Steven R. Gambert MD
Myron Miller MD
DISEASES OF THE THYROID GLAND
ESSENTIALS OF DIAGNOSIS
ESSENTIALS OF DIAGNOSIS
Both subclinical hypothyroidism and subclinical hyperthyroidism affect a relatively large number of elderly persons. Although a small percentage of these cases will progress to overt clinical hypothyroidism each year, individuals with high levels of antimicrosomal antibodies are at greater risk of decline in thyroid function. Several studies have observed beneficial effects of T4 therapy in patients with subclinical hypothyroidism; no studies have specifically addressed this question in older patients.
Elderly patients with subclinical hypothyroidism may present with few or no complaints. Elderly women with atherosclerosis and an even higher percentage of those with a history of myocardial infarction have a higher incidence of subclinical hypothyroidism. Treatment with l-thyroxine compared with placebo has been shown to result in an overall improvement in general well-being. In addition, noninvasive indexes of myocardial contractility also improved, as did memory, psychomotor speed, and serum cholesterol levels. Subclinical hypothyroidism progresses to frank hypothyroidism in 5–8% of affected persons each year, with higher rates in those with high levels of antimicrosomal antibodies.
Although some physicians advocate replacement therapy for all persons with subclinical hypothyroidism, many believe that treatment is best reserved for those individuals with TSH levels >10 mU/L or for those with serum TSH levels between 5—10 mU/L with coexisting high levels of antimicrosomal antibodies. If treatment is not initiated, careful follow-up is essential because a percentage of these individuals will develop hypothyroidism each year. The goal of treatment, when initiated, is to normalize serum TSH values as long as the dose of thyroid hormone that is required produces no unwanted clinical effects.
Canaris GJ et al: The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526. [PMID: 10695694]
Cooper DS: Clinical practice. Subclinical hypothyroidism. N Engl J Med 2001;345:260. [PMID: 11474665]
Helfand M, Redfern CC: Screening for thyroid disease: an update. Ann Intern Med 1998;129:144. [PMID: not available]
Ladenson PW et al: American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Intern Med 2000; 160:1573. [PMID: 10847249]
ESSENTIALS OF DIAGNOSIS
Subclinical hyperthyroidism is a term used to identify individuals with suppressed levels of serum TSH with normal levels of circulating thyroid hormones.
Subclinical hyperthyroidism may occur as a consequence of thyroid hormone replacement for hypothyroidism. Although still maintaining circulating levels of T4within normal range, these individuals are taking higher doses than necessary to normalize serum TSH. Shorter systolic time intervals, atrial fibrillation, and osteopenia have been associated with this entity. Epidemiological data suggest that this problem affects 4–7% of persons older than 60 not on thyroid hormone therapy. Unfortunately, there is little in the literature to help determine whether treatment is indicated. Most agree that treatment should be initiated if there are clearly associated symptoms, such as a worsening of cardiovascular function or cardiac arrhythmias, excessive wasting of muscle, anorexia, depression, or significant osteoporosis. Atrial fibrillation has been described in 10% of these patients. Patients with subclinical hyperthyroidism have been shown to be at increased risk of both cardiovascular and all-cause mortality.
Varied outcomes are reported for affected individuals; 47–61% have normal serum TSH levels on retesting within 1 year without any intervention, and 1.5–13% develop hyperthyroidism. It remains unclear exactly when to treat subclinical hyperthyroidism because therapy has the potential for toxicity and expense, and in some patients the problem may resolve on its own. Treatment is best considered on an individual basis with careful follow-up because hyperthyroidism in the elderly often presents in a nonspecific manner and may lead to a decline in functional capacity before or without more classic signs or symptoms of hyperthyroidism. Treatment of subclinical hyperthyroidism may improve bone mineral density and atrial fibrillation if identified. If treatment is selected, ablation therapy with iodine 131 is the preferred modality.
Parle JV et al: Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 2001;358:861. [PMID: 11567699]
Sawin CT et al: Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994; 331:1249. [PMID: not available]
Toft AD: Clinical practice. Subclinical hyperthyroidism. N Engl J Med 2001;345:512. [PMID: 11519506]
ESSENTIALS OF DIAGNOSIS
Hypothyroidism is a common disease of the elderly, with a reported prevalence of 0.9—17.5%. Hypothyroidism in the elderly most commonly results from an autoimmune thyroiditis. Prior radioiodine treatment and subtotal thyroidectomy are also potential causes. The risk of hypothyroidism is >50% after the first year of radioiodine treatment, with an additional annual incidence of 2—4% each year thereafter. Hypothyroidism may also be the natural end point to previous Graves' disease. Medications may also lead to hypothyroidism, particularly in persons with autoimmune thyroiditis. The most common medications associated with hypothyroidism include iodine-containing radiographic contrast agents, lithium, amiodarone, and iodine-containing cough medicines. Hypothyroidism may also result from a secondary cause: either a pituitary or hypothalamic abnormality.
Many of the presenting complaints are confused with other age-prevalent disorders. This problem is further compounded by the often insidious onset of illness. Whereas younger patients commonly present with weight gain, cold intolerance, paresthesias, and muscle cramps, older patients may not. However, fatigue and weakness are common. Many persons who are later discovered to be hypothyroid are unable to identify exactly when the symptoms actually began. Neurological findings may include dementia, ataxia, and carpal tunnel syndrome.
Classic symptoms of dry skin, paresthesias, constipation, hypothermia, and cold intolerance among others are often present in older persons without a thyroid abnormality. On physical examination, a delay in the relaxation of deep tendon reflexes may not be easily apparent in a person of advancing age. Hypercholesterolemia may be more common in both circumstances as well. For these reasons, the examining physician should maintain a high index of suspicion of hypothyroidism when evaluating any older person, especially women and those with a personal or family history of some form of thyroid disease.
Primary hypothyroidism is associated with an elevated serum TSH concentration. Changes in protein binding may reduce the level of total T4; T3 may be reduced in persons with significant medical illness or malnutrition. Even measures of free T4 may be misleading; T4 may be suppressed in individuals with T3toxicosis. For these reasons, an increase in serum TSH remains the best way to detect primary failure of the thyroid gland regardless of age. During the recovery phase after an acute nonthyroidal illness, however, an elevation of serum TSH level may not represent true clinical hypothyroidism; in this case, the serum TSH returns to the range of normal within 4–6 weeks. Although uncommon in the elderly, hypothyroidism can be secondary to pituitary or hypothalamic failure, with low serum TSH and T4 levels. Although antithyroid antibodies are detectable in the circulation of many persons with hypothyroidism, these tests are not indicated in the workup of every patient suspected of being hypothyroid. TSH screening is indicated in those older patients with cognitive problems, goiter, hypercholesterolemia, family history of thyroid illness, or history of thyroid abnormality.
Many of the presenting signs and symptoms of hypothyroidism in persons of any age resemble findings common to many other age-prevalent disorders, notably congestive heart failure and unexplained ascites resulting from cardiac or hepatic abnormalities. A thick tongue may result from primary amyloidosis. Anemia may result from vitamin B12, folate, or iron deficiency or volume expansion. Depression may be present, and other alterations in cognition may be due to medication toxicity or dementia.
l-Thyroxine is the preferred medication to treat hypothyroidism. In general, brand names are suggested to
minimize variability that may occur with generic preparations. It is also easier for the elderly person to identify the medication with a consistent color and shape. Elderly patients generally require a smaller amount of l-thyroxine to normalize their thyroid status, on average, 110 ¨g/day. Because of the age-related increase in T4 half-life, it will take longer to reach a steady state. A longer time between dose increases is necessary to reduce unwanted side effects.
The commonly adage of “start low and go slow” should be followed when starting any elderly patient on thyroid hormone replacement therapy. Because many elderly patients with hypothyroidism may have underlying cardiovascular disease, therapy should start with 25 ¨g/day, with gradually increasing increments of 25¨g every 4—6 weeks. Individuals with significant cardiac disease may require dose changes as low as 12.5 ¨g and should even be started at that dose. Once a dosage of 75 ¨g/day is achieved without side effects, increments of 12.5 ¨g are advised. The final dose required is the amount of l-thyroxine that reduces the serum TSH into the range of normal and does not have associated side effects.
A euthyroid state is not always desirable for patients with significant coronary artery disease. In this circumstance, the use of a β-adrenergic blocking agent may allow a clinically euthyroid state to be reached without induction of symptoms of myocardial ischemia. Monitoring of TSH is necessary to avoid inducing iatrogenic subclinical hyperthyroidism from excessive doses of replacement thyroid hormone.
With early treatment, return to a normal state of health is expected. Complete response to thyroid treatment, however, may take months, and patients will require replacement therapy with thyroid hormone for life.
ESSENTIALS OF DIAGNOSIS
Myxedema coma is a serious consequence of untreated or inadequately treated hypothyroidism. Although rare, it almost exclusively occurs in the older patients. Coma is seen in the most severe cases; more common features include alteration in cognition, lethargy, seizures, psychotic symptoms, and confusion and disorientation. In most cases, the affected individual has had a precipitating event such as a severe infection, cold exposure, alcoholism, or the use of psychoactive medications, sedatives, or narcotics.
A history of increased fatigue and somnolence is common as is a history of treatment of a thyroid disorder or use of narcotic, sedative, or antipsychotic medication. Infections, particularly pneumonia and urosepsis, are common. Physical examination may demonstrate classic signs and symptoms of hypothyroidism, including dry, scaly skin, bradycardia, and edema. Profound hypothermia as well as hypoventilation and hypotension may exist. Headaches, ataxia, nystagmus, psychotic behavior, muscle spasms, and sinus bradycardia may precede the coma. There may also be a pericardial effusion, ileus, megacolon, and easy bruising.
Laboratory findings classically include a markedly elevated serum TSH and reduced total and free serum T4. Hypoglycemia and hyponatremia are common. Autoimmune deficiency states, including diabetes mellitus and adrenal insufficiency, are sometimes associated with hypothyroidism and other autoimmune disorders. Creatine phosphokinase of muscle origin is often elevated. Myocardial infarction can occur in the presence of myxedema coma and may complicate the initiation of thyroid hormone therapy. In rare circumstances, myoglobinuria and rhabdomyolysis may occur. Arterial blood gases usually demonstrate a decrease in partial pressure of oxygen and an increase in partial pressure of carbon dioxide, indicating acute or impending respiratory failure. Anemia is also a common finding and is often normochromic, normocytic, or macrocytic. Cardiomegaly is often seen on chest x-ray film. Evoked potentials may have abnormal amplitude or latency, and electroencephalogram may demonstrate triphasic waves that disappear with thyroid replacement.
Included in the differential diagnosis are dementia, sepsis, intracranial bleed or tumor, hepatic encephalopathy, congestive heart failure, and hypothyroidism.
In most cases, patients with severe illness and coma are started on thyroid hormone replacement based on clinical suspicion before obtaining confirming laboratory data. When deciding on therapy, the following principles should be considered:
Myxedema coma is a serious condition that occurs largely in elderly hypothyroid persons. Aggressive supportive therapy and thyroid hormone therapy is essential while possible contributing factors are evaluated and treated as necessary. Close monitoring is required when treatment is initiated to avoid toxicity from the relatively large starting doses of thyroid hormone. Even under the best of circumstances, there is considerable mortality related to delay in diagnosis and presence of coexisting morbidities.
Yamamoto T et al: Factors associated with mortality of myxedema coma: report of eight cases and literature survey. Thyroid 1999;9:1167. [PMID: 10646654]
ESSENTIALS OF DIAGNOSIS
Hyperthyroidism is the result of an excessive amount of circulating thyroid hormone either from endogenous production or iatrogenic sources. Clinically, this disorder is accompanied by a broad spectrum of signs and symptoms that vary among individuals and can differ markedly between young and old persons. A greater percentage of affected individuals are older than 60. Several studies of prevalence indicate the presence of hyperthyroidism in 1–3% of community-residing elderly
persons. Hyperthyroidism is far more common in women than in men, with estimates ranging from 4:1 to 10:1.
Graves' disease remains the most common cause of hyperthyroidism in young persons and may still be present in elderly patients. With increasing age, however, more cases of hyperthyroidism result from multinodular toxic goiter. Although multinodular goiters are commonly found in the elderly and are not usually associated with clinical disease, they may evolve into toxic multinodular thyroid goiters. A toxic adenoma may cause hyperthyroidism and is usually identified on thyroid scan as a solitary hyperfunctioning nodule with suppression of activity in the remaining portion of the thyroid gland.
Hyperthyroidism may rarely result from ingestion of iodide or iodine-containing substances. Iodine may be introduced from seafood, although this problem is more common after exposure to iodinated radiocontrast agents and to amiodarone. Up to 40% of patients taking amiodarone will have serum T4 levels above the normal range as a result of the drug's effect on T4 metabolism; far fewer (5%) will develop clinically apparent thyrotoxicosis. The hyperthyroidism can be of rapid onset and severe in magnitude.
Hyperthyroidism must always be considered in the elderly person who is already receiving thyroid hormone therapy. This is particularly important if the dose is >0.15 mg of l-thyroxine daily, although even smaller doses may be excessive, especially in small individuals of advanced age. Persons taking the same dose of thyroid hormone for many years may become hyperthyroid simply because of an age-associated decline in the body's ability to degrade T4.
Although extremely rare, a TSH-producing pituitary tumor may be the cause of hyperthyroidism. Nonsuppressed levels of serum TSH in the presence of increased amounts of circulating thyroid hormone are seen with these tumors. Hyperthyroidism may also rarely result with overproduction of thyroid hormone from a widespread metastatic follicular carcinoma.
Transient hyperthyroidism may occur in patients with silent or subacute thyroiditis as a result of increased release of thyroid hormone into the circulation during the inflammatory phase of the illness. Radiation injury, which may be caused by radioactive iodine therapy for hyperthyroidism, may also result in an outpouring of thyroid hormone.
Hyperthyroidism is usually accompanied by elevated levels of both T4 and T3. However, a subgroup of elderly hyperthyroid individuals have isolated elevations of T3 alone. T4 is either within the normal range or may, in fact, be suppressed. This circumstance is referred to as T3 toxicosis. Although it can occur with any type of hyperthyroidism, it is most commonly seen in older patients with toxic multinodular goiter or solitary toxic adenomas. The diagnosis is made on clinical grounds and measurements demonstrating an elevated level of serum T3 and a suppressed level of serum TSH. T4toxicosis, or an isolated increase in serum T4without an elevation in serum T3, most commonly occurs in a sick elderly person with hyperthyroidism. Disease or malnutrition interferes in the normal removal of iodine from the 5′ position of T4 and thus a decreased ability to convert T4 to T3.
Clinical findings associated with hyperthyroidism in the elderly vary greatly. In general, the clinical presentation of hyperthyroidism at this time of life differs from the more classic findings noted earlier in life (Table 32-1). The presenting feature may be a decline in functional capacity. There may be increased fatigue, muscle weakness, cognitive changes, loss of appetite, weight loss, cardiac arrhythmias, and congestive heart failure. Eye findings associated with the hyperthyroidism are less commonly noted in the elderly. Rather than frequent bowel movements, more commonly there is a return to normal from preexisting constipation. Anemia and hyponatremia are often noted and thought to be due to other coexisting illnesses. Although this relative lack of the classic findings of hyperthyroidism does not occur in every older person with hyperthyroidism, a subgroup develops an apathetic hyperthyroid state. In this circumstance, the patient lacks the hyperactivity, irritability, and restlessness common to young patients who are hyperthyroid and presents instead with severe weakness, lethargy, listlessness, depression, and the appearance of a chronic wasting illness. Often the person is incorrectly diagnosed as having a malignancy or severe depression.
Symptoms less common in the elderly patients include nervousness, increased diaphoresis, increased appetite,
and increased frequency of bowel movements. More common symptoms include marked weight loss, present in >80% of elderly patients, poor appetite, worsening angina, agitation, confusion, and edema.
Table 32-1. Frequency of signs & symptoms of hyperthyroidism in young versus elderly patients.
Similarly, physical findings differ in elderly patients. Hyperreflexia, palpable goiter, and exophthalmos are usually absent, although lid lag and lid retraction may be present. The pulse rate tends to be slower. Cardiac manifestations are particularly important in the elderly person who may have coexisting heart disease. An increased heart rate with a related increase in myocardial oxygen demand, stroke volume, cardiac output, and shortened left ventricular ejection time underlie the clinical consequences of palpitations. There is also an increased risk of atrial fibrillation (often with slow ventricular response), exacerbation of angina in patients with preexisting coronary artery disease, and precipitation of congestive heart failure that responds less readily to conventional therapy.
Gastrointestinal problems may occasionally include abdominal pain, nausea, and vomiting. Diarrhea and increased frequency of bowel movements resulting from the effect of the thyroid hormone on intestinal motility can occur, but these symptoms are often absent and constipation is still common. There may be an alteration in liver enzymes, including elevation of alkaline phosphatase and gamma-glutamyltranspeptidase levels, which become normal after a return to the euthyroid state. Weakness, especially of proximal muscles, is a major feature of hyperthyroidism in the elderly and is often accompanied by muscle wasting and functional decline. Disorders of gait, postural instability, and falling may be noted. Tremor is noted in >70% of elderly persons with hyperthyroidism. The tremor is usually more coarse than in other common tremors. A rapid relaxation phase of the deep tendon reflex is difficult to identify in the older thyrotoxic individual. Central nervous system (CNS) manifestations may be prominent and include confusion, depression, changes in short-term memory, agitation and anxiety, and a decreased attention span. Other findings that have been associated with hyperthyroidism include worsening of glucose tolerance, mild increases in serum calcium, and osteoporosis resulting from increased bone turnover.
The altered and often atypical presentation of hyperthyroidism in the elderly patient warrants a high degree of suspicion among clinicians and the initiation of appropriate laboratory studies. Serum free T4 and a measurement of serum TSH are the preferred tests for diagnosing thyroid dysfunction. The findings of a normal or low serum free T4 with a suppressed serum TSH raises the possibility of T3 toxicosis and warrants a measurement of serum T3by radioimmunoassay. Although the finding of anti-TSH receptor antibodies confirms the diagnosis of Graves' disease, it is rarely necessary to obtain this test.
Thyroid scanning with technetium and measurement of 24-h 131I uptake can be useful in distinguishing Graves' disease from toxic multinodular goiter. Scanning may also demonstrate the presence of a small, diffusely active goiter that could not be detected on physical examination. Very low 131I uptake in a patient with elevated circulating thyroid hormone levels suggests exogenous thyroid hormone ingestion, the hyperthyroid phase of painless or subacute thyroiditis, or iodine-induced hyperthyroidism.
Patients with hyperthyroidism in later life commonly have coexisting illness, and it is important not to attribute all presenting signs and symptoms to the hyperthyroid state itself. The most common differential diagnoses to consider include anxiety, malignancy, depression, diabetes mellitus, menopause, and pheochromocytoma.
Therapy should be directed at the specific cause of the hyperthyroid state. Therefore, the underlying cause must be determined to exclude the possibility of one of the transient forms of illness, such as excessive hormone ingestion, iodine exposure, or subacute thyroiditis. The majority of older patients with either Graves' disease or multinodular toxic goiter can be treated with antithyroid medications, radioactive iodine, or surgery. The preferred treatment, however, is radioactive iodine.
A useful initial step in treating suspected hyperthyroidism is to administer a β-adrenergic blocking agent such as long-acting propranolol, metoprolol, nadolol, or atenolol. These agents quickly control associated palpitations, angina, tachycardia, and agitation. Caution is advised, however, in persons with congestive heart failure, chronic obstructive pulmonary disease, or diabetes mellitus being treated with insulin.
Once a diagnosis of Graves' disease or toxic nodular goiter is confirmed, treatment should be initiated with one of the antithyroid drugs: propylthiouracil or methimazole. These agents impair biosynthesis of thyroid hormone, thus depleting intrathyroidal hormone stores and ultimately leading to decreased hormone secretion. A decline in serum T4 concentration is usually seen within 2–4 weeks after initiation of antithyroid drug therapy, and the dose should be tapered once thyroid hormone levels reach the normal range to avoid hypothyroidism.
In 1–5% of patients, the antithyroid medications may result in fever, rash, and arthralgias. A drug-induced agranulocytosis may be more common in elderly patients and will most likely occur within the first 3 mo of treatment, especially in those who receive >30 mg/day of methimazone. Periodic white blood cell count monitoring should be considered, with discontinuation of the antithyroid medication if there is evidence of neutropenia.
Long-term antithyroid medication use can be effective in patients older than 60 with Graves' disease, who appear to respond fairly quickly and have a greater likelihood of a long-lasting remission. Because these medications rarely will provide a long-lasting effect for those with a toxic multinodular goiter, more definitive therapy is needed once the patient returns to a euthyroid state on medication. The recommended treatment in most elderly persons with hyperthyroidism is thyroid gland ablation with 131I. Once the patient achieves a euthyroid status on antithyroid medication, these agents should be stopped for 3–5 days, after which 131I is given orally. Therapy with β- blockers can be maintained and antithyroid agents restarted 5 days after radiotherapy and should be continued for 1–3 mo until the major effect of radioiodine is achieved. Although some physicians attempt to calculate a specific dose that will render the patient euthyroid without subsequently developing hypothyroidism, many patients will still develop permanent hypothyroidism. For this reason, most clinicians advocate treating the older person with hyperthyroidism with a relatively large dose of 131I to ensure ablation of thyroid tissue and thus avoid the possibility of hyperthyroidism recurrence.
After treatment, the patient is closely monitored in order to start replacement doses of thyroid hormone, because hypothyroidism may develop in as few as 4 weeks after treatment. Regardless of dosing regimen used, 40–50% of patients will be hypothyroid within 12 mo of 131I administration, with 2–5% developing hypothyroidism each year thereafter.
Prior treatment with antithyroid medication prevents the possibility of radiation-induced thyroiditis after 131I therapy. However, in some circumstances, when clinical and laboratory features suggest a mild case of hyperthyroidism and no cardiac problems are noted, it may be appropriate to treat the hyperthyroid patient with 131I without antithyroid medication pretreatment. When this option is chosen, the patients should be started on a β-blocker and continue with it until thyroid hormone levels return to normal.
Surgery is not recommended as a primary treatment for hyperthyroidism in the elderly patients. Coexisting illness, particularly cardiac, increases operative risk. In addition, postoperative complications of hypoparathyroidism and recurrent laryngeal nerve damage are significant risks. Surgery may be indicated in the rare patient with tracheal compression secondary to a large goiter.
Atrial fibrillation occurs in 10–15% of hyperthyroid patients. Treatment of the underlying disease is essential; cardioversion and anticoagulation are considered on an individual basis. The longer the hyperthyroid period, the less likely is the return to normal sinus rhythm; most benefit is found in those who become euthyroid within 3 weeks. Cardioversion is usually reserved for those patients who still remain in atrial fibrillation after 16 weeks of euthyroidism. Many older individuals with hyperthyroidism who develop atrial fibrillation are at greater risk of thromboembolic events, especially those with a history of thromboembolism, hypertension, or congestive heart failure and those with evidence of left atrial enlargement or left ventricular dysfunction. In the absence of contraindications, anticoagulant therapy should be given with warfarin in a dose that will increase the international normalization ratio to 2.0–3.0. Warfarin should be continued until the patient is euthyroid and normal sinus rhythm has been restored.
Allahabadia A et al: Age and gender predict the outcome of treatment for Graves' hyperthyroidism. J Clin Endocrinol Metab 2000;85:1038. [PMID: 10729936]
Trivalle C et al: Differences in the signs and symptoms of hyperthyroidism in older and younger patients. J Am Geriatr Soc 1996;44:50. [PMID: 8537590]
NODULAR THYROID DISEASE & NEOPLASIA
ESSENTIALS OF DIAGNOSIS
Multinodular thyroid glands occur more commonly in individuals who have lived in areas of iodine deficiency. Often there is a history of goiter dating to childhood or young adulthood. Very large multinodular goiters, particularly those with a significant substernal component, may compress the trachea and lead to problems of dyspnea and wheezing or problems with swallowing. All
patients with thyroid nodules should be questioned regarding prior exposure to external radiation of the head, neck, and upper thorax. Radiation to these areas markedly increases the risk of thyroid malignancy. Radiation increases the risk of thyroid malignancy as well as benign nodules and parathyroid adenomas. Approximately 16–29% of persons who received low-dose radiation to the head and neck as children will develop palpable thyroid nodules; approximately 33% become malignant and clinically detected only after 10–20 years, reaching a peak incidence 20–30 years after radiation exposure.
Thyroid nodules usually remain asymptomatic, being discovered by the patient inadvertently or by the physician during a routine physical examination. On occasion, a thyroid nodule may result in an acute onset of neck pain and neck tenderness. This may be an acute or subacute thyroiditis or hemorrhage into a preexisting nodule. Although a single thyroid nodule is more commonly associated with malignancy than a multinodular thyroid gland, only 5% of clinically apparent solitary nodules will be malignant. The vast majority of thyroid nodules are benign and include follicular and colloid adenomas, Hashimoto's thyroiditis, and thyroid cysts.
Malignant thyroid neoplasms may be papillary, follicular, medullary, or anaplastic carcinomas; lymphoma; or, in rare cases, metastatic disease to the thyroid. Nonthyroid lesions may appear as nodules on physical examination; these include lymph nodes, aneurysms, parathyroid cysts and adenomas, and thyroglossal duct cysts. The risk that a solitary thyroid nodule will prove to be malignant is increased by a history of radiation exposure, age >60, rapid increase in size, hoarseness of the voice suggesting an impingement of the recurrent laryngeal nerve, and hardness on palpation. Age is also a factor in predicting the histological type of malignancy. The overall histological distribution of all thyroid cancer is 79% papillary, 13% follicular, 3% Hürthle cell, 3.5% medullary, and 1.7% anaplastic. In patients older than 60, papillary carcinoma accounts for 67% of thyroid cancers. Follicular carcinoma peaks in frequency between the fourth and sixth decades of life (mean age at diagnosis, 44). Together with Hürthle cell carcinoma, these cancers account for 20% of thyroid malignancies in the over-60 population. Medullary carcinoma has a peak incidence during the fifth and sixth decades of life and represents approximately 5% of thyroid cancers in the elderly (Table 32-2). Anaplastic carcinomas occur almost exclusively in elderly people and account for —6% of thyroid cancers in older patients. Anaplastic carcinoma is characterized by rapid growth, rock-hard consistency, and local invasiveness. Involvement of the recurrent laryngeal nerve and compression of the trachea are common. Lymphoma and metastatic cancers occur infrequently in the older patient. Lymphoma usually presents with a rapidly enlarging painless neck mass that may cause compressive symptoms. Coexisting Hashimoto's thyroiditis is common.
Table 32-2. Thyroid malignancy in the older patient.
The major objective in evaluating an elderly person with a thyroid nodule is to rule out the presence of a malignancy. Blood tests of thyroid function will usually be normal unless there is a hyperfunctioning adenoma or toxic multinodular goiter. An elevated serum TSH may be noted in persons with subclinical hypothyroidism and nodular disease, as may result from long- standing Hashimoto's thyroiditis. Serum thyroglobulin is often elevated in the setting of thyroid cancer but cannot differentiate malignancy from benign nodules or thyroiditis with any degree of certainty. It is, therefore, more commonly used as a marker for recurrence or metastasis in patients with papillary or follicular carcinoma who have undergone total thyroidectomy. An elevation of serum calcitonin concentration is indicative of a medullary carcinoma but is not part of the initial evaluation unless there is a family history of multiple endocrine neoplasia (MEN).
Fine-needle aspiration (FNA) of the thyroid remains the best way to obtain tissue for cytological or histological examination. FNA is indicated in any patient with a solitary nodule and when there is suspicion of thyroid malignancy based on clinical evaluation, ultrasonography, or thyroid scan. This procedure, when performed by a skilled clinician, has proven to be safe, inexpensive, and capable of determining presence or absence of malignancy with an accuracy of close to 95% and even greater with sonographic guidance. In general, cytopathological findings from FNA are divided into 4 categories: positive for malignancy, suspicious for malignancy,
negative for malignancy, and nondiagnostic. A repeat FNA is indicated for a nondiagnostic but clinically suspicious nodule. Malignant cells found on FNA indicate the need for surgery. The combination of suspicious cytology by FNA and a cold-appearing nodule on thyroid scan also indicates the need for surgical excision of the suspicious nodule. Benign cytology in either a solid or cystic nodule warrants observation. If the FNA is suggestive of a lymphoma, a repeat biopsy using a large-needle or even a surgical biopsy is indicated.
Isotopic scanning is no longer considered the initial diagnostic test in evaluating a suspicious nodule because of its relatively high false-positive and false-negative rates and high cost. Isotope imaging is best used when evaluating a patient with a thyroid nodule who has had a nondiagnostic result from FNA. Because malignant tissue is more likely unable to take up iodine, the identification of a nodule as hot on 123I or technetium scanning makes malignancy in the nodule less likely, although clearly still possible. Scanning may also reveal an apparent single nodule that is, in fact, part of a multinodular thyroid gland, again decreasing the risk of malignancy. The presence of a nonfunctioning or a cold nodule is not proof of a malignancy because 95% of thyroid nodules will prove to be cold; the frequency of malignancy in cold nodules is 5%. Hot nodules associated with normal circulating levels of thyroid hormone and no compressive symptoms should be observed with repeat examinations performed at 6- to 12-mo intervals. These nodules may eventually result in hyperthyroidism; thus, clinical correlation is also warranted. High-resolution ultrasonography can detect thyroid lesions as small as 2mm and can also permit classification of a nodule as solid, cystic, or mixed solid-cystic. It will often identify multinodularity in a gland even when a single nodule is palpated clinically. This technique cannot be used to distinguish with any degree of certainty malignant from benign nodules because there is a great deal of overlap in the characteristics identified using ultrasonography. Ultrasonography is best used to detect recurrent or residual thyroid cancer as well as to screen persons with a history of radiation exposure earlier in life.
Computed tomography (CT) and magnetic resonance imaging (MRI) are expensive and add little to the initial assessment of malignancy. They may be useful in evaluating the extent of disease in patients found to have anaplastic carcinoma or lymphoma and may provide useful information regarding compression of neck structures and the size and substernal extent of nodules and goiters.
Medullary carcinoma of the thyroid gland can be monitored using blood calcitonin measurements both in the basal state and after stimulation. Blood levels of carcinoembryonic antigen may also be elevated in patients with residual or recurrent medullary carcinoma.
The differential diagnosis includes thyroid duct cysts, benign adenomas, toxic thyroid nodule, thyroid malignancy, hemorrhage, and multinodular thyroid gland.
Although the basic principles for treating thyroid cancer do not differ significantly between the young and old, older individuals need to be more carefully evaluated for comorbid conditions and risk of surgery. Surgery for thyroid cancer should be performed only by an experienced surgeon. Papillary or follicular carcinoma is usually treated with near-total thyroidectomy because of the high frequency of multicentricity of malignancy and the need to remove functional thyroid tissue to monitor the patient with total-body radioiodine scanning. Thyroid remnants detected postoperatively are ablated with 131I. At 6 mo and subsequently at yearly intervals, scanning should be obtained and serum thyroglobulin measured to determine whether residual functional tissue exists. If active tissue is found, large ablative doses of 131I should be administered. This approach has reduced the recurrence rate of both papillary and follicular carcinomas and prolonged survival.
Patients treated for malignancy are treated judiciously with suppressive doses of l-thyroxine as tolerated with the desired objective of reducing serum TSH to below normal as measured by third-generation TSH assays. The administration of suppressive doses of l-thyroxine carries a substantial risk of precipitating or aggravating ischemic heart disease and arrhythmias as well as accelerating bone turnover. The older patient will need to be monitored closely and the dose of thyroid hormone reduced if cardiac symptoms develop. An acceleration of bone loss will occur and necessitate treatment with antibone resorption agents in some circumstances (eg, in osteopenic women). Medullary carcinoma of the thyroid gland is best treated with a total thyroidectomy because the disease is often multicentric. The majority of medullary carcinomas do not respond to 131I treatment; therefore, palliative therapy is recommended using external irradiation if residual thyroid tissue or recurrent disease is detected. Thyroid lymphoma should be clinically staged using CT or MRI. External irradiation in combination with chemotherapy has been associated with a survival rate close to 100%.
Age at diagnosis is an important factor in predicting cancer aggressiveness and mortality from differentiated
thyroid cancer. Individuals diagnosed after the age of 50 have a higher rate of recurrence and death (see Table 32-2). The 10-year survival for patients with papillary carcinoma is —97% in those younger than 45 and <65% for those older than 60 at diagnosis. The 10-year survival rate for persons with follicular carcinoma is 98% for those younger than 45 and <57% for those older than 60 at diagnosis. The older the person is when a follicular carcinoma is diagnosed, the greater is the risk of recurrence and death.
The 10-year survival rate for persons with medullary carcinoma is 84% for individuals younger than 45 and decreases with advancing age. Persons in the seventh decade of life have a high rate of persistent disease even after surgery. Anaplastic carcinoma of the thyroid gland is rarely associated with more than a 1-year survival after diagnosis because of its rapid progression and high propensity to metastasize. Palliative treatment of compressive symptoms may be achieved by surgery followed by high-dose external radiation. Chemotherapy with doxorubicin or cisplatin, or a combination, may be beneficial in combination with surgery and external irradiation.
Mazzaferri EL: An overview of the management of papillary and follicular thyroid carcinoma. Thyroid 1999;9:421. [PMID: 10365671]
DISEASES OF THE ADRENAL CORTEX
Old age is associated with a reduced metabolic clearance rate of cortisol but with a compensatory decrease in secretion rate. Consequently, basal levels of serum cortisol are unaffected over the life span. Basal adrenocorticotropic hormone (ACTH) levels are unchanged or slightly increased with age in healthy individuals. Diurnal cortisol rhythm is reported to show a significant age-related phase advance (earlier peak and nadir level) similar to that observed in depressed patients. This is thought to be related to changes in sleep patterns.
The adrenal androgen precursor dehydroepiandrosterone (DHEA) reaches peak blood levels in both men and women by age 20–30 and then declines steadily so that, after age 70, levels are <20% of the peak. Although early reports and popular lay literature have attributed a number of antiaging properties to DHEA, more recent studies in which DHEA has been administered for 6–12 mo have shown little or no effect on objective measures of physiological function. Some studies, however, suggest a beneficial effect on mood and sense of general well-being.
Hypothalamic-pituitary-adrenal axis response to known major stimuli remains intact with increasing age. Stimulation tests of this axis using insulin-induced hypoglycemia or metyrapone administration result in a normal or slightly longer period of cortisol and ACTH secretory response in older persons. Peak cortisol response to stress is also greater, and both cortisol and ACTH levels remain elevated for a longer period in elderly compared with younger persons. Moreover, dexamethasone causes less inhibition of cortisol in older patients. It is unknown whether this age-related hyperresponsiveness of the pituitary-adrenal axis to stressful situations contributes to age-prevalent illness, including osteoporosis, glucose intolerance, muscle atrophy, and immunosuppression. Adrenal cortical response to exogenous ACTH, measured by circulating cortisol levels, is unaffected by aging.
ACUTE ADRENAL INSUFFICIENCY
ESSENTIALS OF DIAGNOSIS
Acute adrenal insufficiency results from a deficiency in cortisol secretion and, in elderly people, occurs most often as a result of failure of the adrenal gland rather than a pituitary gland disorder. The adrenal gland may be unable to produce an adequate amount of corticosteroids and mineralocorticoids because of an autoimmune process involving the entire adrenal gland or from a replacement of healthy adrenal tissue with tumor or infection, such as in tuberculosis. Adrenal crisis may also result from an increased demand for glucocorticoids in an individual unable to increase output sufficiently. This occurs most commonly as a result of chronic adrenal suppression from exogenous corticoid use and less often from stress from trauma, surgery, hemorrhage, or infection. Rarely, this may result from a sudden increase in the metabolic turnover of corticosteroids,
as can occur when a patient with both adrenal insufficiency and hypothyroidism is treated with thyroid hormone. Corticosteroid-induced adrenal suppression can occur after as few as 3–4 weeks of exogenous steroid treatment with doses >15 mg of prednisone or the equivalent dose of other glucocorticoids. In general, individuals on long-term glucocorticoid therapy who have stopped treatment before the return of function of the suppressed adrenal glands or who need a higher dose will have a less clear picture because of the ability of renin and angiotensin to maintain aldosterone function despite suppression of glucocorticoid activity in the adrenal gland.
Patients with adrenal insufficiency often have nausea and vomiting and abdominal pain and may have an altered mental state and fever. In general, blood pressure is low. Signs of primary adrenal insufficiency may include hyperpigmentation and evidence of dehydration. Elderly persons commonly have sparse or absent pubic and axillary hair; therefore, this is less commonly noted as an abnormality during later life.
Laboratory findings may include hyponatremia or hyperkalemia. Hypoglycemia and elevation of blood urea nitrogen (BUN) and creatinine are common. Eosinophilia may be noted as well. Cultures may be positive ifthere is an underlying infection. The cosyntropin (ACTH 1–24) stimulation test is abnormal, and plasma ACTH is usually elevated in persons with primary failure of the adrenal gland. With this test, patients are given 0.25 mg of cosyntropin intravenously over 2–3 min, and serum cortisol is measured immediately before and 30 and 60 min after administration. Under normal circumstances, serum cortisol rises by at least 7¨g/dL to at least 20 ¨g/dL. Hydrocortisone administration will interfere with the test results, but other glucocorticoids such as dexamethasone or prednisone do not interfere with the specific assay for cortisol.
Although adrenal insufficiency should be considered in any patient who presents with hyperkalemia and hypotension, other possible causes for these findings should be considered.
Other causes of hypotension in particular include sepsis, hemorrhage, and cardiogenic diseases. Renal insufficiency may cause hyperkalemia as may gastrointestinal bleeding, rhabdomyolysis, and medications such as spironolactone and angiotensin-converting enzyme inhibitors. Hyponatremia may occur in hypothyroidism, with diuretic use, in drug and disease states associated with inappropriate ADH secretion, and with malnutrition, cirrhosis, and vomiting. Eosinophilia may be associated with blood dyscrasias, allergies, medication reactions, and parasitic infections. The associated gastrointestinal findings of nausea, vomiting, and abdominal pain may, in fact, be due to other gastrointestinal tract disorders common during later life. Hyperpigmentation may not be noted in older persons of dark complexion or who have sun-induced skin damage.
Replacement of both glucocorticoids and mineralocorticoids is needed in severe cases of adrenal insufficiency. Because hydrocortisone has some mineralocorticoid activity, it is the corticosteroid of choice for patients with mild cases and is effective in doses of 25–37.5 mg orally; two thirds of the dose is given in the morning and one third in the late afternoon or evening. If salt-retaining effects from this therapy are insufficient, fludrocortisone is added to the daily regimen in dosages of 0.05–0.3 mg orally each day or every other day. The exact dose required will vary with the individual and, therefore, should be clinically adjusted in relation to postural blood pressure changes, level of potassium, and body weight. The dose is reduced if hypokalemia, hypertension, or edema occur, especially when fluid and electrolyte management is complicated by cardiac disease or renal insufficiency. Underlying factors that may have contributed to the onset of adrenal insufficiency, particularly infections, should be sought. The dosage of hydrocortisone may need to be adjusted upward to a stress dosage as high as 300 mg/day, although usually 50 mg intravenously or intramuscularly every 6 h will be sufficient, even for the most stressful situations.
With adequate replacement therapy, adrenal insufficiency is a treatable illness. When accompanied by other illnesses the risk mortality is increased. If the underlying cause is an autoimmune disease, other endocrine problems such as diabetes mellitus and hypothyroidism as well as pernicious anemia may be present.
Parker CR et al: Effects of aging on adrenal function in the human: responsiveness and sensitivity of adrenal androgens and cortisol to adrenocorticotropin in premenopausal and postmenopausal women. J Clin Endocrinol Metab 2000;85:48. [PMID: 10634362]
ESSENTIALS OF DIAGNOSIS
Cushing's syndrome is caused by an excessive amount of circulating corticosteroids. In elderly patients, it most commonly results from exogenous exposure to corticosteroids given for a variety of medical disorders. The most frequent endogenous cause is ectopic production of ACTH by neoplasms, especially small cell carcinoma of the lung and carcinoid tumor. Cushing's disease (ie, oversecretion of ACTH by a pituitary tumor) is less common in elderly than younger patients, is usually associated with a small benign adenoma, and occurs more often in women than men. Approximately 15% of cases of endogenous Cushing's syndrome are non-ACTH dependent and result from an adrenal adenoma, carcinoma, or bilateral nodular adrenal hyperplasia. Although adrenal adenomas are generally small and produce mostly glucocorticoids, carcinomas tend to be larger on presentation and more commonly produce excessive amounts of both glucocorticoids and androgens, often resulting in virilization and hirsutism.
Although central obesity, thin arms and legs, and a round “moon face” are classic findings, these may be harder to detect in older patients. For example, the “buffalo hump” deposition of fat at the back of the neck may, in older women, be confused with a kyphosis resulting from osteoporosis. Thin, transparent skin, bruising, muscle atrophy and weakness, diabetes mellitus, and hypertension are other common findings easily confused with many other age-prevalent disorders. Thirst is less often reported by elderly compared with younger patients. Polyuria may result from increases in blood sugar from glucocorticoid-induced diabetes. Blood glucose is often elevated, and glycosuria may be present. Occasionally, there is a leukocytosis and hypokalemia. Wound healing may be impaired, and changes in mental function, including anxiety, psychosis, and depression, may occur.
A low-dose dexamethasone suppression test can be used to screen for hypercortisolism. Dexamethasone, 1 mg, is given orally at 11 pm, and serum is collected at 8 am the next morning for cortisol. A cortisol level <5 ¨g/dL is considered normal and excludes a diagnosis of Cushing's syndrome. If there is failure of suppression, further evaluation should include a 24-h urine collection for free cortisol and creatinine. A high 24-h urine free cortisol or a free cortisol-creatinine ratio of >95 ¨g/g creatinine is suggestive of hypercortisolism. A 2-mg dexamethasone suppression test using 0.5 mg of dexamethasone administered orally every 6 h for 48 h can also be used as a screening test. Urine is collected on day 2, and excretion of urinary free cortisol >20 ¨g/24 h or urinary 17-hydroxycorticosteroid >4.5 mg/day helps confirm hypercortisolism.
Once hypercortisolism is confirmed, plasma ACTH should be determined. A level of ACTH below the normal range indicates a probable adrenal tumor; an elevated level indicates overproduction by either the pituitary or an ectopic ACTH-secreting tumor. MRI of the pituitary can identify a pituitary adenoma with considerable accuracy. Selective inferior petrosal venous sampling for ACTH can be done to confirm a pituitary source of ACTH and to help distinguish its origin from other sites. A CT or MRI scan of the chest and abdomen to look for ectopic sources of ACTH is indicated and can localize a tumor of the adrenal glands.
Hypercortisolism can result from iatrogenic use of steroid medications. Alcoholic patients and those with depression may also have increased levels of cortisol. Abnormal dexamethasone suppression tests have been described in patients with morbid obesity, depression, and a variety of CNS disorders. In these patients, urine free cortisol should be measured and an attempt made to assess diurnal variation in cortisol secretion because these tests are usually within normal limits in the setting of obesity. Hypertension resulting from other causes is common in the elderly, and estrogen replacement
therapy may alter normal dexamethasone suppressibility.
Cushing's disease is best treated by removing the pituitary adenoma responsible for the increase in ACTH secretion. After its removal, the adrenal gland remains unable to respond to normal stimulation for a prolonged time, and there is an altered ability to respond under conditions of stress. Hydrocortisone replacement therapy is necessary until normal pituitary-adrenal axis function returns, often taking as long as 6–24 mo. Radiation therapy has also been used to treat Cushing's disease, with an approximate cure rate of 25%. For patients who are not surgical candidates, inhibition of adrenal steroid biosynthesis can be useful in controlling symptoms and has been achieved with metyrapone, 500mg every 6 h, in combination with aminoglutethimide, 250–500 mg every 6 h, and ketoconazole, 200 mg every 6 h. Physiological replacement doses of a glucocorticoid may be necessary to avoid drug-induced adrenal insufficiency.
Adrenal neoplasms secreting cortisol should be resected when possible and often can be removed laparoscopically. Because the nonaffected adrenal gland is usually suppressed, once again hydrocortisone replacement is indicated until the gland returns to normal function. Metastatic adrenal carcinoma can be managed with the medications just mentioned or with mitotane, 2–10 mg daily in divided doses. Ectopic ACTH-secreting tumors should be surgically resected. If this is not possible, once again, medications may be used to suppress the high levels of cortisol. The somatostatin analogue octreotide has been used to suppress ACTH secretion successfully in as many as 33% of cases in which it has been attempted.
Patients who have hypercortisolism as a result of iatrogenic use of corticosteroids can usually expect a return to normal after discontinuation of the steroid therapy. In hypercortisolism, the best prognosis for total recovery is seen when a benign adrenal adenoma is easily removed. Pituitary adenomas are more difficult to treat and, even in the best of hands, have a failure rate of 10–20%. Even those who respond have a 15–20% recurrence rate over the next decade. The prognosis of patients with ectopic ACTH-producing tumors depends on the underlying type and degree of tumor involvement.
Papanicolaou DA et al: A single midnight serum cortisol measurement distinguishes Cushing's syndrome from pseudo-Cushing states. J Clin Endocrinol Metab 1998;83:1163. [PMID: 9543134]
ESSENTIALS OF DIAGNOSIS
Dyslipidemia is a major health risk regardless of age. The absolute risk of coronary heart disease increases dramatically with age in both men and women. Nearly 50% of all deaths in men older than 65 are thought to result from coronary heart disease, and the rate is even higher for women. Longitudinal studies show that total cholesterol levels increase in men after the onset of puberty until the sixth decade of life. This is followed by a plateau until the eighth decade, after which serum levels of cholesterol fall. In women, serum cholesterol concentrations are slighter higher than in men before age 30. Between 30 and 55 years, serum cholesterol increases although at a slower rate than in men. By age 60, cholesterol levels in women are equal to that of men and thereafter increase at a faster rate. The age-related changes in serum cholesterol concentration are primarily due to an increase in the low-density lipoprotein (LDL) cholesterol component. High-density lipoprotein (HDL) cholesterol levels do not vary greatly with age and are —10 mg/dL higher on average in women than in men. This age-related increase in LDL cholesterol is thought to result from a diminished activity of hepatic LDL receptors.
Although heart disease mortality has declined consistently since the 1960s, coronary heart disease remains the leading cause of death for both men and women in the United States; hypercholesterolemia is a major modifiable risk factor regardless of age. The incidence of dyslipidemia is highest in patients with early-onset coronary heart disease before 55 years of age in men and 65 years of age in women. The prevalence of coronary artery disease in this population exceeds 80% compared with 40–50% in the general population of similar age. Dyslipidemia is defined as a serum total
cholesterol, LDL cholesterol, triglyceride, apo-B, or Lp(a) concentration >the 90th percentile or HDL-cholesterol or apo-A-1 concentration <the 10th percentile. High concentrations of LDL are particularly associated with atherosclerosis. A low level of HDL cholesterol is also highly correlated with coronary heart disease. The total cholesterol-HDL ratio is suggested as a better predictor of future coronary heart disease. In men, a ratio >6.4 is associated with a greater risk; among women, a ratio >5.6 is considered to be a significant risk of coronary disease. The optimal level of LDL cholesterol is considered to be a value <100 mg/dL in both men and women. HDL cholesterol appears to have a protective effect with the goal of achieving levels >40 mg/dL in men and 51 mg/dL in women. The role of isolated elevation of triglycerides as a risk factor for heart disease is controversial, although they appear to be an independent predictor for coronary disease in women.
Lipids are insoluble in plasma and circulate bound to lipoproteins, which transport the lipid to various tissues for energy, steroid hormone production, bile acid formation, and lipid deposition. The lipoprotein consists of esterified and unesterified cholesterol, triglycerides, phospholipids, and protein. The protein components of lipoprotein are referred to as apoproteins or apolipoproteins. These serve as cofactors for enzymes and ligands for receptors. Lipoproteins are classified into 5 major groups, each with a different identifiable function.
Chylomicrons are very large particles that carry dietary lipid. They are associated with a variety of apolipoproteins, including A-1, A-11, A-lV, B-48, C-1, C-11, C-111, and E.
Very low-density lipoproteins (VLDLs) carry endogenous triglycerides and cholesterol. The major apolipoproteins associated with VLDLs are B-100, C-1, C-11, C-111, and E. Intermediate-density lipoproteins (IDLs) carry cholesterol esters and are associated with apolipoprotein B-100. LDLs carry cholesterol esters and are associated with apolipoprotein B-100. HDLs carry cholesterol esters and are associated with apolipoproteins A-l, A-11, C-1, C-11, C-111, D, and E.
Classically, patients can be classified into 1 of 6 subtypes of dyslipidemias, referred to as the Fredrickson Classification (Table 32-3). A serum lipid profile generally includes measurements of total cholesterol, triglycerides, and HDL cholesterol. A lipoprotein analysis is best done after a 12- to 15-h fast. The serum cholesterol is —3% lower than that obtained from plasma. The total cholesterol can vary by 4–10% within an individual because of a variety of factors, including illness (eg, myocardial infarction), infection, trauma, or surgery. There is also some variability between laboratories. For these reasons, more than 1 measurement of total cholesterol should be obtained before initiating treatment. Tissue injury may generate acute-phase proteins, which may impair hepatic lipoprotein production and metabolism, thus reducing serum concentrations of total cholesterol, HDL cholesterol, LDL cholesterol, and apolipoproteins B and A-1; triglyceride and lipoprotein(a) levels may rise under these circumstances.
Several categories of primary lipoprotein disorders lead to dyslipidemia. Most of these are detected early in life, but some may be noted for the first time later in life. Familial hypertriglyceridemia is associated with a decrease in the ability to remove serum triglycerides. This is caused by a decrease in lipoprotein lipase activity and an increased hepatic secretion of triglyceride-rich VLDLs. Although evidence of a relationship of triglycerides to coronary heart disease is unclear, persons with triglyceride levels >2000 mg/dL are at high risk for pancreatitis.
Familial combined hyperlipidemia is associated with increased hepatic secretion of apolipoprotein B containing VLDL that is converted to LDL. Depending on the ability to remove particles, VLDL or LDL or both accumulate. This is associated with a high risk of coronary heart disease, peripheral vascular disease, and stroke.
Table 32-3. Fredrickson classification of dyslipidemias.
Familial dysbetalipoproteinemia, or remnant removal disease, is associated with an increased secretion of VLDL and an impaired ability to remove remnant lipoproteins. This results from either a homozygous or heterozygous pattern for apolipoprotein E-2. This is also associated with a significant risk of vascular disease. Familial or polygenic hypercholesterolemia is associated with a decrease in LDL receptor activity. A defect in apolipoprotein B renders identification by the LDL receptor difficult. Once again, this disorder is associated with a high risk of vascular events, particularly myocardial infarction and stroke. Familial hypoalphalipoproteinemia, or low HDL syndrome, is associated with a decrease in apolipoproteins, increased removal, and increased cholesterol-ester transfer protein or hepatic lipase activity. This disorder commonly is associated with elevated levels of triglycerides and is associated with both peripheral vascular disease and coronary heart disease.
Cholesterol-lowering therapy may have positive effects on patients with atherosclerotic plaques and those with severe hypercholesterolemia who are still free of clinical heart disease. Patients should be stratified according to presumed risk. Recommendations for treatment are based on LDL cholesterol levels and are influenced by the presence of coronary heart disease and other cardiac risk factors. Treatment considerations include cost-effectiveness, patient compliance, and side effects. Discontinuation rates for lipid therapy in long-term studies regardless of age approach 40% for treatment with bile acid sequestrants, 46% for nicotinic acid, 37% for gemfibrozil, and ~15% for statins.
Treatment guidelines have not been established for elderly patients. Individual considerations must be made and careful thought given to patient choice, comorbidities, and expected life span. Age itself should not be a factor in deciding against treatment. It has been estimated that >40% of persons older than 65 will meet the criteria for primary prevention. Treatment appears to be reasonable for elderly patients at highest risk, such as for those with an LDL cholesterol >160 mg/dL with additional cardiac risk factors who have failed at dietary modification.
Persons with homozygous patterns of familial hyperlipidemia, primarily effecting LDL cholesterol, usually present with associated medical problems early in life and have significant morbidity and mortality despite best efforts of treatment. Elderly individuals who first present for treatment of dyslipidemia often have advanced coronary artery, cerebrovascular, or peripheral vascular disease as a result of years of lipid abnormalities. Although the goals of treatment may be the same regardless of age, medication side effects and patient acceptance may result in a less satisfactory outcome. The best way to achieve an optimal outcome is to initiate risk factor modification and appropriate drug therapy before vascular diseases develop.
Aronow WS: Underutilization of lipid lowering drugs in older persons with prior myocardial infarction and a serum low-density lipoprotein cholesterol >125 mg/dL. Am J Cardiol 1998;82:668. [PMID: not available]
National Cholesterol Education Program (NCEP) Expert Panel: Executive summary of the THIRD Report of the NCEP Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel lll). JAMA 2001;285:2486. [PMID: not available]
The ability to secrete growth hormone is impaired with aging, which can reduce muscle mass and alter body composition. The normal nocturnal surges of growth hormone secretion are diminished with age. After stimulation of growth hormone secretion by insulin-induced hypoglycemia, growth hormone increases in both young and old. This response, however, is diminished in some elderly patients, leading to the concept of reduced reserve. A significant effect of age on arginine-induced growth hormone secretion has not been observed.
The ability to produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH) appears to be preserved into old age; elevations occur in response to primary failure of end-organs. Age-related alterations have been described on the feedback in inhibition of gonadotropin secretion by sex steroids. Age has also been associated with changes in plasma levels of prolactin. Until age 45, the mean value for men is —66% of that found in women; levels become more equal with age. Blood levels of ACTH and TSH are within normal limits in healthy older people.
ESSENTIALS OF DIAGNOSIS
Major clinical manifestations of pituitary tumors are due to mass effects or alterations in pituitary hormone production. Most pituitary tumors in elderly persons are nonfunctional adenomas found during CT or MRI imaging of the brain done for other CNS problems. Mass effects include retro-orbital headaches and visual field deficits. Prolactin-producing micro- and macroadenomas are the most common of the functional tumors and can present with galactorrhea. Much less common are ACTH-secreting adenomas with Cushing's syndrome and growth hormone-secreting tumors with acromegaly.
Pituitary adenomas can result in loss of normal pituitary hormone production and present clinically with features of hypopituitarism. Many of the findings noted in younger persons with hypopituitarism are not readily apparent in the elderly because of age-related changes that make it more difficult to note a difference in libido, pubic and axillary hair, menstrual irregularity, and even such constitutional symptoms as weakness, cold intolerance, and impotence. Manifestations of hypopituitarism resulting from adenoma will vary depending on its size and location and the specific hormones affected. A deficiency of TSH results in hypothyroidism. ACTH deficiency causes diminished cortisol secretion and may lead to symptoms of weakness, weight loss, and hypotension. Deficiencies in FSH and LH in men may be associated with a diminished libido, reduced body hair including beard growth, reduced muscle mass, and impotence.
Laboratory findings are related to the specific deficiency noted. Fasting blood glucose may be low. Hyponatremia resulting from cortisol deficiency may be present. TSH, T4, and free T4 will be low if TSH secretion is reduced. Elevated prolactin levels are present in persons with prolactinomas and often in patients with acromegaly. The ACTH stimulation (cosyntropin stimulation) test has an inadequate response; 0.25 mg given intravenously results in <20 ¨g/dL rise within 30–60 min. Baseline ACTH is usually low or normal. Growth hormone deficiency is often found but difficult to detect clinically or with laboratory testing because of age-related effects. Stimulation tests, including hypoglycemia and exercise, are difficult and even dangerous in the elderly patient and are best avoided. Visual field impairments may be found. Rarely, hemorrhage in the pituitary may result in a complete loss of pituitary function with dramatic onset of symptoms. The pituitary and sellar region is visualized with CT or MRI.
In addition to pituitary adenoma, hypopituitarism can result from metastatic lesions to the pituitary and from ischemia causing necrosis of the hypothalamus or pituitary itself, most often in association with severe prolonged hypotension and cerebral anoxia. Severe illness can also cause suppressed pituitary function, especially TSH. Exogenous administration of corticosteroids reduces adrenal reserve and the normal pituitary-adrenal axis.
Hypopituitarism requires prompt treatment with replacement hormone therapy given for thyroid and adrenal insufficiency. If the patient is hypothyroid, l-thyroxine should be started but only after any coexisting cortisol deficiency has been corrected. Testosterone levels in men should be determined and replaced as necessary to alleviate related symptoms. Estrogen replacement should be considered as with any postmenopausal woman.
Depending on the size and extent of the adenoma, surgery or radiation may be indicated to treat manifestations of mass effect, most importantly visual field defects resulting from compression of the optic chiasm. Prolactin-producing adenomas can be managed medically with the dopamine agonists bromocriptine or cabergiline. Prolactin levels are usually reduced to normal, and galactorrhea, if present, resolves. Tumor size will decrease in some patients. Similarly, patients with acromegaly can be treated with somatostatin analogues with consequent reduction in levels of growth hormone and insulin-like growth factor as well as shrinkage of tumor size.
Pinzone JJ et al: Primary medical therapy of micro- and macroprolactinomas in men. J Clin Endocrinol Metab 2000;85:3053. [PMID: 10999785]
Schmidt DN, Wallace K: How to diagnose hypopituitarism. Learning the features of secondary hormonal deficiencies. Postgrad Med 1998;104:77. [PMID: 9676563]
ESSENTIALS OF DIAGNOSIS
Diabetes insipidus is associated with an increased thirst and large volumes of urine with low specific gravity or urine osmolality resulting from deficiency of or resistance to the action of ADH. Most commonly, in elderly patients, diabetes insipidus is due to a hypothalamic or pituitary disorder resulting in an inadequate ability to secrete ADH. It can result from trauma, infection, sarcoidosis, metastases, anoxic damage, and, rarely, pituitary adenoma. Nephrogenic diabetes insipidus results from a defect in the kidney that interferes with water reabsorption; the polyuria is unresponsive to the action of exogenous ADH, and ADH secretion is not impaired. Acquired forms of ADH-resistant diabetes insipidus are most common during later life and may be less severe than congenital forms. A variety of medical conditions, including pyelonephritis, renal amyloidosis, acute tubular necrosis, potassium deficiency, multiple myeloma, Sjögren's syndrome, and chronic hypercalcemia, can cause this problem. Medications, notably lithium and demeclocycline, can also cause a renal-resistant state.
Thirst is a hallmark of this disorder, although fewer elderly complain of this compared with younger patients until much later in the course of illness. Polyuria may lead to dehydration unless the elderly person is able to keep up with the need for increased amounts of volume. Other presenting symptoms and signs include incontinence, hypernatremia, dehydration, altered mental status, hypotension, and hyperuricemia in association with a central cause of diabetes insipidus resulting from reduced clearance of urate, which accompanies this disorder.
A 24–h urine collection should be obtained for volume, creatinine, and glucose. Serum sodium, glucose, urea nitrogen, calcium, uric acid, and potassium should also be measured. In nephrogenic diabetes insipidus, serum ADH levels will be high.
Polyuria may result from other disorders in the older person, including diabetes mellitus, excess circulating levels of corticosteroid (as with Cushing's syndrome or with exogenous administration), lithium use, diuretic use, and excess fluid intake).
Central diabetes insipidus responds to ADH preparations given under carefully supervised conditions. Desmopressin acetate can be given intranasally every 12–24 h as required for thirst and polyuria. Treatment is usually begun with 0.05–0.1 mL (100 ¨g/mL solution) every 12–24 h with individual titration thereafter. Because many elderly patients will not complain of excessive thirst until they are significantly hyperosmolar, monitoring is essential to determine proper dose requirements in a given patient. Desmopressin can also be given intravenously, intramuscularly, or subcutaneously, and an oral preparation is available but with more variable response. Potential side effects of the oral preparation include GI symptoms and elevated hepatic enzymes. Nasal preparations may cause nasal irritation and occasional agitation. Overtreatment may lead to water retention and hyponatremia.
Transient cases of diabetes insipidus may follow pituitary surgery and will usually remit within days to several weeks. Occasionally, permanent diabetes insipidus will remain and require lifelong treatment. Chronic diabetes insipidus can be successfully managed with appropriate desmopressin treatment and in itself should not result in increased morbidity or mortality. Elderly patients frequently have electrolyte disturbances that require careful monitoring.
Bichet DG: Nephrogenic diabetes insipidus. Am J Med 1998;105: 431. [PMID: 9831428]
SYNDROME OF INAPPROPRIATE ADH SECRETION
ESSENTIALS OF DIAGNOSIS
Age is associated with alterations in the secretion of ADH from the hypothalamic-neurohypophysial system and in the renal response to ADH. Basal blood levels of ADH may be increased with advancing age. More importantly, elderly persons have an enhanced secretory response of ADH to the stimuli of plasma hypertonicity and plasma volume reduction. Renal changes associated with normal aging can lead to impaired ability to dilute urine and excrete a water load. As a consequence, the elderly person is at increased risk for water retention and dilutional hyponatremia, characterized as the syndrome of inappropriate ADH secretion (SIADH). Hyponatremia resulting from SIADH has been observed in 7–10% of community-residing older persons and as many as 20% of elderly nursing home residents.
The clinical presentation is related to the effects of hyponatremia on the CNS. There is a general relationship between level of serum sodium and severity of symptoms; however, the more important factor is the rapidity of onset of hyponatremia. Mild symptoms, generally seen with serum sodium in the range of 120–130 mEq/L, are headache, fatigue, and lethargy. With more severe hyponatremia, confusion is often present and can progress to seizures, obtundation, and coma when serum sodium falls to ≤105–110 mEq/L. The more rapid the decline in serum sodium, the more severe the symptoms are likely to be for any given level of serum sodium. Typically, patients with SIADH do not have edema.
There are many potential underlying causes, including CNS disease of any type, the use of any number of classes of drugs, pulmonary diseases, malignancies, and enteral tube feeding (Table 32-4). Idiopathic SIADH (no evident underlying cause), has been observed in —2% of elderly individuals older than 80; whites are at higher risk than blacks. A common factor is the precipitation of SIADH by the administration of free water through hypotonic intravenous fluids (eg, 0.45% saline and 5% dextrose in water), encouragement of large unspecified amounts of oral fluid intake, or excessive water administered with tube-fed diets.
The diagnosis of SIADH requires differentiation of dilutional from depletional hyponatremia. This can usually be accomplished by careful history of diet, fluid intake, and fluid losses (eg, fever, tachypnea, vomiting, diarrhea, polyuria) and drugs. Commonly available laboratory measures such as hematocrit, BUN, creatinine, and uric acid are often helpful in distinguishing between types of hyponatremia. The hallmark of SIADH is the combination of low serum sodium and osmolality, urine osmolality inappropriately concentrated for level of serum osmolality, and excretion of sodium in the urine at a concentration >20 mEq/L.
The diagnosis of SIADH requires the exclusion of other disorders that can cause dilutional hyponatremia, including hypothyroidism, adrenal insufficiency, congestive heart failure, cirrhosis, and renal failure. Pseudohyponatremia can be seen with marked hyperlipidemia or paraproteinemia and can be recognized by measurement of serum osmolality, which will be normal at the same time that serum sodium is reduced. Hyperglycemia is accompanied by a reduction in serum sodium, which corrects when blood glucose level is restored to normal.
Initial treatment is directed at determining and addressing the underlying cause of the SIADH where possible. Mildly symptomatic hyponatremia can be treated with fluid restriction, usually at a level of 1000–1200 mL/24 h. More symptomatic hyponatremia requires the administration of hypertonic (3%) saline intravenously at a rate sufficient to increase serum sodium by 0.5–1.0 mEq/L/h with the objective of increasing serum sodium by no more than 12–15 mEq/L in the first 24 h and to a level no higher than 125 mEq/L to avoid inducing central pontine myelinolysis. The patient with seizures or coma and very low serum sodium may require intravenous furosemide in a dose of 1 mg/kg
body weight to induce a rapid loss of water in excess of sodium. In this circumstance, diuretic-induced potassium and magnesium losses need to be monitored and replaced. Chronic SIADH can often be managed with fluid restriction. If this is not successful, demeclocycline, 600–1200 mg/day, can be given to induce renal resistance to ADH action with consequent enhanced water loss.
Table 32-4. Causes of the syndrome of inappropriate antidiuretic hormone secretion in elderly patients.
Long-term outcome is depends on the underlying cause of the SIADH. CNS disease is often chronic with resultant chronic SIADH. Drug-induced SIADH will usually resolve rapidly with discontinuation of the drug. SIADH resulting from malignancy will depend on the ability to treat the malignancy. Severe hyponatremia is often a marker for the severity of underlying illness and is associated with a high level of morbidity and mortality, especially when accompanied by cachexia.
Gross P et al: The treatment of severe hyponatremia. Kidney Int 1998;64(suppl):S6. [PMID: 9475480]
Miller M: Syndromes of excess antidiuretic hormone release. Critical Care Clin 2001;17:11. [PMID: 11219224]
ESSENTIALS OF DIAGNOSIS
Hyperparathyroidism is a common disorder that affects predominantly postmenopausal women, with an incidence of approximately 2 per 1000. At least 50% of patients have no or minimal nonspecific symptoms or signs (eg, hypertension). The most frequent underlying disease is a single benign parathyroid adenoma. Occasionally, 2 or more glands may be involved. Less commonly,
primary hyperparathyroidism is due to 4-gland hyperplasia. A small number of patients have hyperparathyroidism as a component of MEN type 1 (MEN-1) or MEN-2 syndromes when it is familial and may be accompanied by pancreatic and pituitary tumors (MEN-1) or medullary carcinoma of the thyroid and pheochromocytoma (MEN-2).
The most common clinical circumstance is the unanticipated finding of hypercalcemia during a routine screening, biochemical assessment, or initial evaluation of suspected osteoporosis. Mild nonspecific complaints include fatigue, lack of energy, and generalized weakness. CNS symptoms of depression or mild cognitive impairment may be present. Questioning may disclose increased thirst and polyuria, which is due to the antagonistic effect of hypercalcemia on the renal action of ADH. A history of renal calculi is rare. However, a history of fracture, loss of height, and disproportionately low-for-age bone mineral density on dual energy x-ray absorptiometry scan calls for measurement of serum calcium.
When serum calcium is minimally or only intermittently increased, measurement of ionized serum calcium can establish the presence of hypercalcemia. Other common laboratory findings that support the diagnosis are elevated serum chloride and alkaline phosphatase levels. Serum BUN and creatinine should be measured because secondary hyperparathyroidism is often found in the presence of renal insufficiency. The diagnosis is confirmed by measuring serum PTH using an assay for the intact form of the hormone. Levels are almost always elevated above the upper limit of normal but may occasionally be in the upper normal range, when comparison with simultaneously measured serum calcium will demonstrate failure of PTH to be appropriately suppressed by the hypercalcemia.
The findings of hypercalcemia along with low-normal or low serum phosphorus suggest the diagnosis of primary hyperparathyroidism. Other causes of hypercalcemia will usually be associated with lowered levels of PTH and include a number of malignancies with or without bone metastases (squamous cell carcinoma of the lung, breast cancer, renal cell carcinoma, multiple myeloma, lymphoma). Hypercalcemia in many of these malignancies may be mediated by tumor-secreted PTH-related protein. Other causes of hypercalcemia include thiazide diuretics, vitamin D toxicity, sarcoidosis, hyperthyroidism, and hypocalciuric hypercalemia.
Parathyroid adenoma can be localized with a high degree of sensitivity and specificity by means of isotopic scanning with technetium 99m sestamibi. Other imaging procedures, including CT, MRI, and ultrasonography, are less helpful. Selective sampling of veins draining the parathyroid glands for step-up in PTH levels can be done in patients who have had previous parathyroid surgery with failure to identify abnormal parathyroid tissue.
Parathyroid surgery is often recommended despite uncertainties regarding the benefit of parathyroidectomy in patients with no or only mild symptoms and mild elevation of serum calcium. Elderly patients are at risk for sudden elevation of serum calcium if they become dehydrated. Alleviation of CNS symptoms may become evident after parathyroidectomy, even in those patients thought to be asymptomatic. The increased risk of fracture in the elderly woman with significant osteoporosis can be reduced by correction of the hyperparathyroidism. Surgery should be performed only by a surgeon experienced in parathryoidectomy to reduce the risk of damage to the recurrent laryngeal nerves and of permanent postoperative hypoparathyroidism. In the case of parathyroid adenoma, identification and removal of the adenoma will be curative. If parathyroid hyperplasia is found, 3½ of 4 identified glands must be removed. The availability of intraoperative rapid PTH assays can confirm in the operating room that the surgeon has successfully removed the abnormal tissue.
Medical management can be used in patients who are not candidates for surgery. Acute hypercalcemia can be treated with intravenous infusion of the bisphosphonate pamidronate in doses of 60–90 mg or with intravenous mithramycin in a dose of 25 ¨g/kg body weight. Chronic hypercalcemia can be controlled by oral or intravenous bisphosphonates, but elevated PTH levels are not lowered and may even rise further with the potential for adverse effect on bone. Calcium receptor agonists capable of suppressing PTH secretion are under investigation.
Marx SJ: Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000;343:1863. 
Silverberg SJ et al: A 10 year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249. [PMID: 1052803]