presence of detectable cortisol levels following removal of the primary adrenal tumor. The ENSAT staging system is used: stage 1 is a localized tumor ≤ 5 cm; stage 2 is a localized tumor > 5 cm; stage 3, tumor with local metastases; stage 4, tumor with distant metastases.
Most patients with adrenal carcinoma should be treated postoperatively with mitotane for a course of 2–5 years, since it appears to improve prognosis (see below). Mitotane is given, beginning with 0.5 g twice daily with meals and increasing to 1 g twice daily within 2 weeks. The doses of mitotane are adjusted every 2–3 weeks ideally to reach serum levels of 14–20 mcg/mL; however, only about half the patients can tolerate mitotane levels above 14 mcg/mL. Mitotane side effects include central nervous system depression, lethargy, hypogonadism, hypercholesterolemia, hypocalcemia, hepatotoxicity, leukopenia, hypertension, nausea, rash, and TSH suppression with hypothyroidism. Mitotane also induces the hepatic enzyme CYP3A4, which accelerates the metabolism of sunitinib, cortisol, calcium channel blockers, benzodiazepines, some statins, some opioids, and some macrolide antibiotics. Mitotane often causes primary adrenal insufficiency. Replacement hydrocortisone or prednisone should be started when mitotane doses reach 2 g daily. The replacement dose of hydrocortisone starts at 15 mg in the morning and 10 mg in the afternoon, but must often be doubled or tripled because mitotane increases cortisol metabolism and cortisol binding globulin levels; the latter can artifactually raise serum cortisol levels.
Ketoconazole, metyrapone, or mifepristone can also be used to help treat hypercortisolism in unresectable adrenal carcinoma. Other chemotherapy regimens have been used; for example, the combination of cixutumumab and temsirolimus produced stable disease in 11 of 26 patients in one small study.
Ectopic ACTH-secreting tumors should be located, when possible, and surgically resected. If that cannot be done, laparoscopic bilateral adrenalectomy is usually recommended. Medical treatment with a combination of mitotane (3–5 g/24 h), ketoconazole (0.4–1.2 g/24 h), and metyrapone (3–4.5 g/24 h) often suppresses the hypercortisolism. Octreotide LAR, 20–40 mg injected intramuscularly every 28 days, suppresses ACTH secretion in about one-third of such cases. Pasireotide, a newer somatostatin analogue, may prove more effective. Potassium-sparing diuretics are often helpful.
Patients who are successfully treated for Cushing syndrome typically develop “cortisol withdrawal syndrome,” even when given replacement corticosteroids for adrenal insufficiency. Manifestations can include hypotension, nausea, fatigue, arthralgias, myalgias, pruritus, and flaking skin. Increasing the hydrocortisone replacement to 30 mg orally twice daily can improve these symptoms; the dosage is then reduced slowly as tolerated. Patients with Cushing syndrome are prone to develop osteoporosis. Bone densitometry is recommended for all patients and treatment is commenced for patients with osteoporosis. (See Osteoporosis.)
The manifestations of Cushing syndrome regress with time, but patients are often left with residual mild cognitive impairment, muscle weakness, osteoporosis, and sequelae from vertebral fractures. Younger patients have a better chance for recovery and children with short stature may have catch-up growth following cure.
Patients with Cushing syndrome from a benign adrenal adenoma experience a 5-year survival of 95% and a 10-year survival of 90%, following a successful adrenalectomy. Patients with Cushing disease from a pituitary adenoma experience a similar survival if their pituitary surgery is successful, which can be predicted if the postoperative nonsuppressed serum cortisol is < 2 mcg/dL. Following successful treatment, overall mortality remains particularly higher for patients with older age at diagnosis, higher preoperative ACTH concentrations, and longer duration of hypercortisolism.
Transsphenoidal surgery incurs a failure rate of about 10–20%, often due to the adenoma’s ectopic position or invasion of the cavernous sinus. Those patients who have a complete remission after transsphenoidal surgery have about a 15–20% chance of recurrence over the next 10 years. Patients with failed pituitary surgery may require pituitary radiation therapy, which has its own morbidity. Laparoscopic bilateral adrenalectomy may be required; recurrence of hypercortisolism may occur as a result of growth of an adrenal remnant stimulated by high levels of ACTH. The prognosis for patients with ectopic ACTH-producing tumors depends on the aggressiveness and stage of the particular tumor. Patients with ACTH of unknown source have a 5-year survival rate of 65% and a 10-year survival rate of 55%.
In patients with adrenocortical carcinoma, the 5-year survival rates of treated patients has correlated with the ENSAT stage. For stage 1, the 5-year survival was 81%; for stage 2, 61%; for stage 3, 50%; and for stage 4, 13%. In patients with stage 1 or 2 disease, long-term survival does occur. However, despite apparent complete resection in stage 1, 2 or 3 tumors, visible metastases develop in about 40% of patients within 2 years. Adjuvant therapy with mitotane appears to improve the prognosis. Patients with stage 4 disease at the time of surgery have a poorer prognosis, but debulking surgery and therapy with mitotane may be beneficial.
Cushing syndrome, if untreated, produces serious morbidity and even death. The patient may suffer from the complications of hypertension or diabetes mellitus. Susceptibility to infections is increased. Compression fractures of the osteoporotic spine and aseptic necrosis of the femoral head may cause marked disability. Nephrolithiasis and psychosis may occur. Following bilateral adrenalectomy for Cushing disease, a pituitary adenoma may enlarge progressively (Nelson syndrome), causing local destruction (eg, visual field impairment, cranial nerve palsy) and hyperpigmentation.
When to Refer
When to Admit
Arnaldi G et al. Advances in the epidemiology, pathogenesis, and management of Cushing’s syndrome complications. J Endocrinol Invest. 2012 Apr;35(4):434–48. [PMID: 22652826]
Bertagna X et al. Approach to the Cushing’s disease patient with persistent/recurrent hypercortisolism after pituitary surgery. J Clin Endocrinol Metab. 2013 Apr;98(4):1307–18. [PMID: 23564942]
Graversen D et al. Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur J Intern Med. 2012 Apr;23(3):278–82. [PMID: 22385888]
Kamenický P et al. Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab. 2011 Sep;96(9):2796–804. [PMID: 21752886]
Terzolo M et al. Subclinical Cushing’s syndrome: definition and management. Clin Endocrinol (Oxf). 2012 Jan;76(1):12–8. [PMID: 21988204]
Tritos NA et al. Advances in medical therapies for Cushing’s syndrome. Discov Med. 2012 Feb;13(69):171–9. [PMID: 22369976]
Valassi E et al. Clinical consequences of Cushing’s syndrome. Pituitary. 2012 Sep;15(3):319–29. [PMID: 22527617]
ESSENTIALS OF DIAGNOSIS
Hypertension that may be severe or drug-resistant.
Hypokalemia (in minority of patients) may cause polyuria, polydipsia, muscle weakness.
Elevated plasma and urine aldosterone levels and low plasma renin level.
Primary aldosteronism (hyperaldosteronism) causes hypertension by an inappropriately high aldosterone secretion that does not suppress adequately with sodium loading. Primary aldosteronism is believed to account for 8% of all cases of hypertension and 20% of cases of resistant hypertension. It may be difficult to distinguish primary aldosteronism from cases of low renin essential hypertension, with which it may overlap. Patients of all ages may be affected, but the peak incidence is between 30 years and 60 years. Excessive aldosterone production increases sodium retention and suppresses plasma renin. It increases renal potassium excretion, which can lead to hypokalemia. Cardiovascular events are more prevalent in patients with aldosteronism (35%) than in those with essential hypertension (11%). Primary aldosteronism may be caused by an aldosterone-producing adrenal adenoma (Conn syndrome), 40% of which have been found to have somatic mutations in a gene involved with the potassium channel. Primary aldosteronism is also commonly caused by unilateral or bilateral adrenal hyperplasia. Bilateral aldosteronism may be corticosteroid suppressible, due to an autosomal-dominant genetic defect allowing ACTH stimulation of aldosterone production. Hyperaldosteronism may rarely be due to a malignant ovarian tumor.
Hyperaldosteronism is the most common cause of refractory hypertension in youths and middle-aged adults. Patients have hypertension that is typically moderate but may be severe. Some patients have only diastolic hypertension, without other symptoms and signs. Edema is rarely seen in primary aldosteronism. About 37% of patients have hypokalemia and may consequently have symptoms of muscular weakness (at times with paralysis simulating periodic paralysis), paresthesias with frank tetany, headache, polyuria, and polydipsia.
About 20% of hypertensive patients have a low PRA, and a significant portion of these patients have primary aldosteronism. Initial screening can also include both aldosterone and plasma renin activity to determine an aldosterone to renin ratio (see below).
Plasma potassium should also be determined in hypertensive individuals. However, hypokalemia, once thought to be the hallmark of hyperaldosteronism, is present in only 37% of affected patients: 50% of those with an adrenal adenoma and 17% of those with adrenal hyperplasia. Proper phlebotomy technique is important to avoid spurious increases in potassium. The blood should be drawn slowly with a syringe and needle (rather than a vacutainer) at least 5 seconds after tourniquet release and without fist clenching. Plasma potassium, rather than the routine serum potassium, should be measured in cases of unexpected hyperkalemia, with the separation of plasma from cells within 30 minutes of collection. Besides hypokalemia, many patients with primary aldosteronism have metabolic alkalosis with an elevated serum bicarbonate (HCO–3) concentration.
Testing for primary aldosteronism should be done for all hypertensive patients with hypokalemia, whether spontaneous or diuretic induced. But since only a minority of affected patients have hypokalemia, testing should also be considered for (even normokalemic) hypertensive patients with (1) treatment-resistant hypertension (despite three drugs); (2) severe hypertension: > 160 mm Hg systolic or > 100 mm Hg diastolic; (3) early-onset hypertension; (4) low-renin hypertension; (5) hypertension with an adrenal mass; (6) hypertension with a family history of early-onset hypertension or cerebrovascular accident before age 40 years; and (7) a first-degree relative who has aldosteronism.
For a patient to be properly tested for primary aldosteronism, certain antihypertensive medications should ideally be held. Diuretics should be discontinued for 3 weeks. Dihydropyridine calcium channel blockers can normalize aldosterone secretion, thus interfering with the diagnosis. Beta-blockers suppress PRA in patients with essential hypertension. Antihypertensive medications that have minimal effects on the plasma aldosterone:renin ratio include ACE inhibitors, alpha-blockers, verapamil, hydralazine, prazosin, doxazosin, and terazosin. However, it may be impractical to hold or change antihypertensive medicines; in such cases, testing should proceed.
During the testing period, the patient should have an unrestricted high sodium intake. The patient should be out of bed for at least 2 hours and seated for 5–15 minutes before the blood draw, which should preferably be obtained between 8 AM and 10 AM. Renin is measured as either PRA or direct renin concentration. Serum aldosterone should ideally be measured with a tandem mass spectrometry assay.
For patients who have not been receiving diuretics for at least 3 weeks, a plasma renin activity (PRA) that is normal or elevated makes primary aldosteronism very unlikely. However, a low PRA alone cannot establish the diagnosis of primary aldosteronism, since it occurs in many patients with essential hypertension.
An aldosterone:renin ratio is a sensitive screening test. Serum aldosterone (ng/dL):PRA (ng/mL/h) ratios < 24 exclude primary aldosteronism, whereas ratios between 24 and 67 are suspicious and ratios > 67 are very suggestive of primary aldosteronism. Such elevated ratios are not diagnostic; rather, they indicate the need to document increased aldosterone secretion with a 24-hour urine collection. Another problem with the aldosterone:renin ratio is the use of different units and measurements. For aldosterone, 1 ng/dL converts to 27.7 pmol/L. For renin, a PRA of 1 ng/mL/h (12.8 pmol/L/min) converts to a direct renin concentration of 5.2 ng/L (8.2 mU/L).
When the aldosterone:renin ratio is high, a 24-hour urine collection is assayed for aldosterone, free cortisol, and creatinine. A low PRA (< 5 mcg/L/h) with a urine aldosterone > 20 mcg/24 h (> 555 pmol/L) indicates primary aldosteronism.
All patients with biochemically confirmed primary aldosteronism require a thin-section CT scan of the adrenals to screen for a rare adrenal carcinoma. In the absence of a large adrenal carcinoma, adrenal CT scanning cannot reliably distinguish unilateral from bilateral aldosterone excess, having a sensitivity of 78% and a specificity of 78% for unilateral aldosteronism. Therefore, the decision to perform a unilateral adrenalectomy should not be based solely on an adrenal CT scan. However, since CT scanning and laboratory testing are often inconclusive, adrenal vein sampling is often required.
Patients with primary aldosteronism (whose adrenal CT scan shows normal adrenals or a small nodule) should be considered for an empiric trial of medical therapy with spironolactone or eplerenone (see below). If medical therapy is ineffective or if surgery is desired for an apparent adrenal adenoma, further evaluation for surgical candidacy should be done with further laboratory testing and adrenal vein sampling to assist in distinguishing a unilateral aldosteronoma from bilateral adrenal hyperplasia (see below).
Plasma may be assayed for 18-hydroxycorticosterone; a level > 100 ng/dL (> 2750 pmol/L) is seen with adrenal aldosteronomas, whereas levels < 100 ng/dL (< 2750 pmol/L) are nondiagnostic. In addition, a posture stimulation test may be performed, but this requires overnight hospitalization. The test is performed by drawing blood for aldosterone at 8 AM while the patient is supine after overnight recumbency and again after the patient is upright for 4 hours. Patients with a unilateral adrenal adenoma usually have a baseline plasma aldosterone level > 20 ng/dL (> 550 pmol/L) that does not rise. Patients with bilateral adrenal hyperplasia typically have a baseline plasma aldosterone level < 20 ng/dL (< 550 pmol/L) that rises after 4 hours of upright posture. Exceptions occur and the accuracy of the posture stimulation test is about 85%.
Bilateral selective adrenal vein sampling is recommended to determine whether hypersecretion of aldosterone is lateralized and thereby treatable by unilateral adrenalectomy. Unfortunately, the procedure is invasive, expensive, not widely available, and often unsuccessful. The procedure (and surgery) may not be required for patients whose blood pressure is well controlled with spironolactone or eplerenone. It is indicated only if surgery is contemplated to direct the surgeon to the correct adrenal gland. Adrenal vein sampling is probably not required in patients who have a classic adrenal adenoma (Conn syndrome), which is characterized by hypokalemia and a unilateral adrenal adenoma ≥ 10 mm diameter on CT, and who have an estimated glomerular filtration rate ≥ 100 mL/min. It is most useful for patients who are not hypokalemic, who are over age 40 years, or who have an adrenal adenoma < 1 cm diameter. It is difficult to catheterize the right adrenal vein. Therefore, the venous samples are assayed for both aldosterone and cortisol during a cosyntropin (ACTH1–24) infusion to be sure that the sampling has included both adrenal veins. The procedure has a sensitivity of 95% and a specificity of 100% but only when performed by an experienced radiologist. The complication rate is 2.5%. Risks can be minimized if the radiologist avoids adrenal venography and limits the use of contrast.
The differential diagnosis of primary aldosteronism includes other causes of hypokalemia (see Chapter 21) in patients with essential hypertension, especially diuretic therapy. Chronic depletion of intravascular volume stimulates renin secretion and secondary hyperaldosteronism.
Real (black) licorice (derived from anise) or anise-flavored drinks (sambuca, pastis) contain glycyrrhizinic acid, which has a metabolite that inhibits the enzyme that normally inactivates cortisol in the renal tubule. More renal tubular cortisol activates aldosterone receptors, increasing the renal tubular absorption of sodium and excretion of potassium, thereby causing hypertension. Oral contraceptives may increase aldosterone secretion in some patients. Renal vascular disease can cause severe hypertension with hypokalemia but PRA is high. Excessive adrenal secretion of other corticosteroids (besides aldosterone), certain congenital adrenal enzyme disorders, and primary cortisol resistance may also cause hypertension with hypokalemia. The differential diagnosis also includes Liddle syndrome, an autosomal dominant cause of hypertension and hypokalemia resulting from excessive sodium absorption from the renal tubule; renin and aldosterone levels are low.
Cardiovascular complications occur more frequently in primary aldosteronism than in idiopathic hypertension. Following unilateral adrenalectomy for Conn syndrome, suppression of the contralateral adrenal may result in temporary postoperative hypoaldosteronism, characterized by hyperkalemia and hypotension.
Conn syndrome (unilateral aldosterone-secreting adrenal adenoma) is treated by laparoscopic adrenalectomy, though long-term therapy with spironolactone or eplerenone is an option. Bilateral adrenal hyperplasia is best treated with spironolactone or eplerenone. Spironolactone also has antiandrogen activity and frequently causes breast tenderness, gynecomastia, or reduced libido; it is given at initial doses of 12.5–25 mg orally once daily; the dose may be titrated upward to 200 mg daily. Spironolactone is contraindicated in pregnancy and reproductive-age women are cautioned to use contraception during therapy. Eplerenone is becoming favored for men, since it does not have antiandrogen effects; however, it has a short half-life and must be taken orally twice daily in doses of 25–50 mg. Hyperaldosteronism during pregnancy can cause resistant hypertension; amiloride (10–15 mg orally daily) is effective and the preferred medication, since spironolactone is contraindicated in pregnancy. Blood pressure must be monitored daily when beginning these anti-mineralocorticoid medications; significant drops in blood pressure have occurred when these drugs are added to other antihypertensives. Other antihypertensive drugs may also be required. Glucocorticoid-remediable aldosteronism is very rare but may respond well to suppression with low-dose dexamethasone.
The hypertension is reversible in about two-thirds of cases but persists or returns despite surgery in the remainder. The prognosis is much improved by early diagnosis and treatment. Only 2% of aldosterone-secreting adrenal tumors are malignant.
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PHEOCHROMOCYTOMA & PARAGANGLIOMA
ESSENTIALS OF DIAGNOSIS
“Attacks” of headache, perspiration, palpitations, anxiety. Multisystem crisis.
Hypertension, frequently sustained but often paroxysmal, especially during surgery or delivery.
Elevated urinary plasma free metanephrines. Normal serum T4 and TSH.
Frequent germline mutations.
Both pheochromocytomas and non–head-neck paragangliomas are tumors of the sympathetic nervous system. Pheochromocytomas arise from the adrenal medulla and usually secrete both epinephrine and norepinephrine. Paragangliomas (“extra-adrenal pheochromocytomas”) arise from sympathetic paraganglia, often metastasize, and secrete norepinephrine or are nonsecretory. Excessive levels of norepinephrine or neuropeptide Y cause hypertension, while epinephrine causes tachyarrhythmias. These tumors may be located in either or both adrenals or anywhere along the sympathetic nervous chain, and sometimes in the mediastinum, heart, or bladder.
These tumors are deceptive and deadly. Although they usually produce hypertension, they account for < 0.4% of hypertension cases. The incidence is higher in patients with moderate to severe hypertension. They account for about 4% of adrenal incidentalomas. The yearly incidence is 2 to 4 new cases per million population. However, many cases are undiagnosed during life, since the prevalence of pheochromocytomas and paragangliomas in autopsy series is 1 in 2000.
Nonsecretory paragangliomas arise in the head or neck, particularly in the carotid body, jugular-tympanic region, or vagal body; only about 4% secrete catecholamines. They often arise in patients who harbor SDHD, SDHC, or SDHB germline mutations. (See below.)
Over 30% of patients with pheochromocytomas or paragangliomas harbor a germline mutation in 1 of at least 13 genes that makes them prone to develop the tumor, usually in an autosomal dominant manner with incomplete penetrance. For a patient with a pheochromocytoma or paraganglioma, the chance of harboring a germline mutation is nearly 100% with a family history of pheochromocytoma or paraganglioma or with multiple sites of primary tumor, compared to 17% in patients without such family history.
Pheochromocytomas develop in about 20% of patients with von Hippel–Lindau (VHL) disease type 2 (hemangiomas of the retina, cerebellum, brainstem, and spinal cord; hyperparathyroidism; pancreatic cysts; endolymphatic sac tumors; cystadenomas of the adnexa or epididymis; pancreatic neuroendocrine tumors; renal cysts, adenomas, and carcinomas); inheritance is autosomal dominant. Patients with VHL develop pheochromocytomas that are less likely to be extra-adrenal, less likely to be malignant (3.5%), more likely to be bilateral, and more likely to present at an early age. Pheochromocytomas that arise in patients with VHL secrete exclusively norepinephrine and its metabolite normetanephrine. Therefore, individuals who carry type 2 VHL mutations should be screened for pheochromocytoma with plasma normetanephrine levels.
MEN 2A is associated with pheochromocytomas, hyperparathyroidism, cutaneous lichen amyloidosis, and medullary thyroid carcinoma. MEN 2B may be familial but usually arises from a de novo retmutation; MEN 2B is associated with pheochromocytoma (50%), aggressive medullary thyroid carcinoma, mucosal neuromas, and marfinoid habitus.
von Recklinghausen neurofibromatosis type 1 (NF-1) is associated with an increased risk of pheochromocytomas/paragangliomas as well as cutaneous neurofibromas, optic and brainstem gliomas, astrocytomas, vascular anomalies, hamartomas, malignant nerve sheath tumors, and smooth-bordered café au lait spots. Familial paraganglioma can be caused by mutations in the genes encoding succinate dehydrogenase (SDH) subunits B, C, or D. Patients with such germline mutations are more apt to have bilateral pheochromocytomas or multicentric paragangliomas. Patients with SDHB germline mutations are particularly prone to develop paragangliomas that metastasize aggressively; they are also prone to develop renal cell carcinomas and neuroblastomas.
Some kindreds are prone to develop pheochromocytomas and paragangliomas due to less common germline mutations in other tumor susceptibility genes: SDHA, SDHAF2, TMEM127, MAX, KIF1B, HIF2A, and PHD2. Pheochromocytomas are also more common in patients with Carney triad, Sturge-Weber syndrome, and tuberous sclerosis.
Table 26–12. Clinical manifestations of pheochromocytoma and paraganglioma.
Pheochromocytomas can be lethal unless they are diagnosed and treated appropriately. Catastrophic hypertensive crisis and fatal cardiac arrhythmias can occur spontaneously or may be triggered by intravenous contrast dye or glucagon injection, needle biopsy of the mass, anesthesia, or surgical procedures. Exercise, bending, lifting, or emotional stress can trigger paroxysms. Certain drugs can precipitate attacks: monoamine oxidase (MAO) inhibitors, caffeine, nicotine, decongestants, amphetamines, cocaine, ionic intravenous contrast, and epinephrine. Bladder paragangliomas may present with paroxysms during micturition.
Paroxysms typically produce hypertension (90%), severe headache (80%), perspiration (70%), and palpitations (60%); other symptoms may include anxiety (50%), a sense of impending doom, or tremor (40%). Vasomotor changes during an attack cause mottled cyanosis and facial pallor. As the attack subsides, facial flushing may occur as a result of reflex vasodilation. Epinephrine secretion by an adrenal pheochromocytoma may cause episodic tachyarrhythmias, hypotension, or even syncope. Acute coronary syndrome can be caused by coronary vasoconstriction. Confusion, psychosis, seizures, transient ischemic attacks, or stroke may occur with cerebrovascular vasoconstriction or hemorrhagic stroke. Aortic aneurysms may dissect and rupture. Abdominal pain, nausea, vomiting, and even ischemic bowel can be due to splanchnic vasoconstriction. Large or hemorrhagic abdominal tumors can also cause abdominal pain. Peripheral vasoconstriction can cause Raynaud phenomenon or even gangrene. Patients may experience nervousness and irritability, increased appetite, and loss of weight. Other patients have pulmonary edema and heart failure due to cardiomyopathy. Although most patients are symptomatic, some patients are normotensive and asymptomatic, particularly when the tumor is nonsecretory or discovered at an early stage.
In a pheochromocytoma multisystem crisis, tumoral cytokine release can cause proteinuria and nephrotic syndrome, acute heart failure, severe hypotension, kidney failure, liver failure, and death. Patients with proteinuria are at increased risk for acute respiratory distress syndrome (ARDS). Multisystem crisis can occur spontaneously, or it may be provoked by surgery, vaginal delivery, or treatment of metastatic disease.
Plasma fractionated free metanephrines is the single most sensitive test for secretory pheochromocytomas and paragangliomas. To improve test specificity, the patient should rest in a quiet room in the supine position for at least 20–30 minutes before the blood is drawn. Normal levels rule out pheochromocytoma and paraganglioma with some certainty and the work-up can usually end there. However, misleading elevations in metanephrines or normetanephrines can be caused by factors such as a blood draw in a sitting position, physical or emotional stress, sleep apnea, and MAO inhibitors. Assay interference can occur with HPLC-ECD assays with certain drugs: acetaminophen, labetalol, buspirone, mesalamine, and sulphasalazine. LC-MS/MS assays do not suffer from such drug interference and these assays are now used by most major laboratories in the United States. Patients with elevated plasma metanephrines or normetanephrines levels require further evaluation.
Assay of urinary fractionated metanephrines and creatinine effectively confirms most pheochromocytomas that were detected by elevated plasma fractionated metanephrines. A 24-hour urine specimen is usually obtained, although an overnight or shorter collection may be used; patients with pheochromocytomas generally have more than 2.2 mcg of total metanephrine per milligram of creatinine, and more than 135 mcg total catecholamines per gram creatinine. Urinary assay for total metanephrines is about 97% sensitive for detecting functioning pheochromocytomas. Urinary assay for vanillylmandelic acid (VMA) is not usually required.
Some drugs and foods can interfere with certain assays for catecholamines, and stresses can also cause misleading elevations in catecholamine excretion (Table 26–13). About 10% of hypertensive patients have a misleadingly elevated level of one or more tests.
Table 26–13. Factors potentially causing misleading catecholamine results: High-performance liquid chromatography with electrochemical detection (HPLC-ECD).
Serum chromogranin A is elevated in 90% of patients with pheochromocytoma and the levels correlate with tumor size, being higher in patients with metastatic disease. Serum chromogranin A levels can be misleadingly elevated in patients with azotemia or hypergastrinemia, and in those treated with corticosteroids or proton pump inhibitors. Serum may also be assayed for neuron-specific enolase; high levels implicate a malignant pheochromocytoma, while normal levels are nonspecific.
Serum methoxytyramine is another tumor marker that is often elevated, particularly in patients with “nonsecreting” tumors and in patients with pheochromocytoma or paraganglioma associated with aSDHB or SDHC germline mutation.
Initial testing results are frequently inconclusive. When metanephrines are elevated but less than three times the upper limit of normal, there is a significant chance of the test result being falsely positive. False-positive test results should be particularly suspected when the ratio of normetanephrine to norepinephrine is < 0.52 or the ratio of metanephrine to epinephrine is < 4.2. In such cases, it is best to repeat biochemical testing under optimal conditions, eg, after eliminating potentially interfering drugs. Pharmacologic provocative and suppressive tests that evaluate the rise or fall in blood pressure are usually not required or recommended.
Hyperglycemia is present in about 35% of patients but is usually mild. Proteinuria is present in about 10–20% of patients. Leukocytosis is common. Eosinophilia occurs rarely. The ESR is sometimes elevated. PRA may be increased by catecholamines.
Genetic testing should ideally be performed on all patients with pheochromocytoma or paraganglioma. Testing for VHL, ret protooncogene, and SDHB/SDHC/SDHD mutations is advisable. Family members may then be screened for the specific gene mutation.
MRI scanning has the advantage of not requiring intravenous contrast dye; its lack of radiation makes it the imaging of choice during pregnancy and childhood and for serial imaging. Pheochromocytomas typically have a low T1 signal and 70% have a high T2 signal. Both CT and MRI scanning have a sensitivity of about 90% for adrenal pheochromocytoma and a sensitivity of 95% for adrenal tumors over 0.5 cm in diameter. However, both CT and MRI are less sensitive for detecting recurrent tumors, metastases, and extra-adrenal paragangliomas. If no adrenal tumor is found, the scan is extended to include the entire abdomen, pelvis, and chest.
Somatostatin receptor imaging using 111In-labeled octreotide is only 25% sensitive for detecting an adrenal pheochromocytoma. However, 111In-labeled octreotide scanning is quite sensitive for detecting extra-adrenal pheochromocytomas (paragangliomas) and metastatic pheochromocytomas, sometimes locating tumors that were missed by 123I-MIBG scanning.
PET/CT scanning usually detects tumors using 18F-labeled deoxyglucose (18FDG-PET) or 18F-labeled dopamine (18FDA-PET), and may demonstrate tumors that are not visible on 123I-MIBG scanning.
Certain conditions mimic pheochromocytoma: thyrotoxicosis, essential hypertension, myocarditis, glomerulonephritis or other renal lesions, eclampsia, and psychoneurosis (anxiety attack). Toxemia of pregnancy is associated with hypertension and increased catecholamine production.
Conditions that have manifestations similar to those of pheochromocytoma include the following: essential labile hypertension, renal hypertension, anxiety attacks, thyrotoxicosis, toxemia of pregnancy, acute intermittent porphyria, hypogonadal vascular instability (hot flushes), cocaine or amphetamine use, and clonidine withdrawal. Patients taking nonselective MAO inhibitor antidepressants can have hypertensive crisis after eating foods that contain tyramine (eg, fermented cheeses, aged wines, certain beers, fava beans, vegemite, marmite). Patients with erythromelalgia can have hypertensive crises; their episodic painful flushing and leg swelling are relieved by cold, distinguishing this condition from pheochromocytoma. Pheochromocytomas can cause chest pain and ECG changes that mimic acute cardiac ischemia. Renal artery stenosis can cause severe hypertension and may coexist with pheochromocytoma.
False-positive testing for catecholamines and metabolites occurs in about 10% of hypertensives, but levels are usually < 50% above normal and typically normalize with repeat testing.
All of the complications of severe hypertension may be encountered. In addition, a catecholamine-induced cardiomyopathy may develop. Severe heart failure and cardiovascular collapse may develop in patients during a paroxysm. Sudden death may occur due to cardiac arrhythmia. Multisystem crisis and ARDS can occur acutely and thus the initial manifestation of pheochromocytoma may be hypotension or even shock. Hypertensive crises with sudden blindness or cerebrovascular accidents are not uncommon. Paroxysms may be spontaneous or precipitated by sudden movement, exertion, manipulation, vaginal delivery, emotional stress, trauma, surgery unrelated to the tumor, or surgery for removal of the tumor. Decongestant medications, fluoxetine, and other selective serotonin reuptake inhibitors may induce hypertensive paroxysms and death.
After removal of the tumor, a state of severe hypotension and shock (resistant to epinephrine and norepinephrine) may ensue with precipitation of acute kidney injury or myocardial infarction. Hypotension and shock may occur from spontaneous infarction or hemorrhage of the tumor.
Pheochromocytoma cells may be seeded within the peritoneum, either spontaneously or as a complication during surgical resection. Such seeding of the abdomen can result in multifocal recurrent intra-abdominal tumors, a condition known as pheochromocytomatosis.
Patients must receive adequate treatment for hypertension and tachyarrhythmias prior to surgery for pheochromocytoma/paraganglioma. Patients are advised to use a portable sphygmomanometer and measure their blood pressures daily and immediately during paroxysms. Some patients with pheochromocytoma or paraganglioma are not hypertensive and do not require preoperative antihypertensive management. Alpha-blockers or calcium channel blockers can be used, either alone or in combination. Blood pressure should be controlled before cardioselective beta-blockers are added for control of tachyarrhythmias.
Alpha-blockers are typically administered preparatory to surgery. Phenoxybenzamine is a long-acting nonselective alpha-blocker with a half-life of 24 hours; it is given initially in a dosage of 10 mg orally every 12 hours, increasing gradually by about 10 mg/d about every 3 days until hypertension is controlled. Maintenance doses range from 10 mg/d to 120 mg/d. Selective alpha-1-blockers may be used: doxazosin (half-life 22 hours), terazosin (half-life 12 hours), or prazosin (half-life 3 hours). Patients given preoperative phenoxybenzamine experience less intraoperative hypertension but greater post-resection hypotension than patients given preoperative selective alpha-1-blockers. Optimal alpha-blockade is achieved when supine arterial pressure is below 140/90 mm Hg or as low as possible for the patient to have a standing arterial pressure above 80/45 mm Hg.
Calcium channel blockers (nifedipine ER or nicardipine ER) are very effective and may be used with or without alpha-blockers. Nifedipine ER is initially given orally at a dose of 30 mg/d, increasing the dose gradually to a maximum of 60 mg twice daily. Calcium channel blockers are superior to phenoxybenzamine for long-term use, since they cause less fatigue, nasal congestion, and orthostatic hypotension. For acute hypertensive crisis (systolic blood pressure > 170 mm Hg) a nifedipine 10-mg capsule may be chewed and swallowed. Nifedipine is quite successful for treating acute hypertension in patients with pheochromocytoma/paraganglioma, even at home; it is reasonably safe as long as the blood pressure is carefully monitored.
Beta-blockers (eg, metoprolol XL) are often required after institution of alpha-blockade or calcium channel blockade. The use of a beta-blocker as initial antihypertensive therapy has resulted in an “unopposed alpha” that causes paradoxical worsening of hypertension. Labetalol has combined alpha- and beta-blocking activity and is an effective agent but can cause paradoxical hypertension if used as the initial antihypertensive agent. Labetalol can also interfere with catecholamine determinations in some laboratories and reduces the tumor’s uptake of radioisotopes, such that it must be discontinued for at least 4–7 days before123I-MIBG or 18FDA-PET scanning or therapy with high-dose 131I-MIBG.
Surgical removal of pheochromocytomas or abdominal paragangliomas is the treatment of choice. For surgery, a team approach—endocrinologist, anesthesiologist, and surgeon—is critically important. Laparoscopic surgery is preferred, but large and invasive tumors require open laparotomy. Patients with small familial or bilateral pheochromocytomas may undergo selective resection of the tumors, sparing the adrenal cortex; however, there is a recurrence rate of 10% over 10 years.
Prior to surgery, blood pressure control should be maintained for a minimum of 4–7 days or until optimal cardiac status is established. The ECG should be monitored until it becomes stable. (It may take a week or even months to correct ECG changes in patients with catecholamine myocarditis, and it may be prudent to defer surgery until then in such cases.) Patients must be very closely monitored during surgery to promptly detect sudden changes in blood pressure or cardiac arrhythmias.
Intraoperative severe hypertension is managed with continuous intravenous nicardipine (a short-acting calcium channel blocker), 2–6 mcg/kg/min, or nitroprusside, 0.5–10 mcg/kg/min. Prolonged nitroprusside administration can cause cyanide toxicity. Tachyarrhythmia is treated with intravenous atenolol (1 mg boluses), esmolol, or lidocaine.
Autotransfusion of 1–2 units of blood at 12 hours preoperatively plus generous intraoperative volume replacement reduces the risk of postresection hypotension and shock caused by desensitization of the vascular alpha-1-receptors. Shock is treated with intravenous saline or colloid and high doses of intravenous norepinephrine. Intravenous 5% dextrose is infused postoperatively to prevent hypoglycemia.
Detecting & Managing Metastatic Pheochromocytoma & Paraganglioma
Surgical histopathology for pheochromocytoma and paraganglioma cannot reliably determine whether a tumor is malignant. Therefore, all pheochromocytomas and paragangliomas must be approached as possibly malignant. Even if no metastases are visible at the time of surgery, they may become apparent years later. So all patients require lifetime follow-up. Therefore, it is essential to recheck blood pressure and plasma fractionated metanephrine levels about 4–6 weeks postoperatively, at least every 6 months for 5 years, then once yearly for life and immediately if hypertension, suspicious symptoms, or metastases become evident. Patients with nonsecretory tumors frequently have elevated serum levels of chromogranin A that can also be used as a tumor marker. It is also prudent to perform a whole-body 123I-MIBG scan about 3 months postoperatively, since previously undetected metastases may become visible.
Since some metastases are indolent, it is important to tailor treatment to each individual according to their tumor’s aggressiveness. Most surgeons resect the main tumor and larger metastases (debulking). Asymptomatic, indolent metastases may be kept under close surveillance without treatment.
Various chemotherapy regimens have been used, but there have been no controlled clinical trials to prove the effectiveness of one regimen over another or whether any regimen actually improves overall survival. The most common chemotherapy regimen combines intravenous cyclophosphamide, vincristine, and dacarbazine over 2 days in cycles that are repeated every 3 weeks. About one-third of patients experience some degree of temporary remission. Another chemotherapy regimen uses temozolomide, 250 mg/d orally for 5 days, repeating the cycle every 28 days. Sunitinib, a tyrosine kinase inhibitor, can also produce remissions, given orally in doses of 50 mg/d for 4 weeks on and then 2 weeks off; alternatively, a dose of 37.5 mg/d can be given continuously. Each chemotherapy regimen has toxicities.
Metyrosine reduces catecholamine synthesis but does not impede the progressive growth of metastases; the initial metyrosine dosage is 250 mg four times daily, increased daily by increments of 250–500 mg to a maximum of 4 g/d. Metyrosine causes central nervous system side effects and crystalluria; hydration must be ensured.
About 60% of patients with metastatic pheochromocytoma or paraganglioma have tumors with sufficient uptake of 123I-MIBG on diagnostic scanning to allow for therapy with high-activity 131I-MIBG. Medications that reduce MIBG uptake must be avoided, particularly labetalol, phenothiazines, tricyclics, and sympathomimetics. Activities of 125–500 mCi are infused, with many centers administering repeated infusions of 2 mCi/kg to cumulative activities of at least 500–800 mCi. Radioisotope therapy can suppress the bone marrow temporarily. Myelodysplastic syndrome and leukemia can develop several years after 131I-MIBG therapy, with the risk proportional to the cumulative amount of isotope. ARDS and multisystem failure occur rarely after 131I-MIBG therapy, particularly in patients with pretreatment proteinuria.
Patients with significant osteolytic bone metastases may be treated with external beam radiation therapy, which is often helpful in relieving pain and stabilizing local osseous disease. Patients with vertebral metastases and spinal cord compression may require surgical decompression and kyphoplasty. Intravenous zoledronic acid or subcutaneous denosumab may also be administered to patients with osteolytic bone metastases.
The malignancy of a pheochromocytoma or sympathetic paraganglioma cannot be determined by its size or histologic examination. A tumor is considered malignant if metastases are present; metastases may take many years to become clinically evident. Therefore, lifetime surveillance is required. Malignancy is more likely for larger tumors and for sympathetic paragangliomas. The prognosis is good for patients with pheochromocytomas that are resected before causing cardiovascular damage. Hypertension usually resolves after successful surgery but may persist or return in 25% of patients despite successful surgery. Although this may be essential hypertension, biochemical reevaluation is then required, looking for a second or metastatic pheochromocytoma.
Formerly, the surgical mortality was as high as 30%, but the development of laparoscopic surgical techniques, improved anesthesia, intraoperative monitoring, and preoperative blood pressure control with alpha-blockers or calcium channel blockers has reduced surgical mortality to < 3%.
Patients with metastatic pheochromocytoma and paraganglioma have an extremely variable prognosis. Patients with a heavy and progressive tumor burden and distant metastases have a worse prognosis. Patients harboring SDHB germline mutations tend to have more aggressive tumors as do patients with pulmonary metastases. Patients with metastases limited to bones or the abdomen tend to have a better prognosis. Some patients with intra-abdominal spread of tumor have intraperitoneal seeding (pheochromocytomatosis) rather than true metastases and seem to have a better prognosis.
Patients who receive surgery and chemotherapy have a median 5-year survival of about 44%. Patients receiving surgery followed by high-activity 131I-mIBG therapy have been reported to have a 5-year survival rate of 75%. Some patients have an indolent malignancy; prolonged survivals of up to 30 years have been reported with no treatment.
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GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS1
ISLET CELL TUMORS
ESSENTIALS OF DIAGNOSIS
Half of islet cell tumors are nonsecretory; weight loss, abdominal pain, or jaundice may be presenting signs.
Secretory tumors cause a variety of manifestations depending on the hormones secreted.
The pancreatic islets are composed of several types of cells, each with distinct chemical and microscopic features: the A cells (20%) secrete glucagon, the B cells (70%) secrete insulin,1 the D cells (5%) secrete somatostatin or gastrin, and the F cells secrete “pancreatic polypeptide.”
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) constitute < 5% of all pancreatic tumors. GEP-NETs are rare, with an incidence of about 10 per million yearly. About 40% are functional, producing hormones that are tumor markers, which are important for diagnosis and follow-up. Although most pancreatic and duodenal neuroendocrine tumors arise spontaneously, they may occur as part four different inherited disorders: MEN 1, von Hippel-Lindau disease (VHL), neurofibromatosis 1 (NF-1) and the rare tuberous sclerosis complex (TSC). At presentation, 65% of GEP-NETs are unresectable or metastatic.
Insulinomas are usually benign (about 90%) and secrete excessive amounts of insulin that causes hypoglycemia. Insulinomas also produce proinsulin and C-peptide. Insulinomas are solitary in 95% of sporadic cases but are multiple in about 90% of cases arising in MEN 1. (See Chapter 27.)
Gastrinomas secrete excessive quantities of the hormone gastrin (as well as “big” gastrin), which stimulates the stomach to hypersecrete acid, thereby causing hyperplastic gastric rugae and peptic ulceration (Zollinger–Ellison syndrome). About 50% of gastrinomas are malignant and metastasize to the liver. Gastrinomas are typically found in the duodenum (49%), pancreas (24%), or lymph nodes (11%). Sporadic Zollinger–Ellison syndrome is rarely suspected at the onset of symptoms; typically, there is a 5-year delay in diagnosis. About 22% of patients have MEN 1. In patients with MEN 1, gastrinomas usually present at a younger age; hyperparathyroidism may occur from 14 years preceding the Zollinger–Ellison diagnosis to 38 years afterward.
Glucagonomas are usually malignant; liver metastases are ordinarily present by the time of diagnosis. They usually secrete other hormones besides glucagon, often gastrin.
Somatostatinomas are very rare and are associated with weight loss, diabetes mellitus, malabsorption, and hypochlorhydria.
VIPomas are rare and produce vasoactive intestinal polypeptide (VIP), a substance that causes profuse watery diarrhea and profound hypokalemia (Verner-Morrison syndrome).
Carcinoid pancreatic neuroendocrine tumors are typically indolent but usually metastasize to local and distant sites, particularly to the liver and endocrine organs.
Nonfunctional pancreatic neuroendocrine tumors produce no significant hormones and usually grow to large size prior to detection. They typically present with symptoms caused by mass effect.
Presenting symptoms and signs of gastrinomas include abdominal pain (75%), diarrhea (73%), heartburn (44%), bleeding (25%), or weight loss (17%). Endoscopy usually shows prominent gastric folds (94%).
The 5-, 10-, and 20-year survival rates with MEN 1 are 94%, 75%, and 58%, respectively, while the survival rates for sporadic Zollinger–Ellison syndrome are 62%, 50%, and 31%, respectively. (SeeChapter 15.)
Initial symptoms of glucagonoma often include weight loss, diarrhea, nausea, peptic ulcer, or necrolytic migratory erythema. About 35% of patients ultimately develop diabetes mellitus. The median survival is 34 months after diagnosis.
With somatostinomas, a classic triad of symptoms frequently occurs due to the excessive somatostatin secretion: diabetes mellitus, with polyuria, polydipsia, and polyphagia due to its inhibition of insulin and glucagon secretion; cholelithiasis, because of its inhibition of gallbladder motility; and steatorrhea, because of its inhibition of pancreatic exocrine function. Diarrhea, hypochlorhydria, and anemia can also occur.
With VIPomas, there is profuse watery diarrhea; hypokalemia and achlorhydria are additional defining features.
Carcinoid pancreatic neuroendocrine tumors secrete serotonin and can produce an atypical carcinoid syndrome manifested by pain, diarrhea, and weight loss; skin flushing occurs in 39% of patients.
Islet cell tumors can secrete ectopic hormones (eg, ACTH) in addition to native hormones and produce related clinical syndromes (eg, Cushing syndrome).
Localization of noninsulinoma pancreatic islet cell tumors and their metastases is best done with somatostatin receptor scintigraphy (SRS) with 111In-DTPA-octreotide (Octreoscan); SRS detects about 75% of noninsulinomas. CT and MRI are also useful.
For insulinomas, preoperative localization studies are less successful and have the following sensitivities: ultrasonography 25%, CT 25%, endoscopic ultrasonography 27%, transhepatic portal vein sampling 40%, and arteriography 45%. Nearly all insulinomas can be successfully located at surgery by the combination of intraoperative palpation (sensitivity 55%) and ultrasound (sensitivity 75%). An abdominal CT scan is usually obtained, but extensive preoperative localization procedures, especially with invasive methods, are not required. Tumors may be located in the pancreatic head or neck (57%), body (15%), or tail (19%) or in the duodenum (9%).
Direct resection of the tumor (or tumors), which often spread locally, is the primary form of therapy for all types of islet cell neoplasms. In Zollinger–Ellison syndrome, gastrinomas are most commonly found in the duodenum but also in the pancreas. Gastric hyperacidity in Zollinger–Ellison syndrome is treated with a proton pump inhibitor at quadruple the usual doses. Proton pump inhibitors increase serum gastrin, which is otherwise useful as a tumor marker for gastrinoma recurrence after surgical resection.
Octreotide LAR is useful in the therapy of islet cell tumors with the exception of insulinoma; subcutaneous injections of Octreotide LAR 20–30 mg are required every 4 weeks. Treatment with octreotide LAR improves the symptoms caused by excessive VIP but does not halt tumor growth. Selective radioembolization of hepatic metastases can be accomplished with the use of 90Y-labeled resin or glass microspheres.
The prognosis in P-NETs is variable, but certainly better than pancreatic adenocarcinoma. The surgical complication rate is about 40%, with patients commonly developing fistulas and infections. Extensive pancreatic resection may cause diabetes mellitus. The overall 5-year survival is higher with functional tumors (77%) than with nonfunctional ones (55%) and higher with benign tumors (91%) than with malignant ones (55%). The prognosis is decidedly worse for patients with metastatic gastropancreatic neuroendocrine tumors that express thymidylate synthase.
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DISEASES OF THE TESTES & MALE BREAST
ESSENTIALS OF DIAGNOSIS
Diminished libido and erections.
Fatigue, depression, reduced exercise endurance.
Decreased growth of body hair.
Testes may be small or normal in size.
Serum total testosterone or free testosterone level is decreased.
Serum gonadotropin (LH and FSH) levels are decreased or normal in hypogonadotropic hypogonadism; they are increased in testicular failure (hypergonadotropic hypogonadism).
Male hypogonadism is caused by deficient testosterone secretion by the testes. It may be classified according to whether it is due to (1) insufficient gonadotropin secretion by the pituitary (hypogonadotropic); (2) pathology in the testes themselves (hypergonadotropic); or (3) both (Table 26–14). Partial male hypogonadism may be difficult to distinguish from the physiologic reduction in serum testosterone seen in normal aging, obesity, and illness.
Table 26–14. Causes of male hypogonadism.
A deficiency in FSH and LH may be isolated or associated with other pituitary hormonal abnormalities. (See Hypopituitarism.) Hypogonadotropic hypogonadism can be primary, with a failure to enter puberty by age 14; the differential diagnosis is isolated hypogonadotropic hypogonadism, hypopituitarism, or simple constitutional delay of growth and puberty. Hypogonadotropic hypogonadism may also be acquired; causes include pituitary or hypothalamic tumors, granulomatous diseases, lymphocytic hypophysitis, or hemochromatosis; Cushing syndrome; adrenal insufficiency; and thyroid hormone excess or deficiency. Genetic conditions (eg, Kallmann syndrome or PROKR2 mutations) account for about 40% of cases of acquired hypogonadotropic hypogonadism that is isolated, and apparently idiopathic, with a serum testosterone < 150 ng/dL (< 5.2 nmol/L).
Partial male hypogonadotropic hypogonadism is defined as a serum testosterone in the range of 150–300 ng/dL (5.2–10.4 nmol/L). The main causes of acquired hypogonadotropic hypogonadism include obesity, poor health, or normal aging. Spermatogenesis is usually preserved. After age 40, serum total testosterone declines variably by an average of 1–2% per year; serum free testosterone levels decline even faster, since sex hormone binding globulin increases with age. After age 70 years, 28% of men have low serum total testosterone and 68% have low serum free testosterone levels, compared with the levels found in young men. Serum levels of free testosterone are lower in men aged 40–70 compared with younger men, without any increase in serum LH. Increasing obesity is the main reversible condition that contributes to the general decline in serum free testosterone with aging. After age 70, LH levels tend to rise, indicating a contribution of primary gonadal dysfunction with advancing age.
There is considerable clinical and laboratory overlap between patients with partial hypogonadotropic hypogonadism and those with normal aging, obesity, or illness. A multicenter European study concluded that the diagnosis of testosterone deficiency in older men should include a serum testosterone < 320 ng/mL and at least three of the following six symptoms: erectile dysfunction, poor morning erection, low libido, depression, fatigue, and inability to perform vigorous activity. Such men are most likely to benefit from testosterone replacement.
A failure in testicular secretion of testosterone causes a rise in LH. If testicular Sertoli cell function is deficient, FSH will be elevated. Conditions that can cause testicular failure include viral infection (eg, mumps), irradiation, cancer chemotherapy or radioisotope therapy, autoimmunity, myotonic dystrophy, uremia, XY gonadal dysgenesis, partial 17-ketosteroid reductase deficiency, Klinefelter syndrome, and male climacteric. In men who have had a unilateral orchiectomy for cancer, the remaining testicle can fail even in the absence of radiation or chemotherapy. Male hypogonadism can also be caused by a congenital partial deficiency in the steroidogenic enzyme CYP17 (17-hydroxylase). CYP17 may be deliberately inhibited by abiraterone acetate (Zytiga), a drug for prostate cancer. CYP17 inhibition also causes adrenocortical insufficiency, hypertension, and hypokalemia.
Klinefelter syndrome (47,XXY and its variants) is the most common chromosomal abnormality among males, with an incidence of about 1:500. It is caused by the expression of an abnormal karyotype, classically 47,XXY. Other forms are common, eg, 46,XY/47,XXY mosaicism, 48,XXYY, 48,XXXY, or 46,XX males. The manifestations of Klinefelter syndrome are variable and < 25% of patients are diagnosed. Testes feel normal during childhood, but during adolescence they usually become firm, fibrotic, small, and nontender to palpation. Affected children have an increased risk of cryptorchidism, decreased penile size, delayed speech, learning disabilities, psychiatric disturbances, and mediastinal malignancies. Up to 75% of boys experience some gynecomastia at puberty. Although puberty occurs at the normal time, the degree of virilization is variable. Serum testosterone is usually low and gonadotropins are elevated. Adult men usually have somewhat reduced facial and pubic hair. Over 95% of affected adult men have azoospermia or severe oligospermia. Other common findings include tall stature and abnormal body proportions that are unusual for hypogonadal men (height greater than arm span; crown-pubis length greater than pubis-floor). Patients with multiple X or Y chromosomes are more apt to have mental deficiency and other abnormalities such as clinodactyly or synostosis. They may also exhibit problems with coordination and social skills. Other problems include a higher incidence of breast cancer, chronic pulmonary disease, varicosities of the legs, osteoporosis, and diabetes mellitus (8% of patients); impaired glucose tolerance occurs in an additional 19% of patients.
The diagnosis of Klinefelter syndrome is confirmed by karyotyping or by determining the presence of RNA for X-inactive-specific transcriptase (XIST) in peripheral blood leukocytes by polymerase chain reaction.
On semen analysis, most men (about 95%) with classic Klinefelter syndrome have azoospermia, although some sperm production is often present in their early teens. Men with 46,XY/47,XXY mosaicism may have spontaneous fertility. Also, testicular biopsy reveals sperm in up to 50% of affected patients, allowing some of them to be fertile with the use of in vitro fertilization using intracytoplasmic sperm injection (ICSI).
XY gonadal dysgenesis describes several conditions that result in the failure of the testes to develop normally. SRY is a gene on the Y chromosome that initiates male sexual development. Mutations inSRY result in testicular dysgenesis. Affected individuals lack testosterone, which results in sex reversal: female external genitalia with a blind vaginal pouch, no uterus, and intra-abdominal dysgenetic gonads. Affected individuals are raised as girls and appear normal until their lack of pubertal development and amenorrhea leads to the diagnosis. Intra-abdominal rudimentary testes have an increased risk of developing a malignancy and are usually resected. Patients are considered women and receive estrogen replacement therapy.
Partial resistance to testosterone is a rare condition in which phenotypic males have variable degrees of apparent hypogonadism, hypospadias, cryptorchism, and gynecomastia. Serum testosterone levels are normal.
Hypogonadism that is congenital or acquired during childhood presents as delayed puberty. Men with acquired hypogonadism have variable manifestations. Most men experience decreased libido. Others complain of erectile dysfunction, poor morning erection, or hot sweats. Men often have depression, fatigue, or decreased ability to perform vigorous physical activity. The presenting complaint may also be infertility, gynecomastia, headache, fracture, or other symptoms related to the cause or result of the hypogonadism. The patient’s history often gives a clue to the cause (Table 26–14).
Physical signs associated with hypogonadism may include decreased body, axillary, beard, or pubic hair; such diminished sexual hair growth is not reliably present except after years of severe hypogonadism. Men in whom hypogonadism develops tend to lose muscle mass and gain weight due to an increase in subcutaneous fat. Examination should include measurements of arm span and height. Testicular size should be assessed with an orchidometer (normal volume is about 10–25 mL; normal length is usually over 6 cm). Testicular size may decrease but usually remains within the normal range in men with postpubertal hypogonadotropic hypogonadism, but it may be diminished with testicular injury or Klinefelter syndrome. The testes must also be carefully palpated for masses, since Leydig cell tumors may secrete estrogen and present with hypogonadism. The testicles must be carefully examined for evidence of trauma, infiltrative lesions (eg, lymphoma), or ongoing infection (eg, leprosy, tuberculosis).
The evaluation for hypogonadism begins with a morning serum testosterone or free testosterone measurement (or both). Serum testosterone levels are considered low if they are confirmed to be < 320 ng/dL (11 nmol/L). Free testosterone is best measured by calculation, using accurate assays for testosterone and sex hormone binding globulin. Serum free testosterone levels are considered low if they are confirmed to be < 64 pg/mL (220 pmol/L).
Normal ranges for serum testosterone have been derived from nonfasting morning blood specimens, which tend to be the highest of the day. Later in the day, serum testosterone levels can be 25–50% lower. Therefore, a serum testosterone drawn fasting or late in the day may be misleadingly below the “normal range.” Serum testosterone levels in men are highest at age 20–30 years and slightly lower at age 30–40 years; testosterone falls gradually but progressively after age 40 years. Testing for serum free testosterone is especially important for detecting hypogonadism in elderly men, who generally have high levels of sex hormone binding globulin. A low serum testosterone should be verified with a repeat assay and further evaluated with serum LH and FSH levels. LH and FSH tend to be high in patients with hypergonadotropic hypogonadism but low or inappropriately normal in men with hypogonadotropic hypogonadism or normal aging. High serum estradiol levels are seen in men with obesity-related hypogonadotropic hypogonadism; sufficient weight loss causes a decrease in serum estradiol in such men.
Testosterone stimulates erythropoiesis in men, causing the normal red blood count range to be higher in men than in women; mild anemia is common in men with hypogonadism, with red blood counts below the normal male range. For men with long-standing male hypogonadism, bone densitometry is recommended. Men with severe osteoporosis may require treatment with bisphosphonates and vitamin D, in addition to testosterone replacement therapy. (See Osteoporosis.)
Testosterone replacement is beneficial to most men with hypergonadotropic hypogonadism or severe hypogonadotropic hypogonadism. Men with symptoms of hypogonadism (see above) and a repeatedly low serum testosterone or free testosterone can also benefit from testosterone replacement. For men with borderline low serum testosterone levels and marginal hypogonadal symptoms, the decision to treat should consider the potential benefits versus risks. Such men may be given a trial of testosterone therapy for several months while monitoring their response.
Testosterone therapy should not be administered to men with active prostate or breast cancer, or erythrocytosis. In men over age 50 years, a digital prostate examination and serum prostate-specific antigen (PSA) level should be done before beginning testosterone therapy. Men with symptoms of prostatic hypertrophy, a palpable prostate nodule, or a PSA > 4 ng/mL (> 3 ng/mL in men of African ancestry) should have a urologic evaluation prior to treatment. Serum PSA should be measured yearly during therapy. Similarly, testosterone therapy is not given to men with untreated sleep apnea or heart failure. In men who have coronary risk factors or are over age 65, special attention should be given to improving cardiac risk factors (eg, controlling hypertension or hyperlipidemia) and administering low-dose aspirin while receiving testosterone replacement.
Drug interactions can occur. Testosterone should be administered cautiously to men receiving coumadin, since the combination can increase the INR and risk of bleeding. Similarly, testosterone therapy can increase serum levels of cyclosporine, tacrolimus, and tolvaptan. Testosterone can predispose to hypoglycemia in diabetic men receiving insulin or oral hypoglycemic agents, so close monitoring of blood sugars is advisable during initiation of testosterone therapy.
Oral androgen therapy with methyltestosterone is not advisable due to the potential for causing liver tumors, peliosis hepatis, and cholestatic jaundice.
The skin serves as a reservoir that slowly releases about 10% of the testosterone into the blood; serum testosterone levels reach a steady state in 1–3 days. The serum testosterone level should be determined about 14 days after starting therapy; if the level remains below normal or the clinical response is inadequate, the daily dose may be increased to 1.5 to 2 times the initial dose. After the application of topical testosterone, the hands should be washed. The application site should be allowed to dry for 5–10 minutes before dressing. Before close contact with women or children, a shirt must be worn or the areas of application washed with soap and water to prevent transfer of testosterone to them.
Testosterone undecanoate (Nebido) is a long-lasting depot testosterone formulation that is administered in doses of 1000 mg (4 mL) by slow intramuscular injection. The initial injection is followed by another 1000 mg injection 6 weeks later and maintenance doses of 1000 mg every 3 months. A serum testosterone level is measured before the fourth dose; if the serum testosterone remains low, the dosing interval is shortened to every 10 weeks. It is not available in the United States or Canada.
Testosterone therapy usually benefits men with low serum testosterone and at least three manifestations of hypogonadism. Testosterone therapy can improve overall mood, sense of well-being, sexual desire, and erectile function. It also increases physical vigor and muscle strength as manifested in measurements of leg-press and chest-press strength. Testosterone replacement also improves exercise endurance and stair climbing ability. Long-term testosterone replacement causes significant weight loss and a reduction in waist circumference.
Testosterone therapy may improve survival. In a Veterans Administration study, men with hypogonadism who received testosterone replacement therapy over 3–5 years experienced an overall mortality rate of 10.3% compared to a 20.7% mortality rate in untreated hypogonadal men.
Testosterone replacement therapy appears to increase the risk of cardiovascular events in men older than age 65 with cardiac risk factors or preexisting angina. This increased risk may be due to the decrease in serum HDL that can occur with testosterone therapy.
Testosterone therapy can aggravate benign prostatic hypertrophy (BPH). However, aggravation of voiding problems is uncommon. In men with BPH, finasteride may be coadministered with testosterone to reduce prostate size. The incidence of prostate cancer does not appear to be increased by testosterone therapy. However, testosterone therapy is contraindicated in the presence of active prostate cancer. Hypogonadal men who have had a prostatectomy for low-grade prostate cancer, and who have remained in complete remission for several years, may have testosterone therapy given cautiously while monitoring serum PSA levels.
Erythrocytosis develops in some men who are treated with testosterone. Erythrocytosis is more common with intramuscular injections of testosterone enanthate than with transcutaneous testosterone. However, no increase in the incidence of thromboembolic events has been reported.
Testosterone therapy tends to aggravate sleep apnea in older men, likely through central nervous system effects. Surveillance for sleep apnea is recommended during testosterone therapy and a formal evaluation with nocturnal pulse oximetry recording is recommended for all high-risk patients with snoring, obesity, partner’s report of apneic episodes, nocturnal awakening, unrefreshing sleep with daytime fatigue, or hypertension.
Men who are treated with testosterone frequently experience some increase in acne that is usually mild and tolerated; topical antiacne therapy or a reduction in testosterone replacement dosage may be required. Increases in intraocular pressure have occurred during testosterone therapy. During the initiation of testosterone replacement therapy, gynecomastia develops in some men, which usually is mild and tends to resolve spontaneously; switching from testosterone injections to testosterone transdermal gel may help this condition.
Performance-enhancing agents, particularly androgenic anabolic steroids, are used by up to 2% of young athletes and by 20–65% of power sport athletes. They are often used as part of a “stacking” polypharmacy that may include nandrolone decanoate, dimethandrolone, testosterone propionate, or testosterone enanthate. These androgens are usually illegal and often contaminated by toxic substances and can produce toxic hepatitis, dependence, aggression, depression, dyslipidemias, gynecomastia, acne, male pattern baldness, hepatitis, thromboembolism, and cardiomyopathy. Shared needles may transmit hepatitis or HIV. Arsenic contamination has been reported to cause multiorgan failure and death.
Prognosis of Male Hypogonadism
If hypogonadism is due to a pituitary lesion, the prognosis is that of the primary disease (eg, tumor, necrosis). The prognosis for restoration of virility is good if testosterone is given.
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One or both testes may be absent from the scrotum at birth in about 20% of premature or low-birth-weight male infants and in 3–6% of full term infants. Cryptorchism is found in 1–2% of males after 1 year of age but must be distinguished from retractile testes, which require no treatment. Cryptorchism should be corrected before age 12–24 months in an attempt to reduce the risk of infertility, which occurs in up to 75% of men with bilateral cryptorchism and in 50% of men with unilateral cryptorchism. Some patients have underlying hypogonadism, including hypogonadotropic hypogonadism.
If the testes are not palpable, it is important to determine whether they are cryptorchid or intra-abdominal. MRI is more reliable than ultrasound for locating cryptorchid testes. Surgery for cryptorchid testes (orchiopexy) is generally successful and is usually the treatment of choice. Alternatively, hCG, 1500 units intramuscularly daily for 3 days, causes a significant rise in testosterone if the testes are present. Therapy with hCG results in a testicular descent rate of about 25%.
The lifetime risk of testicular neoplasia is 0.002% in normal males. The risk of malignancy is higher for cryptorchid testes (0.06%) and for intra-abdominal testes (5%). Orchiopexy decreases the risk of neoplasia when performed before 10 years of age. Orchiectomy after puberty is an option for intra-abdominal testes.
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ESSENTIALS OF DIAGNOSIS
Palpable enlargement of the male breast, often asymmetric or unilateral.
Glandular gynecomastia characterized by tenderness.
Fatty gynecomastia typically nontender.
Must be distinguished from carcinoma or mastitis.
Gynecomastia is defined as the presence of palpable glandular breast tissue in males. Pubertal gynecomastia develops in about 60% of boys; the swelling usually subsides spontaneously within a year. Gynecomastia is particularly common in teenagers who are very tall or overweight. Gynecomastia develops in about 50% of athletes who abuse androgens and anabolic steroids. It is seen in Klinefelter syndrome, which affects 1:500 men. (See Klinefelter syndrome.) About 20% of adult gynecomastia is caused by drug therapy. Gynecomastia can develop in HIV-infected patients treated with highly active antiretroviral therapy (HAART), especially in men receiving efavirenz or didanosine; breast enlargement resolves spontaneously in 73% of patients within 9 months. Gynecomastia is common among elderly men, particularly when there is associated weight gain. However, it can be the first sign of a serious disorder.
The causes of gynecomastia are multiple and diverse (Table 26–15).
Table 26–15. Causes of gynecomastia.
The male breasts must be palpated carefully to distinguish true glandular gynecomastia from fatty pseudogynecomastia in which only adipose tissue is felt. The breasts are best examined both seated and supine. Using the thumb and forefinger as pincers, the subareolar tissue is compared to nearby adipose tissue. Fatty tissue is usually diffuse and nontender. True glandular enlargement beneath the areola may be tender. Pubertal gynecomastia is characterized by tender discoid enlargement of breast tissue 2–3 cm in diameter beneath the areola. The following characteristics are worrisome for malignancy: asymmetry; location not immediately below the areola; unusual firmness; or nipple retraction, bleeding, or discharge. Gynecomastia is graded according to severity: I, mild; II, moderate; III, severe.
Obtain plasma levels of PRL (see Hyperprolactinemia) and beta-hCG. Detectable levels of beta-hCG implicate a testicular tumor (germ cell or Sertoli cell) or other malignancy (usually lung or liver), though detectable low levels (< 5 mU/mL) may be reported in primary hypogonadism and high serum LH levels if the assay for beta-hCG cross-reacts with LH. Measurements of serum free testosterone and LH are valuable in the diagnosis of primary or secondary hypogonadism. A low serum free testosterone and high LH are seen in primary hypogonadism. High testosterone levels plus high LH levels characterize partial androgen resistance. Serum estradiol is determined but is usually normal; increased levels may result from testicular tumors, increased beta-hCG, liver disease, obesity, adrenal tumors (rare), true hermaphroditism (rare), or aromatase gene gain of function mutations (rare). Serum TSH and FT4 levels are also recommended. A karyotype (for Klinefelter syndrome) is obtained in men with persistent gynecomastia without obvious cause.
Investigation of unclear cases should include a chest radiograph to search for metastatic or bronchogenic carcinoma. Needle biopsy with cytologic examination may be performed on suspicious male breast enlargement (especially when unilateral or asymmetric) to distinguish gynecomastia from tumor or mastitis.
Pubertal gynecomastia often resolves spontaneously within 1–2 years. Drug-induced gynecomastia resolves after the offending drug is removed (eg, spironolactone stopped, with substitution of eplerenone). Patients with painful or persistent gynecomastia may be treated with medical therapy, usually for 9–12 months. Generally, it is prudent to treat patients for gynecomastia only when it becomes a troubling and continuing problem for them.
Selective estrogen receptor modulator (SERM) therapy is effective for true glandular gynecomastia. Raloxifene, 60 mg orally daily, may be somewhat more effective than tamoxifen, 10–20 mg orally daily.
Aromatase inhibitor (AI) therapy is also reasonably effective. For example, anastrozole reduces breast volume significantly over 6 months in adolescents given in a dose of 1 mg orally daily. Serum estradiol levels fall slightly while serum testosterone levels rise. Long-term AI therapy in adolescents is not recommended because of the possibility of inducing osteoporosis and of delaying epiphyseal fusion, which could cause an increase in adult height.
Testosterone therapy for men with hypogonadism may improve or worsen preexistent gynecomastia.
Radiation therapy has been used prophylactically to prevent gynecomastia in men with prostate cancer being treated with antiandrogen therapy. Low-dose prophylactic radiation therapy reduces its incidence from 71% to 28%. Existing gynecomastia improves in 33% with radiation therapy. Radiation doses of 12 to 20 Gy have been used in 2–5 fractions. However, the long-term cancer risks of such radiation are unknown.
Surgical correction is reserved for patients with persistent or severe gynecomastia. For best results, the procedure should be performed by an experienced plastic surgeon.
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HIRSUTISM & VIRILIZATION
ESSENTIALS OF DIAGNOSIS
Hirsutism, acne, menstrual disorders.
Virilization: increased muscularity, androgenic alopecia, deepening of the voice, clitoromegaly.
Rarely, a palpable pelvic tumor.
Urinary 17-ketosteroids and serum DHEAS and androstenedione elevated in adrenal disorders; variable in others.
Serum testosterone is often elevated.
Hirsutism is defined as cosmetically unacceptable terminal hair growth that appears in women in a male pattern. Some degree of hirsutism affects about 5–10% of non-Asian women of reproductive age. The amount of hair growth deemed unacceptable depends on a woman’s ethnicity and familial and cultural norms.
Hirsutism may be idiopathic or familial or be caused by the following disorders: polycystic ovary syndrome (PCOS), steroidogenic enzyme defects, neoplastic disorders; or rarely by medications, acromegaly, or ACTH-induced Cushing disease.
Most women with hirsutism or androgenic alopecia have no detectable hyperandrogenism. Patients often have a strong familial predisposition to hirsutism that may be considered normal in the context of their genetic background. Such patients may have elevated serum levels of androstenediol glucuronide, a metabolite of dihydrotestosterone that is produced by skin in cosmetically unacceptable amounts.
PCOS is a common functional disorder of the ovaries, affecting about 4–6% of premenopausal women in the United States and accounting for at least 50% of all cases of hirsutism associated with elevated testosterone levels. It is familial and transmitted as a modified autosomal dominant trait. Affected women have elevated serum testosterone or free testosterone levels. Affected women have signs of androgen excess, including hirsutism, acne, and male-pattern thinning of scalp hair. About 50% of affected women have oligomenorrhea or amenorrhea with anovulation. Hyperandrogenism persists after natural menopause. Despite the syndrome’s name, the presence of ovarian cysts is not helpful diagnostically and is actually a misnomer, since about 30% of women with PCOS do not have cystic ovaries and 25–30% of normal menstruating women have cystic ovaries. Obesity and high serum insulin levels (due to insulin resistance) contribute to the syndrome in 70% of women. The serum LH:FSH ratio is often > 2.0. Both adrenal and ovarian androgen hypersecretion are commonly present. Women with PCOS have a 35% risk of depression, compared with 11% in age-matched controls. Diabetes mellitus is present in about 13% of cases. Obstructive sleep apnea is particularly common, even in slender women with PCOS. Untreated women with amenorrhea have a slightly increased risk of endometrial carcinoma. Hypertension and hyperlipidemia are often present, increasing the risk of cardiovascular disease. Women frequently regain normal menstrual cycles with aging.
Congenital adrenal steroidogenic enzyme defects result in reduced cortisol secretion with a compensatory increase in ACTH that causes adrenal hyperplasia. The most common enzyme defect is 21-hydroxylase deficiency, with a prevalence of about 1:18,000.
Partial deficiency in adrenal 21-hydroxylase can present in women as hirsutism. About 2% of patients with adult-onset hirsutism have been found to have a partial defect in adrenal 21-hydroxylase. The condition is more common in Ashkenazi Jews, Yupic Alaskans, and natives of La Reunion Island. The phenotypic expression is delayed until adolescence or adulthood; such patients do not have salt wasting. Polycystic ovaries and adrenal adenomas are more likely to develop in these women.
Some rare patients with hyperandrogenism and hypertension have 11-hydroxylase deficiency. This is distinguished from cortisol resistance by high cortisol serum levels in the latter and by high serum 11-deoxycortisol levels in the former.
Patients with an XY karyotype and a deficiency in 17-beta-hydroxysteroid dehydrogenase-3 or a deficiency in 5-alpha-reductase-2 may present as phenotypic girls in whom virilization develops at puberty.
Ovarian tumors are very uncommon causes of hirsutism (0.8%) and include arrhenoblastomas, Sertoli-Leydig cell tumors, dysgerminomas, and hilar cell tumors. Adrenal carcinoma is a rare cause of Cushing syndrome and hyperandrogenism that can be quite virilizing. Pure androgen-secreting adrenal tumors occur very rarely; about 50% are malignant.
Acromegaly and ACTH-induced Cushing syndrome can cause hirsutism. Porphyria cutanea tarda can cause periorbital hair growth in addition to dermatitis in sun-exposed areas. Maternal virilization during pregnancy may occur as a result of a luteoma of pregnancy, hyperreactio luteinalis, or polycystic ovaries. In postmenopausal women, diffuse stromal Leydig cell hyperplasia is a rare cause of hyperandrogenism. Acquired hypertrichosis lanuginosa is manifested by the appearance of diffuse fine lanugo hair growth on the face and body along with stomatologic symptoms; the disorder is usually associated with an internal malignancy, especially colorectal cancer, and may regress after tumor removal. Pharmacologic causes include minoxidil, cyclosporine, phenytoin, anabolic steroids, interferon, cetuximab, diazoxide, and certain progestins.
Modest androgen excess from any source increases sexual hair (chin, upper lip, abdomen, and chest) and increases sebaceous gland activity, producing acne. Menstrual irregularities, anovulation, and amenorrhea are common. If androgen excess is pronounced, defeminization (decrease in breast size, loss of feminine adipose tissue) and virilization (frontal balding, muscularity, clitoromegaly, and deepening of the voice) occur. Virilization points to the presence of an androgen-producing neoplasm. Hirsutism is quantitated using the Ferriman-Gallwey score in which hirsutism is graded from 0 (none) to 4 (severe) in nine areas of the body with a maximum possible score of 36; scores 8–15 indicate moderate hirsutism, while scores over 15 indicate severe hirsutism.
A pelvic examination may disclose clitoromegaly or ovarian enlargement that may be cystic or neoplastic. Hypertension may be present and should prompt consideration for the possible diagnosis of Cushing syndrome, adrenal 11-hydroxylase deficiency, or cortisol resistance syndrome.
Serum androgen testing is mainly useful to screen for rare occult adrenal or ovarian neoplasms. Some general guidelines are presented here, though exceptions are common.
Serum is assayed for total testosterone and free testosterone. A serum testosterone level > 200 ng/dL (> 6.9 nmol/L) or free testosterone > 40 ng/dL (> 140 pmol/L) indicates the need for pelvic examination and ultrasound. If that is negative, an adrenal CT scan is performed.
Most radioimmunoassays and enzyme-linked immunosorbent assays (ELISAs) for testosterone are inaccurate when serum testosterone levels are < 300 ng/dL (< 10.4 nmol/L). The more accurate testosterone assays rely on extraction and chromatography, followed by mass spectrometry or immunoassay. Free testosterone is best measured by calculation, using accurate assays for testosterone and sex hormone–binding globulin. A serum androstenedione level > 1000 ng/dL (> 34.9 nmol/L) also points to an ovarian or adrenal neoplasm. Patients with milder elevations of serum testosterone or androstenedione usually are treated with an oral contraceptive.
Patients with a serum DHEAS > 700 mcg/dL (> 35 nmol/L) have an adrenal source of androgen. This usually is due to adrenal hyperplasia and rarely to adrenal carcinoma. An adrenal CT scan is performed.
No firm guidelines exist as to which patients (if any) with hyperandrogenism should be screened for “late-onset” 21-hydroxylase deficiency. The evaluation requires levels of serum 17-hydroxyprogesterone to be drawn at baseline and at 30–60 minutes after the intramuscular injection of 0.25 mg of cosyntropin (ACTH1–24). Ideally, this test should be done during the follicular phase of a woman’s menstrual cycle. Patients with congenital adrenal hyperplasia will usually have a baseline 17-hydroxyprogesterone level > 300 ng/dL (> 9.1 nmol/L) or a stimulated level > 1000 ng/dL (> 30.3 nmol/L). Patients with any clinical signs of Cushing syndrome should receive a screening test. (See Cushing Syndrome.)
Serum levels of FSH and LH are elevated if amenorrhea is due to ovarian failure. An LH:FSH ratio > 2.0 is common in patients with PCOS. On abdominal ultrasound, about 25–30% of normal young women have polycystic ovaries, so the appearance of ovarian cysts on ultrasound is not helpful. Pelvic ultrasound or MRI can usually detect virilizing tumors of the ovary. However, small virilizing ovarian tumors may not be detectable on imaging studies; selective venous sampling for testosterone may be used for diagnosis in such patients.
Any drugs causing hirsutism (see above) should be stopped. Any underlying medical causes of hirsutism (eg, Cushing syndrome, acromegaly) should be treated.
Androgenizing tumors of the adrenal or ovary are resected laparoscopically. Postmenopausal women with severe hyperandrogenism should undergo laparoscopic bilateral oophorectomy (if CT scan of the adrenals and ovaries is normal), since small hilar cell tumors of the ovary may not be visible on scans. Girls with classic salt-wasting congenital adrenal hyperplasia and infertility or treatment-resistant hyperandrogenism may be treated with laparoscopic bilateral adrenalectomy.
Spironolactone may be taken in doses of 50–100 mg orally twice daily on days 5–25 of the menstrual cycle or daily if used concomitantly with an oral contraceptive. Spironolactone is contraindicated in pregnancy, so reproductive-age women must use reliable contraception during this therapy. Side effects such as hyperkalemia are uncommon, but it is prudent to monitor serum potassium during therapy. If necessary, metformin (see below) can be added and may enhance the anti-hirsutism effect of low-dose spironolactone.
Finasteride inhibits 5-alpha-reductase, the enzyme that converts testosterone to active dihydrotestosterone in the skin. Given as 2.5-mg doses orally daily, it provides modest reduction in hirsutism over 6 months—somewhat less than that achieved with spironolactone. Finasteride is ineffective for androgenic alopecia in women. Side effects are rare.
Flutamide inhibits testosterone binding to androgen receptors and also suppresses serum testosterone. It is given orally in a dosage of 250 mg/d for the first year and then 125 mg/d for maintenance. Used with an oral contraceptive, it appears to be more effective than spironolactone in improving hirsutism, acne, and male pattern baldness. Women with congenital adrenal hyperplasia who take replacement hydrocortisone experience decreased renal cortisol clearance when treated with flutamide, resulting in lower hydrocortisone dosage requirements. Flutamide decreases cortisol renal clearance and corticosteroid replacement doses should be reduced when flutamide is added. Hepatotoxicity has been reported but is rare. Antiandrogens like flutamide must be given only to nonpregnant women. Women must be counseled to take contraceptive measures, since antiandrogen drug use during pregnancy causes malformations and disorders of sexual development (pseudohermaphroditism) in male infants.
Oral contraceptives stimulate menses (if that is desired) and reduce acne vulgaris. They are not very effective for hirsutism, but increase serum sex hormone–binding globulin and thereby slightly reduce serum free testosterone levels. Oral contraceptives containing antiandrogen progestins include desogestrel (Azurette, Kariva), drospirenone (Gianvi), or norgestimate (Ortho Tri-Cyclen Lo). Cyproterone is a particularly potent antiandrogen that is not available in the United States but is available as Diane-35 in Canada and the United Kingdom. These preparations may be more effective for treating hirsutism but are associated with an increased risk of deep venous thrombosis.
Metformin may improve menstrual function in women with PCOS and amenorrhea or oligomenorrhea but is less effective than oral contraceptives. Metformin is not effective in promoting fertility in women with PCOS. Metformin alone is ineffective in improving hirsutism, but can enhance the anti-hirsutism effect of spironolactone. Metformin therapy is usually given orally with meals and is started at a dose of 500 mg/d with breakfast for 1 week, then increased to 500 mg with breakfast and dinner. If this dose is clinically insufficient but tolerated, the dose may be increased to 850–1000 mg twice daily. The most common side effects are dose-related gastrointestinal upset and diarrhea or constipation. Metformin appears to be nonteratogenic. Although metformin reduces insulin resistance, it does not cause hypoglycemia in nondiabetics. Metformin is contraindicated in renal and hepatic disease.
Simvastatin can reduce hirsutism in women with PCOS. In one study, simvastatin 20 mg orally daily was given to women receiving an oral contraceptive for PCOS. Besides improving their serum lipid profiles, women receiving simvastatin had greater decreases in hirsutism and serum free testosterone levels than the women receiving an oral contraceptive alone.
Clomiphene is the treatment of choice for women with PCOS and infertility. Over 6 months, clomiphene therapy resulted in a 22.5% rate of conception with live births. The rate of pregnancy with multiple fetuses is 6%.
Women with classic congenital adrenal hyperplasia (21-hydroxylase deficiency) have hirsutism and adrenal insufficiency that requires glucocorticoid and mineralocorticoid replacement. However, women with partial “late onset” 21-hydroxylase deficiency do not require hormone replacement. Treating such women with dexamethasone risks iatrogenic Cushing syndrome and is not particularly more effective than the other treatments for hirsutism listed below.
GnRH agonist therapy has been successful in treating postmenopausal women with severe ovarian hyperandrogenism when laparoscopic oophorectomy is contraindicated or declined by the patient.
Local treatment by shaving or depilatories, waxing, electrolysis, or bleaching should be encouraged. Eflornithine (Vaniqa 13.9%) topical cream retards hair growth when applied twice daily to unwanted facial hair; improvement is noted within 4–8 weeks. However, local skin irritation may occur. Hirsutism returns with discontinuation. Laser therapy (photoepilation) is a fairly effective treatment for facial hirsutism, particularly for women with dark hair and light skin; longer-wavelength lasers are used for women with darker skin. Complications of laser therapy include skin hypopigmentation (rare) and hyperpigmentation (20%) that usually resolves; a paradoxical increase in hair growth occurs infrequently. Repeated laser treatments are usually required.
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AMENORRHEA & MENOPAUSE (SEE ALSO CHAPTER 18)
Menarche ordinarily occurs between ages 11 and 15 years (average in the United States: 12.7 years). The failure of any menses to appear is termed “primary amenorrhea,” and evaluation is commenced (1) at age 14 years if neither menarche nor any breast development has occurred or if height is in the lowest 3%, or (2) at age 16 years if menarche has not occurred.
Etiology of Primary Amenorrhea
The differential diagnoses for primary amenorrhea include hypothalamic-pituitary causes, hyperandrogenism, ovarian causes, disorders of sexual development (pseudohermaphroditism), uterine causes, and pregnancy.
The most common cause of primary amenorrhea is a variant of normal known as constitutional delay of growth and puberty, which accounts for about 30% of delayed puberty cases. There is a strong genetic basis for this condition, such that over 50% of girls with it have a family history of delayed puberty. However, constitutional delay of growth and puberty is a diagnosis of exclusion and other etiologies must be considered.
A genetic deficiency of GnRH and gonadotropins may be isolated or associated with other pituitary deficiencies or diminished olfaction (Kallmann syndrome). Hypothalamic lesions, particularly craniopharyngioma, may be present. Pituitary tumors may be nonsecreting or may secrete PRL or GH. Cushing syndrome may be caused by corticosteroid treatment, a cortisol-secreting adrenal tumor, or an ACTH-secreting pituitary tumor. Hypothyroidism can delay adolescence. Head trauma or encephalitis can cause gonadotropin deficiency. Primary amenorrhea may also be caused by constitutional delay of adolescence, severe illness, vigorous exercise (eg, ballet dancing, running), stressful life events, dieting, or anorexia nervosa; however, these conditions should not be assumed to account for amenorrhea without a full physical and endocrinologic evaluation. (See Hypopituitarism.)
Polycystic ovaries and ovarian tumors can secrete excessive testosterone. Excess testosterone can also be secreted by adrenal tumors or by adrenal hyperplasia caused by steroidogenic enzyme defects such as P450c21 deficiency (salt-wasting) or P450c11 deficiency (hypertension). Androgenic steroid abuse may also cause this syndrome.
Gonadal dysgenesis (Turner syndrome and variants; see below) is a frequent cause of primary amenorrhea. Ovarian failure due to autoimmunity is a common cause. Rare deficiencies in certain ovarian steroidogenic enzymes are causes of primary hypogonadism without virilization: 3-beta-hydroxysteroid dehydrogenase deficiency (adrenal insufficiency with low serum 17-hydroxyprogesterone) and P450c17 deficiency (hypertension and hypokalemia with high serum 17-hydroxyprogesterone). Deficiency in P450 aromatase (P450arom) activity produces female hypogonadism associated with polycystic ovaries, tall stature, osteoporosis, and virilization.
Prenatal deficits of testosterone production or testosterone action in XY individuals results in ambiguous or female external genitalia. Patients with ambiguous genitalia are usually diagnosed in infancy.
However, XY patients with complete androgen insensitivity syndrome typically present in adolescence as a sexually immature phenotypic girl with normal breast development but with primary amenorrhea and no sexual hair. The uterus is absent and testes are intra-abdominal or cryptorchid. Intra-abdominal testes must be surgically resected. Such patients are treated as normal but infertile, hypogonadal women and should receive replacement estrogen therapy. Due to the complete lack of testosterone effect, affected women have a high rate of diminished libido.
Congenital absence or malformation of the uterus may be responsible for primary amenorrhea, as may an unresponsive or atrophic endometrium. An imperforate hymen is occasionally the reason for the absence of visible menses.
Pregnancy may be the cause of primary amenorrhea even when the patient denies ever having had sexual intercourse.
Patients with primary amenorrhea require a thorough history and physical examination to look for signs of the conditions noted above. Headaches or visual field abnormalities implicate a hypothalamic or pituitary tumor. Signs of pregnancy may be present. Blood pressure abnormalities, acne, and hirsutism should be noted. Short stature may be seen with an associated GH or thyroid hormone deficiency. Short stature with manifestations of gonadal dysgenesis indicates Turner syndrome (see below). Olfactory deficits are seen in Kallmann syndrome. Obesity and short stature may be signs of Cushing syndrome. Tall stature may be due to eunuchoidism or gigantism. Hirsutism or virilization suggests excessive testosterone.
An external pelvic examination plus a rectal examination should be performed to assess hymen patency and the presence of a uterus.
The initial endocrine evaluation should include serum determinations of FSH, LH, PRL, testosterone, TSH, FT4, and beta-hCG (pregnancy test). Patients who are virilized or hypertensive require serum electrolyte determinations and further hormonal evaluation. MRI of the hypothalamus and pituitary is used to evaluate teens with primary amenorrhea and low or normal FSH and LH—especially those with high PRL levels. Pelvic duplex/color sonography is very useful. Girls who have a normal uterus and high FSH without the classic features of Turner syndrome may require a karyotype to diagnose X chromosome mosaicism.
Treatment of primary amenorrhea is directed at the underlying cause. Girls with permanent hypogonadism are treated with hormone replacement therapy (HRT, see below).
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SECONDARY AMENORRHEA & MENOPAUSE
Secondary amenorrhea is defined as the absence of menses for 3 consecutive months in women who have passed menarche. Menopause is defined as the terminal episode of naturally occurring menses; it is a retrospective diagnosis, usually made after 6 months of amenorrhea.
The causes of secondary amenorrhea include pregnancy, hypothalamic-pituitary causes, hyperandrogenism, uterine causes, premature ovarian failure, and menopause.
Pregnancy is the most common cause for secondary amenorrhea in women of childbearing age. The differential diagnosis includes rare ectopic secretion of hCG by a choriocarcinoma or bronchogenic carcinoma.
The hypothalamus must release GnRH in a pulsatile manner for the pituitary to secrete gonadotropins. GnRH pulses occurring more than once per hour favor LH secretion, while less frequent pulses favor FSH secretion. In normal ovulatory cycles, GnRH pulses in the follicular phase are rapid and favor LH synthesis and ovulation; ovarian luteal progesterone is then secreted that slows GnRH pulses, causing FSH secretion during the luteal phase. Most women with hypothalamic amenorrhea have a persistently low frequency of GnRH pulses.
Secondary “hypothalamic” amenorrhea may be caused by stressful life events such as school examinations or leaving home. Such women usually have a history of normal sexual development and irregular menses since menarche. Amenorrhea may also be the result of strict dieting, vigorous exercise, organic illness, or anorexia nervosa. Intrathecal infusion of opioids causes amenorrhea in most women. These conditions should not be assumed to account for amenorrhea without a full physical and endocrinologic evaluation. Young women in whom the results of evaluation and progestin withdrawal test are normal have noncyclic secretion of gonadotropins resulting in anovulation. Such women typically recover spontaneously but should have regular evaluations and a progestin withdrawal test about every 3 months to detect loss of estrogen effect.
PRL elevation due to any cause (see section on hyperprolactinemia) may cause amenorrhea. Pituitary tumors or other lesions may cause hypopituitarism. Corticosteroid excess of any cause suppresses gonadotropins.
Elevated serum levels of testosterone can cause hirsutism, virilization, and amenorrhea. In PCOS, GnRH pulses are persistently rapid, favoring LH synthesis with excessive androgen secretion; reduced FSH secretion impairs follicular maturation. Progesterone administration can slow the GnRH pulses, thus favoring FSH secretion that induces follicular maturation. Rare causes of secondary amenorrhea include adrenal P450c21 deficiency, ovarian or adrenal malignancies, and Cushing syndrome. Anabolic steroids also cause amenorrhea.
Infection of the uterus commonly occurs following delivery or D&C but may occur spontaneously. Endometritis due to tuberculosis or schistosomiasis should be suspected in endemic areas. Endometrial scarring may result, causing amenorrhea (Asherman syndrome). Such women typically continue to have monthly premenstrual symptoms. The vaginal estrogen effect is normal.
Early menopause refers to primary ovarian failure that occurs before age 45. It affects approximately 5% of women. About 1% of women experience premature menopause that is defined as ovarian failure before age 40; about 30% of such cases are due to autoimmunity against the ovary. X chromosome mosaicism accounts for 8% of cases of premature menopause. Other causes include surgical bilateral oophorectomy, radiation therapy for pelvic malignancy, and chemotherapy. Women who have undergone hysterectomy are prone to premature ovarian failure even though the ovaries were left intact. Myotonic dystrophy, galactosemia, and mumps oophoritis are additional causes. Early or premature menopause is frequently familial. Ovarian failure is usually irreversible.
Normal menopause refers to primary ovarian failure that occurs after age 45. “Climacteric” is defined as the period of natural physiologic decline in ovarian function, generally occurring over about 10 years. By about age 40 years, the remaining ovarian follicles are those that are the least sensitive to gonadotropins. Increasing titers of FSH are required to stimulate estradiol secretion. Estradiol levels may actually rise during early climacteric.
The normal age for menopause in the United States ranges between 48 and 55 years, with an average of about 51.5 years. Serum estradiol levels fall and the remaining estrogen after menopause is estrone, derived mainly from peripheral aromatization of adrenal androstenedione. Such peripheral production of estrone is enhanced by obesity and liver disease. Individual differences in estrone levels partly explain why the symptoms noted above may be minimal in some women but severe in others.
Vasomotor instability (hot flushes) is experienced by 80% of women, lasting seconds to many minutes. Hot flushes with drenching sweats may be most severe at night or may be triggered by emotional stress. Women may also experience fatigue, insomnia, headache, diminished libido, or rheumatologic symptoms. Psychological symptoms of the “climacteric” include depression and irritability. Some women continue to menstruate for many months despite symptoms of estrogen deficiency. The acute symptoms of estrogen deficiency noted above tend to gradually decline in severity. However, the median duration of moderate to severe hot flushes is about 10 years. Hot flushes tend to continue longer in thin versus obese women and in black versus white women. The late manifestations of estrogen deficiency include urogenital atrophy with vaginal dryness and dyspareunia; dysuria, frequency, and incontinence may occur. Increased bone osteoclastic activity increases the risk for osteoporosis and fractures. The skin becomes more wrinkled. Increases in the LDL:HDL cholesterol ratio cause an increased risk for atherosclerosis.
A careful pelvic examination is always required to check for uterine or adnexal enlargement and to obtain a Papanicolaou smear and a vaginal smear for assessment of estrogen effect. Various life stresses, vigorous exercise, and “crash” dieting all predispose to amenorrhea; however, such factors should not be assumed to account for amenorrhea without a complete workup to screen for other causes.
Since pregnancy is the most common cause of amenorrhea, women of childbearing age are immediately screened with a pregnancy test (serum or urine hCG). An elevated hCG overwhelmingly indicates pregnancy; false-positive testing may occur very rarely with ectopic hCG secretion (eg, choriocarcinoma or bronchogenic carcinoma). Women who are not pregnant receive further laboratory evaluation including serum PRL, FSH, LH, and TSH. Hyperprolactinemia or hypopituitarism (without obvious cause; see Hypopituitarism) should prompt an MRI study of the pituitary region. Routine testing for kidney and liver function (eg, BUN, serum creatinine, bilirubin, alkaline phosphatase, and alanine aminotransferase) is also performed. A serum testosterone level is obtained in hirsute or virilized women. Patients with manifestations of hypercortisolism receive a 1-mg overnight dexamethasone suppression test for initial screening (see Cushing syndrome). Nonpregnant women without any laboratory abnormality may receive a 10-day course of a progestin (eg, medroxyprogesterone acetate, 10 mg/d); absence of withdrawal menses typically indicates a lack of estrogen or a uterine abnormality.
Therapy of symptomatic hypogonadism generally consists of estrogen replacement therapy. Slow, deep breathing can ameliorate hot flushes. For hot flushes in women who cannot take estrogen, gabapentin is quite effective in oral doses titrated up to 200–800 mg every 8 hours. However, gabapentin is frequently associated with side effects such as fatigue, headache, dizziness, and cognitive impairment; such symptoms are most pronounced during the first 2 weeks of therapy but often improve within 4 weeks. An herb, black cohosh, may possibly relieve hot flushes. Tamoxifen and raloxifene offer bone protection but aggravate hot flushes. Treatment or prevention of postmenopausal osteoporosis with bisphosphonates such as alendronate, risedronate, or intravenous zoledronic acid (see Osteoporosis) is another therapeutic option. Women with low serum testosterone levels may experience hypoactive sexual desire disorder that may respond to low-dose testosterone replacement.
Hormone Replacement Therapy
Two large, prospective studies have evaluated the effect of HRT on postmenopausal women. The Women’s Health Initiative (WHI) monitored 16,606 mostly-older postmenopausal women in the United States in a prospective, double-blinded, placebo-controlled study of postmenopausal HRT. A control group of women taking a daily placebo was compared with (1) women receiving daily conventional-dose oral combined HRT (conjugated equine estrogens [CEE] 0.625 mg/d with medroxyprogesterone acetate 2.5 mg/d) and (2) women, having had a hysterectomy, receiving only CEE 0.625 mg/d. The California Teachers Study prospectively followed up 71,237 postmenopausal women of all ages (mean age 63 years, range 36–94 years) for mortality, breast cancer, and other outcomes.
The WHI and California Teachers Study risk–benefit findings (described below) have dramatically changed postmenopausal HRT. The overall use of HRT has declined. When HRT is prescribed, lower-dose estrogen regimens are preferred over conventional-dose therapy. Estrogen preparations other than CEE have become increasingly favored. Transdermal and vaginal estrogen preparations are widely preferred over oral estrogen replacement. Also, the potential adverse effects of progestins are now recognized, such that women taking very low-dose estrogen replacement may not require progestins or may receive progestin therapy only periodically, if at all. For moderate- to high-dose estrogen therapy, progestins are being used in lower doses. Also, clinicians are now tending to prescribe progesterone-eluting intrauterine devices and oral progestins other than medroxyprogesterone acetate.
In the California Teachers Study, HRT in women under age 60 was associated with a dramatic 46% reduction in all-cause mortality, particularly cardiovascular disease. This association of HRT and lower mortality may suffer from self-selection bias. Nevertheless, there appears to be a survival advantage of HRT in women under age 60 that diminishes with age; no reduction in mortality was noted in the group of women aged 85–94 years. The reduction in cardiovascular disease among younger postmenopausal women taking HRT may be explained by the reduction in serum levels of atherogenic lipoprotein(a) with HRT, with or without a progestin. Improvement in serum HDL cholesterol is greatest with unopposed estrogen but is also seen with the addition of a progestin.
Estrogen replacement improves or eliminates postmenopausal hot flushes and diaphoretic episodes. Vaginal moisture is improved and libido is enhanced in some women. Estradiol vaginal rings can improve symptoms of an overactive bladder. Sleep disturbances are common in menopause and can be reversed with estrogen replacement. Some women notice a mild impairment in memory and cognitive function at menopause that may improve with HRT. Sex hormone replacement may also improve the body pain and reduced physical function experienced by some women at the time of menopause. Many women taking HRT experience a significantly improved quality of life. Estrogen replacement does not prevent facial skin wrinkling; however, it may improve facial skin moisture and thickness, reducing seborrhea and atrophy. Estrogen therapy does not appear to reduce the risk of Alzheimer dementia.
The risks of estrogen replacement depend on the dose. Conventional doses (eg, oral conjugated estrogens ≥ 0.625 mg/d or transdermal estradiol ≥ 0.05 mg/d) carry higher risks than lower doses (eg, oral conjugated estrogens, ≤ 0.3 mg/d or transdermal estradiol ≤ 0.025 mg/d). Route of administration also affects risks, since oral estrogens pass through the liver and increase hepatic production of clotting factors (thereby increasing the risks of thrombotic stroke), whereas transdermal or vaginal administration of estrogen does not significantly increase clotting proclivity. The risks for HRT also depend on whether estrogen is administered alone (unopposed HRT) or with a progestin (combined HRT).
Conventional-dose unopposed estrogen replacement (0.625–1.25 mg daily) increases the risk of endometrial hyperplasia and dysfunctional uterine bleeding, which often prompts patients to stop the estrogen. However, lower-dose unopposed estrogen confers a much lower risk of dysfunctional uterine bleeding. Recurrent dysfunctional bleeding necessitates a pelvic examination and possibly an endometrial biopsy. There has been considerable concern that unopposed estrogen replacement might increase the risk for endometrial carcinoma. However, a Cochrane Database Review found no increased risk of endometrial carcinoma in a review of 30 randomized controlled trials. Therefore, lower-dose unopposed estrogen replacement does not appear to confer any increased risk for endometrial cancer.
Long-term conventional-dose unopposed estrogen increases the mortality risk from ovarian cancer, although the absolute risk is small. The annual age-adjusted ovarian cancer death rates for women taking estrogen replacement for ≥ 10 years are 64:100,000 for current users, 38:100,000 for former users, and 26:100,000 for women who had never taken estrogen. Lower-dose estrogen replacement is believed to confer a negligible increased risk for ovarian cancer.
The WHI trial was stopped in 2002 because of an increased risk of stroke among women taking conjugated oral estrogens in doses of 0.625 mg daily; the risk was about 44 strokes per 10,000 person-years versus about 32 per 10,000 person-years in women taking placebo. Transdermal or transvaginal estrogen is not expected to increase the risk of stroke.
Conventional-dose therapy with oral estrogen alone had been thought to increase the risk of deep venous thrombosis and stroke, but the WHI follow-up study found no such increased risk for deep venous thrombosis or stroke. Oral estrogens can cause hypertriglyceridemia, particularly in women with preexistent hyperlipidemia, rarely resulting in pancreatitis. Postmenopausal estrogen therapy also slightly increases the risk of gallstones and cholecystitis. Oral estrogens reduce the effectiveness of GH replacement. These side effects can be reduced or avoided by using non-oral estrogen replacement.
Elderly women, receiving long-term conventional-dose estrogen replacement, experience an increased risk of urinary incontinence. Some women complain of estrogen-induced edema or mastalgia. Estrogen replacement has been reported to lower the seizure threshold in some women with epilepsy. Untreated large pituitary prolactinomas may enlarge if exposed to estrogen.
Conventional-dose oral combined HRT results in an increased risk of myocardial infarction (24% or six additional heart attacks per 10,000 women), mostly in older women with high-risk LDL levels or preexistent coronary disease. Most of the risk for myocardial infarction occurs in the first year of therapy. This increased risk is attributable to the progestin component, since the estrogen-only arm of the WHI study found no increased risk of myocardial infarction.
Long-term conventional-dose oral combined HRT increases breast density and the risk for abnormal mammograms (9.4% versus 5.4% for placebo). There is also a higher risk of breast cancer (8 cases per 10,000 women/year versus 6.5 cases per 10,000 women/year for placebo); the increased risk of breast cancer is highest shortly after menopause (about 2 cases per 1000 women annually). No increased risk of breast cancer has been found with estrogen-only HRT. This increased risk for breast cancer appears to mostly affect relatively thin women with a BMI < 24.4. The Iowa Women’s Health Study reported an increase in breast cancer with HRT only in women consuming more than 1 oz of alcohol weekly. No accelerated risk of breast cancer has been seen in users of HRT who have benign breast disease or a family history of breast cancer. Women in whom new-onset breast tenderness develops with combined HRT have an increased risk of breast cancer, compared with women without breast tenderness.
The Women’s Health Initiative Mental Study (WHIMS) followed the effect of combined conventional-dose oral HRT on cognitive function in women 65–79 years old. HRT did not protect these older women from cognitive decline. In fact, they experienced an increased risk for severe dementia at a rate of 23 more cases/year for every 10,000 women over age 65 years.
In the WHI study, women receiving conventional-dose combined oral HRT experienced an increased risk of stroke (31 strokes per 10,000 women/year versus 26 strokes per 10,000 women/year for placebo). Stroke risk was also increased by hypertension, diabetes, and smoking.
Women taking combined estrogen–progestin replacement do not experience an increased risk of ovarian cancer. They do experience an increased risk of developing asthma.
Progestins may cause moodiness, particularly in women with a history of premenstrual dysphoric disorder. Cycled progestins may trigger migraines in certain women. Many other adverse reactions have been reported, including breast tenderness, alopecia, and fluid retention. Contraindications to the use of progestins include thromboembolic disorders, liver disease, breast cancer, and pregnancy.
The type of progestin preparation, its dosage, and the timing of administration may be tailored to the given situation. Progestins may be given daily, monthly, or at longer intervals. When given episodically, progestins are usually administered for 7–14 day periods. Progestins are available in different formulations: Micronized progesterone (100 mg and 200 mg/capsule), medroxyprogesterone acetate (2.5, 5.0, and 10 mg/scored tablet), norethindrone acetate (5 mg/tablet), and norethindrone (0.35 mg/tablet).
Progesterone is also available as vaginal gels (eg, Prochieve, 4% = 45 mg/applicatorful, and 8% = 90 mg/applicatorful) that are typically administered vaginally every other day for six doses.
Topical progesterone (20–50 mg/d) may reduce hot flushes in women who are intolerant to oral HRT. It may be applied to the upper arms, thighs, or inner wrists daily. It may be compounded as micronized progesterone 250 mg/mL in a transdermal gel. Its effects upon the breast and endometrium are unknown.
Tibolone (Livial) is an SERM whose metabolites have mixed estrogenic, progestogenic, and weak androgenic activity. It is comparable to HRT for the treatment of climacteric-related complaints. It does not appear to significantly stimulate proliferation of breast or endometrial tissue. It depresses both serum triglycerides and HDL cholesterol. Long-term studies are lacking. It is not available in the United States.
In women, diminished libido is common and multifactorial. Although low serum testosterone levels may contribute to hypoactive sexual desire disorder, hysterectomy and sexual isolation are major causes. Low serum testosterone levels may also cause fatigue, a diminished sense of well-being, and a dulled enthusiasm for life. Androgen replacement may improve these problems.
Testosterone therapy is often effective, while DHEA therapy is not. Selected women may be treated with low-dose testosterone. Methyltestosterone can be taken orally in doses of 1.25–2.5 mg daily. Testosterone can also be compounded as a cream containing 1 mg/mL, with 1 mL applied to the abdomen daily. Methyltestosterone is also available in combination with conjugated estrogens (eg, Estratest). This formulation is convenient but carries the same disadvantage as oral estrogen—increased risk of thromboembolism. Tablets contain either 1.25 mg conjugated estrogens with 2.5 mg methyltestosterone or 0.625 mg conjugated estrogens with 1.25 mg methyltestosterone. Estratest is usually started at the lowest strength. It should be given cyclically at the lowest dose that controls symptoms.
Women receiving testosterone therapy must be monitored for the appearance of any acne or hirsutism, and serum testosterone levels are determined periodically if women feel that they are benefitting and long-term testosterone therapy is instituted. Side effects of low-dose testosterone therapy are usually minimal but may include polycythemia, emotional changes, hirsutism, acne, an adverse effect on lipids, and potentiation of warfarin anticoagulation therapy. Testosterone therapy tends to reduce both triglyceride and HDL cholesterol levels. Hepatocellular neoplasms and peliosis hepatis, rare complications of oral androgens at higher doses, have not been reported with methyltestosterone at lower doses of 2.5 mg orally daily.
Vaginal testosterone is an option for postmenopausal women who cannot use systemic or vaginal estrogen due to breast cancer. Testosterone 150–300 mcg/d vaginally appears to reduce vaginal dryness and dyspareunia without increasing systemic estrogen levels.
Androgens should not be given to women with liver disease or during pregnancy or breast-feeding. Testosterone replacement therapy for women should be used judiciously, since long-term prospective clinical trials are lacking. An analysis of the Nurses’ Health Study found that women who had been taking CEEs plus methyltestosterone experienced an increased risk of breast cancer. Yearly mammography is recommended for all women over 40 years of age.
Lifestyle changes, such as dressing coolly, avoiding down bedding and foam mattresses, sleeping with light bedclothes, keeping the ambient room temperature cool, sipping cold beverages, and stress reduction may help reduce hot flushes. Women may try avoiding known triggers for hot flushes, such as smoking, alcohol, caffeine, and hot spicy foods. Idiosyncratic triggers for hot flushes may be discerned and avoided. Clinical hypnosis greatly reduced hot flushes over 12 weeks in one study. Selective serotonin reuptake inhibitors may also reduce hot flushes. Gabapentin can relieve hot flushes when estrogen replacement therapy is contraindicated or not desired and when lifestyle changes are insufficient. Women with moderate to severe postmenopausal hot flushes may obtain relief with gabapentin 600–2400 mg daily in divided doses. Side effects are most prominent in the first 2 weeks of treatment and may include somnolence, unsteadiness, and dizziness. Acupuncture may also be helpful.
Replens is a vaginal lubricant that can be used daily or 2 hours prior to intercourse. It improves vaginal moisture and elasticity and reduces vaginal irritation and dyspareunia.
Canonico M et al. Further evidence for promoting transdermal estrogens in the management of postmenopausal symptoms. Menopause. 2011 Oct;18(10):1038–9. [PMID: 21946050]
Carpenter JS et al. Effect of escitalopram on hot flash interference: a randomized, controlled trial. Fertil Steril. 2012 Jun;97(6):1399–404. [PMID: 22480818]
Chlebowski RT et al. Estrogen alone and joint symptoms in the Women’s Health Initiative randomized trial. Menopause. 2013 Jun;20(6):600–8. [PMID: 23511705]
Clarkson TB et al. Timing hypothesis for postmenopausal hormone therapy: its origin, current status, and future. Menopause. 2013 Mar;20(3):342–53. [PMID: 23435033]
Lobo RA. Where are we 10 years after the Women’s Health Initiative? J Clin Endocrinol Metab. 2013 May;98(5):1771–80. [PMID: 23493433]
Maclaran K et al. Premature ovarian failure. J Fam Plann Reprod Health Care. 2011 Jan;37(1):35–42. [PMID: 21367702]
Marjoribanks J et al. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2012 Jul 11;7:CD004143. [PMID: 22786488]
Moilanen JM et al. Effect of aerobic training on menopausal symptoms—a randomized controlled trial. Menopause. 2012 Jun;19(6):691–6. [PMID: 22334056]
Nelson HD et al. Menopausal hormone therapy for the primary prevention of chronic conditions: a systematic review to update the U.S. Preventive Services Task Force recommendations. Ann Intern Med. 2012 Jul 17;157(2):104–13. [PMID: 22786830]
Rozenberg S et al. Postmenopausal hormone therapy: risks and benefits. Nat Rev Endocrinol. 2013 Apr;9(4):216–27. [PMID: 23419265]
Silveira LF et al. Approach to the patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013 May;98(5):1781–8. [PMID: 23650335]
Simon JA. What’s new in hormone replacement therapy: focus on transdermal estradiol and micronized progesterone. Climacteric. 2012 Apr;15(Suppl 1):3–10. [PMID: 22432810]
TURNER SYNDROME (Gonadal Dysgenesis)
ESSENTIALS OF DIAGNOSIS
Short stature with normal GH levels.
Primary amenorrhea or early ovarian failure.
Epicanthal folds, webbed neck, short fourth metacarpals.
Renal and cardiovascular anomalies.
Turner syndrome comprises a group of X chromosome disorders that are associated with spontaneous abortion, primary hypogonadism, short stature, and other phenotypic anomalies (Table 26-16). It affects 1–2% of fetuses, of which about 97% abort, accounting for about 10% of all spontaneous abortions. Nevertheless, it affects about 1 in every 2500 live female births. Patients with the classic syndrome (about 50% of cases) lack one of the two X chromosomes (45,XO karyotype). Other patients with Turner syndrome have X chromosome abnormalities, such as ring X or Xq (X/abnormal X) or X chromosome deletions affecting all or some somatic cells (mosaicism, XX/XO).
Table 26–16. Manifestations of Turner syndrome.
Features of Turner syndrome are variable and may be subtle in girls with mosaicism. Turner syndrome may be diagnosed in infant girls at birth, since they tend to be small and may exhibit severe lymphedema. Evaluation for childhood short stature often leads to the diagnosis. Girls and women with Turner syndrome have an increased risk of aortic coarctation (11%) and bicuspid aortic valves (16%); these cardiac abnormalities are more common in patients with a webbed neck. If a woman with Turner syndrome becomes pregnant, there is a 2% risk of death from aortic dissection or rupture. Typical manifestations in adulthood include short stature, hypogonadism, webbed neck, high-arched palate, wide-spaced nipples, hypertension, and renal abnormalities (Table 26–16). Emotional disorders are common. Affected women are also more prone to autoimmune disease, particularly thyroiditis (37%), inflammatory bowel disease (4%), and celiac disease (3%).
Hypogonadism presents as “delayed adolescence” (primary amenorrhea, 80%) or early ovarian failure (20%); girls with 45,XO Turner (blood karyotyping) who enter puberty are typically found to have mosaicism if other tissues are karyotyped.
Hypogonadism is confirmed in girls who have high serum levels of FSH and LH. A blood karyotype showing 45,XO (or X chromosome abnormalities or mosaicism) establishes the diagnosis. GH and IGF-1 levels are normal.
An ultrasound and MRI scan of the chest and abdomen should be done in all patients with Turner syndrome to determine whether cardiac, aortic, and renal abnormalities are present.
Treatment of short stature with daily injections of GH (0.1 unit/kg/d) plus an androgen (eg, oxandrolone) for at least 4 years before epiphyseal fusion increases final height by a mean of about 10.3 cm over the mean predicted height of 144.2 cm. Rarely, such GH treatment causes pseudotumor cerebri. After age 12 years, estrogen therapy is begun with low doses of conjugated estrogens (0.3 mg) or ethinyl estradiol (5 mcg) given on days 1–21 per month. When growth stops, HRT is begun with estrogen and progestin; transdermal estrogen may be used to initiate pubertal development.
Complications & Surveillance
Bicuspid aortic valves are associated with an increased risk of infective endocarditis, aortic valvular stenosis or insufficiency, and ascending aortic aneurysm and dissection. Partial anomalous pulmonary vein connections occur in 13% and can lead to left-to-right shunting of blood. Adults with Turner syndrome have a high incidence of ECG abnormalities.
Women with Turner syndrome have a reduced life expectancy due in part to their increased risk of diabetes mellitus (types 1 and 2), hypertension, dyslipidemia, and osteoporosis.
Diagnostic vigilance and aggressive treatment of these conditions reduce the risk of aortic aneurysm dissection, ischemic heart disease, stroke, and fracture. Patients are prone to keloid formation after surgery or ear piercing. Yearly ocular examinations and periodic thyroid evaluations are recommended.
Repeat cardiovascular evaluations should be done every 3–4 years. Patients with the classic 45,XO karyotype have a high risk of renal structural abnormalities, whereas those with 46 X/abnormal X are more prone to malformations of the urinary collecting system. The risk of aortic dissection is increased more than 100-fold in women with Turner syndrome, particularly those with pronounced neck webbing and shield chest. Patients with aortic root enlargement are usually treated with beta-blockade and serial imaging. Women with Turner syndrome who are able to become pregnant (spontaneously or with oocyte donation) are at high risk for complications, including fetal morbidity, severe hypertension, and aortic dissection. They are strongly advised to deliver via cesarean section due to the risk of aortic aneurysm rupture during vaginal delivery.
Patients with small distal short arm deletions of the X chromosome (Xp-) that include the SHOX gene often have short stature and skeletal abnormalities but have a low risk of ovarian failure. Transmission of Turner syndrome from mother to daughter can occur. There may be an increased risk of trisomy 21 in the conceptuses of women with Turner syndrome. Patients with deletions of the long arm of the X chromosome (distal to Xq24) often have amenorrhea without short stature or other features of Turner syndrome. Abnormalities or deletions of other genes located on both the long and short arms of the X chromosome can produce gonadal dysgenesis with few other somatic features.
45,XO/46,XX mosaicism results in a modified form of Turner syndrome. Such girls tend to be taller and may have more gonadal function and fewer other manifestations of Turner syndrome.
45,XO/46,XY mosaicism can produce some manifestations of Turner syndrome. Patients may have ambiguous genitalia or male infertility with an otherwise normal phenotype. Germ cell tumors, such as gonadoblastomas and seminomas, develop in about 10% of patients with 45,XO/46,XY mosaicism; most such tumors are benign.
Bakalov VK et al. Autoimmune disorders in women with Turner syndrome and women with karyotypically normal primary ovarian insufficiency. J Autoimmun. 2012 Jun;38(4):315–21. [PMID: 22342295]
Pinsker JE. Clinical review. Turner syndrome: updating the paradigm of clinical care. J Clin Endocrinol Metab. 2012 Jun;97(6):E994–1003. [PMID: 22472565]
Practice Committee of American Society for Reproductive Medicine. Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome. Fertil Steril. 2012 Feb;97(2):282–4. [PMID: 22192347]
Reindollar RH. Turner syndrome: contemporary thoughts and reproductive issues. Semin Reprod Med. 2011 Jul;29(4):342–52. [PMID: 21969268]
Ross JL et al. Growth hormone plus childhood low-dose estrogen in Turner’s syndrome. N Engl J Med. 2011 Mar 31;364(13):1230–42. [PMID: 21449786]
Trolle C et al. Sex hormone replacement in Turner syndrome. Endocrine. 2012 Apr;41(2):200–19. [PMID: 22147393]
MULTIPLE ENDOCRINE NEOPLASIA (MEN)
ESSENTIALS OF DIAGNOSIS
MEN 1: tumors of the parathyroid glands, endocrine pancreas and duodenum, anterior pituitary, adrenal, thyroid; carcinoid tumors; lipomas and facial angiofibromas.
MEN 2: medullary thyroid cancers, pheochromocytomas, Hirschsprung disease.
MEN 3: medullary thyroid cancers, pheochromocytomas, Marfan-like habitus, mucosal neuromas, intestinal ganglioneuroma, delayed puberty.
MEN 4: tumors of the parathyroid glands, anterior pituitary gland, adrenal gland, ovary, testicle, kidney.
Syndromes of MEN are inherited as autosomal dominant traits that cause a predisposition to the development of tumors of two or more different endocrine glands (Table 26–17). MEN syndromes are caused by different germline mutations and tumors arising when certain additional somatic mutations occur in predisposed organs. Patients with MEN should have genetic testing so that their first-degree relatives may then be tested for the specific mutation.
Table 26–17. Multiple endocrine neoplasia (MEN) syndromes: Incidence of tumor types.
Multiple endocrine neoplasia type 1 (MEN 1, Wermer syndrome) is a tumor syndrome with a prevalence of 2–10 per 100,000 people. About 90% of affected patients harbor a detectable germline mutations in the menin gene. Genetic testing is able to detect the specific mutation in 60–95% of cases.
The presentation of MEN 1 is quite variable, even in the same kindred. Affected patients are prone to develop many different tumors, particularly involving the parathyroids, endocrine pancreas and duodenum, and anterior pituitary. In some affected individuals, tumors may start developing in childhood, whereas in others, tumors develop late in adult life. With close endocrine surveillance of affected individuals, the initial biochemical manifestations (usually hypercalcemia) can often be detected as early as age 14–18 years in patients with a MEN 1 gene mutation, although clinical manifestations usually present in the third or fourth decade.
Hyperparathyroidism is the first clinical manifestation of MEN 1 in two-thirds of affected patients, but it may present at any time of life. Patients with the MEN 1 mutation have a > 90% lifetime risk of developing hyperparathyroidism. The hyperparathyroidism of MEN 1 is notoriously difficult to treat surgically, due to multiple gland involvement and the frequency of supernumerary glands and ectopic parathyroid tissue. Typically, three and one-half glands are resected, leaving one-half of the most normal-appearing gland intact. Also, during neck surgery, a thymectomy is performed to resect any intrathymic parathyroid glands or occult thymic carcinoid tumors. Nevertheless, the surgical failure rate is about 38%, and there is a recurrence rate of about 16%, with hypercalcemia often recurring many years after neck surgery. Aggressive parathyroid resection can cause permanent hypoparathyroidism. Patients with persistent or recurrent hyperparathyroidism should avoid oral calcium supplements and thiazide diuretics; oral therapy with calcimimetic drug, such as cinacalcet, is effective but expensive. The diagnosis and treatment of hyperparathyroidism is described earlier in this chapter.
Enteropancreatic tumors occur in up to 70% of patients with MEN 1. These tumors may secrete only pancreatic polypeptide or be nonsecretory altogether (20–55%). Gastrinomas occur in about 40% of patients with MEN 1; they secrete gastrin, thereby causing severe gastric hyperacidity (Zollinger–Ellison syndrome) with peptic ulcer disease or diarrhea. Concurrent hypercalcemia, due to hyperparathyroidism (see above), stimulates gastrin and gastric acid secretion; control of the hypercalcemia often reduces gastric acid secretion and serum gastrin levels. These gastrinomas tend to be small, multiple, and ectopic; they are frequently found outside the pancreas, usually in the duodenum. Gastrinomas of MEN 1 can metastasize to the liver; but in patients with MEN 1, depending upon the kindred, hepatic metastases tend to be less aggressive than those from sporadic gastrinomas. Treatment of patients with gastrinomas in MEN 1 is usually conservative, utilizing long-term high-dose proton pump inhibitor therapy and control of hypercalcemia; surgery is palliative and usually reserved for aggressive gastrinomas and those tumors arising in the duodenum. (See Chapter 15.)
Insulinomas cause hyperinsulinism and fasting hypoglycemia. They occur in about 10% of patients with MEN 1. Surgery is usually attempted, but the tumors can be small, multiple, and difficult to detect. (See Chapter 27.) Glucagonomas (1.6%) secrete glucagon and cause diabetes and migratory necrolytic erythema. VIPomas (1%) secrete VIP and cause profuse watery diarrhea, hypokalemia, and achlorhydria (WDHA, Verner-Morrison syndrome). Somatostatinomas (0.7%) can cause diabetes mellitus, steatorrhea, and cholelithiasis.
Extrapancreatic neuroendocrine tumors (NETs) commonly occur and include carcinoid tumors that tend to occur in foregut locations (69%), such as the lung, thymus, duodenum, or stomach. Such carcinoid tumors are frequently malignant.
Pituitary adenomas occur in about 42% of patients with MEN 1. They are more common in women (50%) than men (31%) and are the presenting tumor in 17% of patients with MEN 1. These tumors tend to be more aggressive macroadenomas (> 1 cm diameter, 85%) compared to sporadic pituitary tumors (42%). Of MEN 1–associated pituitary tumors, about 62% secrete PRL, 8% secrete GH, 13% secrete both PRL and GH, and 13% are nonsecretory; only 4% secrete ACTH. (See Pituitary Tumors and Cushing disease.) These pituitary tumors can produce local pressure effects and hypopituitarism.
Adrenal adenomas or hyperplasia occurs in about 40% of patients with MEN 1 and 50% are bilateral. They are generally benign and nonfunctional, but a feminizing adrenal carcinoma has been reported. These adrenal lesions are pituitary independent.
Benign thyroid adenomas or multinodular goiter occurs in about 55% of affected patients. Patients may undergo a thyroidectomy at the time of parathyroidectomy.
Nonendocrine tumors occur commonly in MEN 1, particularly small head-neck angiofibromas (85%) and lipomas (30%). Collagenomas are common (70%), presenting as firm dermal nodules. Affected patients may also be more prone to develop meningiomas, colorectal cancers, prostate cancer, and malignant melanomas.
The differential diagnosis of MEN 1 includes sporadic or familial tumors of the pituitary, parathyroids, or pancreatic islets. Hypercalcemia (from any cause) may cause gastrointestinal symptoms and increased gastrin levels, simulating a gastrinoma. Routine suppression of gastric acid secretion with H2-blockers or proton pump inhibitors causes a physiologic increase in serum gastrin that can be mistaken for a gastrinoma. H2-blockers and metoclopramide cause hyperprolactinemia, simulating a pituitary prolactinoma.
Variants of MEN 1 also occur. Kindreds with MEN 1 Burin variant have a high prevalence of prolactinomas, late-onset hyperparathyroidism, and carcinoid tumors, but rarely enteropancreatic tumors. Overall, patients with MEN 1 face an increased mortality risk with a mean life expectancy of only 55 years.
Multiple endocrine neoplasia type 2A (MEN 2, Sipple syndrome) is a rare autosomal-dominant tumor syndrome that arises in patients with a germline ret protooncogene mutation. Genetic testing identifies about 95% of affected individuals. Each kindred has a certain ret codon mutation that correlates with a particular variation in the MEN 2 syndrome.
Patients with MEN 2A may develop medullary thyroid carcinoma (> 90%); hyperparathyroidism (20–50%), with hyperplasia or adenomas of multiple parathyroid glands developing in over 70% of cases; pheochromocytomas (20–35%), which are often bilateral; or Hirschsprung disease. The medullary thyroid carcinoma is of mild to moderate aggressiveness. Children harboring an MEN 2A retprotooncogene mutation are advised to have a prophylactic total thyroidectomy by age 6 years. Before any surgical procedure, MEN 2 carriers should be screened for pheochromocytoma. However, there is incomplete penetrance, and about 30% of those with such mutations never manifest endocrine tumors.
Patients may be screened for medullary thyroid carcinoma with a thyroid ultrasound and with a serum calcitonin drawn after 3 days of omeprazole, 20 mg orally twice daily; in the presence of medullary thyroid carcinoma, calcitonin levels usually rise to above 80 pg/mL (23 pmol/L) in women or above 190 pg/mL (56 pmol/L) in men.
Multiple endocrine neoplasia type 2B (MEN 3) is a familial, autosomal dominant multiglandular syndrome that is caused by a mutation of the ret protooncogene. MEN 2B is characterized by mucosal neuromas (> 90%) with bumpy and enlarged lips and tongue, Marfan-like habitus (75%), adrenal pheochromocytomas (60%) that are rarely malignant and often bilateral, and medullary thyroid carcinoma (80%). Patients also have intestinal abnormalities (75%) such as intestinal ganglioneuromas, skeletal abnormalities (87%), and delayed puberty (43%). Medullary thyroid carcinoma is aggressive and presents early in life. Therefore, infants having a parent with MEN 2B must receive early genetic screening, with those carrying the ret protooncogene mutation undergoing a prophylactic total thyroidectomy by age 6 months.
Multiple endocrine neoplasia type 4 (MEN 4) is a rare autosomal-dominant familial tumor syndrome caused by germline mutations in the gene CDKN1B. Affected patients are particularly prone to develop adenomas of the pituitary, parathyroid glands, and neuroendocrine tumors (NETs) of the pancreas. This makes them appear to have MEN 1, but they have no mutation in the menin gene. They also appear to be prone to adrenal tumors, renal tumors, testicular cancer, and neuroendocrine cervical carcinoma.
OTHER SYNDROMES OF MULTIPLE ENDOCRINE NEOPLASIA
Patients with Carney complex develop tumors in the adrenal cortex, pituitary, thyroid, and gonads as well as cardiac myxomas and hyperpigmentation. Patients with Cowden disease develop thyroid abnormalities (66%) such as benign adenomas and follicular adenocarcinomas, along with breast cancer (20–36% in women), and multiple hamartomas that affect the skin and multiple other organs. Patients with McCune-Albright syndrome may develop precocious puberty (particularly girls) due to gonadal hypersecretion, Cushing syndrome caused by multiple adrenal nodules, hyperthyroidism from hypersecretory thyroid nodules, and acromegaly caused by GH-secreting pituitary tumors. Patients have fibrous dysplasia of bones and hypophosphatemia, with bone fractures being common. Sudden death has been reported.
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CLINICAL USE OF CORTICOSTEROIDS
Mechanisms of Action
Cortisol is a steroid hormone that is normally secreted by the adrenal cortex in response to ACTH. It exerts its action by binding to nuclear receptors, which then act upon chromatin to regulate gene expression, producing effects throughout the body.
Relative Potencies (Table 26–18)
Table 26–18. Systemic versus topical activity of orticosteroids.1
Hydrocortisone and cortisone acetate, like cortisol, have mineralocorticoid effects that become excessive at higher doses. Other synthetic corticosteroids such as prednisone, dexamethasone, and deflazacort (an oxazoline derivative of prednisolone) have minimal mineralocorticoid activity. Anticonvulsant drugs (eg, phenytoin, carbamazepine, phenobarbital) accelerate the metabolism of corticosteroids other than hydrocortisone, making them significantly less potent. Megestrol, a synthetic progestin, has slight corticosteroid activity that becomes significant when administered in high doses for appetite stimulation.
Prolonged treatment with systemic high-dose corticosteroids causes a variety of adverse effects that can be life threatening. Patients should be thoroughly informed of the major possible side effects of treatment such as insomnia, cognitive and personality changes, weight gain with central obesity, bruising, striae, muscle weakness, polyuria, kidney stones, diabetes mellitus, glaucoma, cataracts, sex hormone suppression, candidiasis and opportunistic infections. High-dose corticosteroids have adverse cardiovascular effects, increasing the risk of hypertension, dyslipidemia, myocardial infarction, stroke, atrial fibrillation or flutter, and heart failure. Prolonged corticosteroid therapy for systemic inflammatory disorders commonly suppresses pituitary ACTH secretion, causing secondary adrenal insufficiency.
Bone fractures (especially spine and hip) ultimately occur in about 40% of patients receiving long-term corticosteroid therapy. Osteoporotic fractures can also occur in patients who receive extensive topical, inhaled, or intermittent oral corticosteroids (eg, prednisone ≥ 10 mg daily and cumulative dose > 1 g). Osteoporotic fractures can occur even in patients receiving long-term corticosteroid therapy at relatively low doses (eg, 5–7.5 mg prednisone daily). Patients at increased risk for corticosteroid osteoporotic fractures include those who are over age 60 or who have a low body mass index, pretreatment osteoporosis, a family history of osteoporosis, or concurrent disease that limits mobility. Avascular necrosis of bone (especially hips) develops in about 15% of patients who receive corticosteroids at high doses (eg, prednisone ≥ 15 mg daily) for more than 1 month with cumulative prednisone doses of ≥ 10 g.
Bisphosphonates (eg, alendronate, 70 mg orally weekly) prevent the development of osteoporosis among patients receiving prolonged courses of corticosteroids. For patients who are unable to tolerate oral bisphosphonates (due to esophagitis, hiatal hernia, or gastritis), periodic intravenous infusions of pamidronate, 60–90 mg, or zoledronic acid, 2–4 mg, should also be effective. Teriparatide, 20 mcg subcutaneously daily for up to 2 years, is also effective against corticosteroid-induced osteoporosis. (See Osteoporosis section.) It is wise to follow an organized treatment plan such as the one outlined inTable 26–19.
Table 26–19. Pituitary hormones.
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1The amount of radioiodine radioactivity given in a procedure is referred to as “activity” and is expressed as Curies (Ci) or Becquerels (Bq), whereas the term “dose” is reserved to describe the amount of radiation absorbed by a given organ or tumor and is expressed as Gray (Gy) or radiation-absorbed dose (RAD).
1Insulinomas and hypoglycemia are discussed in Chapter 27.