Adolescent Health Care: A Practical Guide
Thyroid Disease in Adolescents
Stephen A. Huang
Lawrence S. Neinstein
The prevalence of thyroid abnormalities in adolescents 11 to 18 years of age is cited to be 3.7% (Rallison et al., 1991) with more females than males affected. This chapter presents a summary of thyroid disease that occurs during adolescence, discussing thyromegaly, thyroid dysfunction (hypo- and hyperthyroidism), and nodular thyroid disease, with an emphasis on their clinical management. By maintaining an appropriate index of suspicion, the clinician can often recognize thyroid disease in its early stages. This can be very important during adolescence as thyroid abnormalities can lead to altered growth and development, menstrual irregularities, deterioration in school performance, or changes in behavior. Aspects of thyroid management related to pregnancy and the transition to adult care are also discussed.
Changes in Thyroid Gland Size and Function During Adolescence
Marked changes in thyroid volume occur during puberty as an adaptation to body and sexual development (Chanoine et al., 1991; Fleury et al., 2001).
Volume and Weight
- Thyroid volume significantly increases until the age of 8 without being influenced by sex and thereafter varies widely (Chanoine et al., 1991).
- The volume increases from 2.7 mL (SD = 0.8) in prepubertal subjects aged 8 to 11 years to 11.6 mL (SD = 4.4) in late pubertal subjects older than 17 years. This increase significantly correlates not only with chronological age but also with body weight, height, body mass index (BMI), and with pubertal stage (Fleury et al., 2001; Chanoine et al., 1991).
- The increase in volume occurs early between the ages of 11 and 15, usually with the onset of the first clinical signs of puberty (Fleury et al., 2001).
- Weight—several pediatric norms have been published and the equation of T= 1.48 + 0.054A, where T is the weight of the thyroid in grams and A is the age in months describes the average thyroid weight from birth to 20 years (Kay, et al., 1966). In North America, the normal adult thyroid weighs approximately 14 to 20 g (average weight 14.4 g for females 20 to 69 years of age and 16.4 g for males 20 to 29 years of age) (Mochizuki et al., 1963; Pankow et al., 1985).
- From the age of 1 year onwards, the concentration of total thyroxine (T4), free T4, and thyroid-stimulating hormone (TSH) tend to decrease until adult age, with the exception of thyroxine binding globulin (TBG) which increases by >60% and reaches a maximum at approximately 5 years of age (Elmlinger et al., 2001).
- Thyroid hormone levels do not appear to be associated with sexual development, except for TBG, which decreases slightly (p <0.04) between sexual maturity ratings of 1 and 5 (Elmlinger et al., 2001).
Clinical Evaluation for Thyroid Disease
It is critical to take a careful history and perform a thorough physical examination to evaluate adolescents for thyroid dysfunction.
Duration and severity of symptoms, fever, swelling, and pain must be recorded.
- Family history of goiter, thyroiditis, other thyroid problems, or other autoimmune disease
- Drug history—use of goitrogens, including lithium, iodine excess or anticonvulsants, exposure to radiation
- Pubertal and menstrual history
- Change in weight
- Growth problems
- Change in behavior, sleep pattern, activity level, or function in school
- Change in bowel habits
Important signs to consider in thyroid dysfunction include abnormal changes in:
- Height, weight, and BMI
- Pulse, blood pressure
- Skin texture or lesions
- Presence of tremor
- Eye examination—presence of exophthalmos or lid lag
- Deep tendon reflexes—normal or delayed relaxation phase
- Thyroid examination
- Normal gland: The normal thyroid gland is bilobed and connected by an isthmus that overlies the second through fourth tracheal cartilages. The main lobes of the thyroid are usually equal in size, but the right lobe tends to enlarge to a greater degree than the left in patients with diffuse thyromegaly.
- Physical examination: Physical examination of the thyroid is best performed with the patient seated and the neck in moderate extension. The health care provider should first inspect the neck visually, and then palpate the thyroid gland and the cervical and supraclavicular lymph nodes. Because the thyroid is ensheathed in the pretracheal fascia, it moves on swallowing and this feature is critical to the differentiation of thyroid tissue from other neck structures. Accordingly, the patient must be provided a cup of water and instructed to swallow sips of water at appropriate intervals during palpation. Some health care providers prefer to stand behind the seated patient and palpate the thyroid with their fingertips. Alternatively, the clinician can face the seated patient and use gentle pressure with the thumb to locate the thyroid isthmus and then move laterally, without release of pressure, to compress the lobe of the thyroid against the trachea as the patient sips water (Larsen and Davies, 2003). With practice, one should be able to palpate the normal thyroid in nearly all adolescents. The assessment of a goiter should take into account the normal thyroid size for age as described earlier. The health care provider should note size/shape/nodularity of the gland, location of any thyroid mass, mobility of any masses, and any tenderness.
Many thyroid tests are available, but only few are typically necessary for appropriate diagnosis. In euthyroid individuals, 99.98% of serum thyroxine (T4) and 99.7% of serum triiodothyronine (T3) is bound to serum protein (mostly TBG) and is biologically inactive (Larsen and Hay, 1998). Total thyroid hormone concentrations can therefore be abnormal not only in individuals with thyroid dysfunction but also in those with abnormal binding. This issue can be addressed by measuring serum free T4 (or free T3). Such tests are widely available for routine use. Alternatively, one can simultaneously measure total T4 and the T3-resin uptake (an estimate of protein binding), and then use the results to calculate a free T4 index (FT4I) (Baloch et al., 2002). These approaches are detailed in guidelines provided by the National Academy of Clinical Biochemistry at http://www.aacc.org/AACC/members/nacb/LMPG/. For nearly all patients, the simultaneous measurement of serum TSH and free T4 (or FT4I) is sufficient to diagnosis thyroid dysfunction (or to rule it out).
Common thyroid tests include the following:
- Serum total T4: Total T4is usually measured by competitive immunoassay.
- Adjusted T4: This is a calculation using total T4and T3 resin uptake with adjustment for changes in thyroid-binding capability, including TBG levels. This is also referred to as thefree T 4 index (FT4I). Adjusted T4 is generally high in patients with hyperthyroidism and low in patients with hypothyroidism. In individuals with normal hypothalamic-pituitary-thyroid function, conditions that alter thyroid hormone binding and thereby total T4 concentrations but yield a normal adjusted T4 (or free T4) level include the following:
- Factors increasing TBG: Oral contraceptives, pregnancy, heredity, heroin, methadone, acute hepatitis.
- Factors decreasing TBG: Androgens, cirrhosis, nephrosis, acromegaly, genetic, high-dose steroids (Sarlis, 2006).
- Drugs decreasing binding of T4and T3: Salicylates, furosemide, mefenamic acid, heparin, phenytoin, barbital, (Surks and Sievert, 1995).
- Serum free T4: Free T4can be assayed by methods that employ the physical separation of free hormone from bound hormone (equilibrium dialysis, ultrafiltration, gel filtration). Most routine clinical laboratories estimate free hormone concentrations by a two-test strategy or a ligand assay approach.
- Serum total T3: Total T3is usually measured by competitive immunoassay. Measurement of T3 can be useful in the rare thyrotoxic patient with a low serum TSH but a normal serum free T4. T3 measurements are generally not useful in evaluating hypothyroidism.
- Serum free T3: Measured in a manner similar to that of free T4.
- Serum TSH: Serum TSH is usually measured by nonisotopic immunometric assay (IMA) principles. Modern TSH assays are sufficiently sensitive to detect the suppressed TSH concentrations associated with hyperthyroidism. TSH is the most sensitive test for diagnosing primary hypothyroidism (high TSH) or thyrotoxicosis (low TSH, usually <0.1 µU/mL).
- Thyroid radioiodine uptake (RAIU): A measurement of thyroidal uptake of iodine-131 (131I) or iodine-123 (123I). 123I is preferred because of the lower radiation dose. The chief value of this test is in the differential diagnosis of thyrotoxicosis. The RAIU value is typically high in Graves hyperthyroidism or hyperthyroidism from hyperfunctioning thyroid nodule(s). The RAIU value is low in factitious hyperthyroidism and the thyrotoxic phase of transient thyroiditis. In the United States, dietary iodine intake renders the RAIU values in hypothyroidism indistinguishable from the lower end of the normal range, so RAIU measurements are usually not helpful in the evaluation of hypothyroidism. Addition of a perchlorate discharge test to the RAIU can be used to diagnose defects in iodine organification.
- Thyroid scan: A thyroid scan evaluates thyroid anatomy and function. It can be useful in the differential diagnosis of thyroid nodules and in the identification of ectopic thyroid tissue. 123I is the preferred radionuclide.
- Thyroid antibodies: Titers of antithyroglobulin and antimicrosomal (anti-thyroid peroxidase [TPO])
antibodies are elevated in most patients with Hashimoto thyroiditis. Antimicrosomal antibodies are more sensitive (99% sensitivity) than antithyroglobulin antibodies (36% sensitivity) (Nordyke et al., 1993). Titers of thyroid-stimulating immunoglobulin (TSI) and other TSH-receptor antibodies are typically elevated in Graves disease. These antibodies can be assayed at the time of diagnosis of Graves disease and monitored as an indicator of the resolution of the autoimmune process. The sensitivity of serum thyrotropin-receptor antibody (TRAb) assays is cited to be 75% to 96% for TSH-binding inhibitor immunoglobulin (TBII, a competitive binding assay with TSH) and 85% to 100% for thyroid-stimulating antibody (TSAb) measurements (a bioassay of TSH receptor activation) in untreated Graves disease (Saravanan and Dayan, 2001; Weetman, 2000). In practice, the measurement of TRAb is rarely needed to diagnose Graves disease.
- Reverse T3(rT3): Reverse T3 is an inactive isomer of T3, produced from the inner-ring deiodination of T4. In nonthyroidal illnesses, such as starvation and anorexia nervosa, T3concentrations can be low and reverse T3 concentrations can be normal or elevated. In hypothyroidism, levels of both T3 and reverse T3 are usually low.
- Thyroxine binding globulin: TBG can be measured directly by immunoassay.
- Thyroglobulin level: Serum thyroglobulin is high in hyperthyroidism, thyroiditis (thyroid inflammation), certain types of dyshormonogenesis, and in some patients with differentiated thyroid cancers of follicular cell origin and high tumor burden. Its utility in the monitoring of patients with thyroid cancer is realized only after the normal thyroid gland has been removed.
Thyroid deficiency and thyroid hyperfunction are associated with abnormalities of the hypothalamic-pituitary axis. In hypothyroidism, growth hormone, gonadotropin, and prolactin secretory dynamics are altered. This can cause impaired growth, menstrual irregularities, pseudoprecocity, and galactorrhea. Hyponatremia can occur in hypothyroidism due to impaired free water clearance. In prolonged hyperthyroidism, menstrual irregularities can also occur, and linear growth and bone maturation are accelerated.
Thyromegaly and goiter are synonyms that refer to enlargement of the thyroid gland. These disorders may be categorized by cause.
Causes of Thyromegaly
- Diffuse thyromegaly
- Autoimmune thyroid disease (Table 9.1): Classic Hashimoto thyroiditis Graves disease
- Painless sporadic thyroiditis (see “Hyperthyroidism and Thyrotoxicosis” section).
- Because of multiple classification schemes, the terms silent sporadic thyroiditis and subacute lymphocytic thyroiditis are used as synonyms for painless sporadic thyroiditis. (Huang, 2006)
- Postpartum thyroiditis (see “Hyperthyroidism and Thyrotoxicosis” section).
- Painful subacute thyroiditis (see “Hyperthyroidism and Thyrotoxicosis” section).
- Because of multiple classification schemes, the terms deQuervain disease, deQuervain thyroiditis, subacute thyroiditis, subacute nonsuppurative thyroiditis, giant-cell thyroiditis, migratory “creeping” thyroiditis, subacute granulomatous thyroiditis, pseudogranulomatous thyroiditis, and struma granulomatosa are all used variably as synonyms for painful subacute thyroiditis. (Huang, 2006)
- Environmental goitrogens: Iodine deficiency, medications (thionamides, lithium).
- Familial goiter.
- Idiopathic: An asymptomatic, euthyroid goiter may be discovered on routine physical examination, noted by a parent, or discovered by the teenager. The incidence is 9 of 1,000 per year, with most affected teens being female.
- Nodular thyromegaly:
- Hypofunctioning thyroid nodules (see “Thyroid Nodules” section).
- Hyperfunctioning thyroid nodules (see “Hyperthyroidism and Thyrotoxicosis” section).
Thyromegaly often occurs in combination with thyroid dysfunction, and such patients typically present with hypothyroid or thyrotoxic symptoms. In euthyroid individuals, thyroid enlargement may be noted as a cosmetic issue. Symptoms related to the compression/displacement of the trachea (stridor), esophagus (dysphagia), or recurrent laryngeal nerve (hoarseness) are unusual and generally limited to rare individuals with very large and rapidly growing goiters. Painful subacute thyroiditis can present with thyroid pain or tenderness, sometimes preceded by symptoms of fever or upper respiratory infection.
Although some goiters are idiopathic, the finding of thyromegaly obligates an investigation for underlying pathology and a focused evaluation will identify the cause in most cases. Assessment of goiter should take into account the normal thyroid size for age as described earlier. Thyroid ultrasonography can be used to estimate thyroid size more accurately and to address the possibility of any nodule appreciated by palpation. Because the most common causes of goiter are associated with thyroid dysfunction, thyroid function tests should be obtained in all patients with thyromegaly and monitored every 4 to 6 months through adolescence.
The management of nodular thyromegaly focuses on the evaluation for possible malignancy (hypofunctioning nodules) or hyperthyroidism (hyperfunctioning thyroid nodules). If thyroid dysfunction is present, it should be treated (see “Hypothyroidism” and “Hyperthyroidism and Thyrotoxicosis” sections). There is controversy over the approach to idiopathic goiter as many teenagers remain euthyroid for years and spontaneous resolution is possible. Specialists are divided between the use of exogenous thyroid hormone versus close observation without treatment. Rapid thyroid growth, compressive symptoms, or cosmetic concerns are indications to consider treatment. Thyroid hormone, if indicated, can be given as levothyroxine and titrated to a low normal serum TSH concentration (0.2–0.3 µU/mL).
Mostly, congenital hypothyroidism is permanent and requires lifelong hormone replacement. Outside of the newborn period, acquired hypothyroidism is usually due to autoimmune thyroiditis and so chronic autoimmune thyroiditis is the focus of this section. The childhood prevalence of chronic autoimmune thyroiditis peaks in early to midpuberty and a female preponderance of 2:1 has been reported (Lafranchi, 1992). Improvements in the measurement of circulating autoantibodies have obviated the need for biopsy in the diagnosis of autoimmune thyroid disease and the nomenclature itself has been redefined only during recent years (Table 9.1) (Davies and Amino, 1993; Larsen, 2003). The term thyroiditis is defined as evidence of “intrathyroidal lymphocytic infiltration,” with or without follicular damage. Two types of chronic autoimmune thyroiditis (also known as chronic lymphocytic thyroiditis) are causes of persistent hypothyroidism, Hashimoto disease (goitrous form, type 2A), and atrophic thyroiditis (nongoitrous form, type 2B).
The presentation of chronic autoimmune thyroiditis includes either hypothyroidism or goiter, or both. Thyromegaly is typically diffuse with a “pebbly” or “seedy” surface that evolves into a firm and nodular consistency. As the disease progresses, subclinical and then clinical hypothyroidism appears. Symptoms of hypothyroidism may be subtle, even with marked biochemical derangement (Table 9.2). Growth and pubertal development may be delayed. Gain in height is usually compromised to a greater degree than weight gain, and the bone age is delayed (Boersma et al., 1996; Chiesa et al., 1998). Hypothyroidism typically causes pubertal delay in teenagers, but in children may also induce a syndrome of pseudoprecocity manifested as testicular enlargement in boys and breast enlargement and vaginal bleeding in girls (Anasti et al., 1995; Castro-Magana et al., 1988; Jannini et al., 1995).
- Laboratory evaluation
- TSH and free T4: The serum TSH concentration is elevated in primary hypothyroidism. If the differential diagnosis includes central hypothyroidism or if the overall suspicion for hypothyroidism is high, a
free T4 measurement should be included. In mild hypothyroidism, serum T3 can remain in the normal range because of the increased peripheral conversion of T4 to T3 and the preferential secretion of T3 by the gland during hyperthyrotropinemia (elevated TSH). For these reasons, measurement of the serum T3 concentration is not useful in the diagnosis or monitoring of patients with primary hypothyroidism.
- Anti-TPO antibodies and antithyroglobulin antibodies: The presence of goiter or elevated TSH values should prompt the measurement of anti-TPO antibodies. Anti-TPO antibodies are the most sensitive screen for chronic autoimmune thyroiditis (Nordyke et al., 1993). Antithyroglobulin antibodies may be added if anti-TPO titers are negative. The typical patient with hypothyroidism secondary to chronic autoimmune thyroiditis has an elevated TSH level (more than 10 µU/mL), a low free T4, and positive anti-TPO antibodies (Saravanan and Dayan, 2001). However, in early stages of the disease, TSH may be normal (type 1A) or only modestly elevated. If antithyroid antibodies are absent, less common etiologies of primary hypothyroidism such as transient hypothyroidism (post subacute thyroiditis), external irradiation, and consumptive hypothyroidism should be considered (Hancock et al., 1995; Huang et al., 2002; Huang, 2005).
- Evaluation after biochemical hypothyroidism is confirmed: The initial history should include inquiry into energy level, sleep pattern, menses, cold intolerance, and school performance. In addition to palpation of the thyroid, the health care provider should assess the extraocular movements, fluid status, and deep tendon reflexes. Chronic autoimmune thyroiditis may be the initial presentation of an autoimmune polyglandular syndrome and the possibility of coexisting autoimmune diseases such as type 1 diabetes, Addison disease, and pernicious anemia must be addressed by the history.
Levothyroxine (L-T4) is the replacement of choice. There are virtually no adverse reactions and its long half-life of 5 to 7 days allows the convenience of daily administration.
- Initiation of levothyroxine: Some authors advocate a graded approach to the initiation of levothyroxine (Slyper and Swenerton, 1998). Alternatively, a starting dose can be estimated on the basis of the patient's age and ideal body weight with a full dose of thyroxine. The medication's long half-life ensures a gradual equilibration over the course of 5 to 6 weeks. Average daily requirements approximate 2 to 4 µg/kg in 10- to 15-year olds and 1.6 µg/kg during adulthood (average maintenance is between 50 and 200 µg), but dosing needs to be individualized ultimately on the basis of biochemical monitoring (LaFranchi, 1992). Current average replacement doses equal approximately 127 ± 39 µg in adults. Overtreatment with thyroxine should be avoided because it could lead to osteoporosis. Health care providers should counsel adolescents on thyroid hormone supplementation to have adequate calcium intake. However, calcium carbonate has been shown to interfere with thyroid hormone absorption. Patients taking this preparation need to be monitored to ensure that thyroid hormone replacement doses are adequate.
- Response to levothyroxine and monitoring: TSH normalization is the goal of replacement and we aim for a target range of 0.5 to 3 µU/mL. This will usually be associated with a free T4in the upper half of the normal range. Thyroid function tests should be obtained 6 weeks after the initiation or adjustment of the levothyroxine dosage. Once biochemical euthyroidism has been achieved, TSH can be monitored every 4 to 6 months in the growing teenager and yearly once linear growth is complete. If noncompliance is suspected as the cause of treatment failure, a free T4 may be measured because a serum TSH greater than twice the normal in the context of a normal free T4 suggests intermittent omission of the medication. A variety of conditions or drugs may
alter levothyroxine requirements (Table 9.3). In theory, levothyroxine should be administered at least 30 minutes before eating or any medication known to impair its absorption. However, from a practical viewpoint, the most important goal is to establish a regular time for levothyroxine administration. Growth and sexual development should be followed systematically as in any pediatric patient.
- Side effects: Although very rare, case reports have described the development of pseudotumor cerebri around the initiation of levothyroxine in a small number of school-aged children (Van Dop et al., 1983). A temporary reduction in the levothyroxine dose is appropriate to consider in this situation. Reactions to specific dyes or binders can be addressed by switching the levothyroxine preparation/manufacturer.
- Subclinical hypothyroidism: Subclinical hypothyroidism is defined as TSH elevation with normal serum free T4. The log-linear relation between serum TSH and free T4explains how small reductions in serum free T4 lead to large deviations in TSH. Most patients with subclinical hypothyroidism are asymptomatic and there is debate as to the need for treatment. Because studies in adults suggest that individuals with the combined risk factors of hyperthyrotropinemia and positive thyroid antibodies are at high risk for progression to overt hypothyroidism, it is our practice to recommend thyroid hormone replacement in patients with TSH values >10 µU/mL or with TSH values >5 µU/mL in combination with goiter or thyroid autoantibodies (Mandel et al., 1993).
- Counseling issues: Although rare exceptions have been reported, parents of teens with chronic autoimmune thyroiditis should be advised that the hypothyroidism will likely be permanent (Sklar et al., 1986). The monitoring of thyroid function is lifelong, but after the completion of linear growth, serum TSH measurements can be obtained annually, once euthyroidism has been restored. The initiation of medications which can alter levothyroxine requirements, such as those shown in Table 9.3, warrants additional monitoring.
- Pregnancy: Levothyroxine requirements increase by an average of 45% to 47% during gestation and untreated maternal hypothyroidism may adversely affect the intellectual development of the fetus (Alexander et al., 2004; Haddow et al., 1999; Mandel et al., 1993). Accordingly, a TSH should be checked if pregnancy is diagnosed and the frequency of monitoring increased. Young women who are treated for hypothyroidism and are euthyroid on replacement can be advised to increase empirically their prepregnancy levothyroxine dose by taking two extra daily doses each week (a 29% increase) beginning with the week pregnancy is confirmed. They should then undergo thyroid function testing and obtain appropriate professional guidance as soon as possible (Alexander et al., 2004).
Hyperthyroidism and Thyrotoxicosis
The term thyrotoxicosis refers to the manifestations of excessive quantities of circulating thyroid hormone from any source. In contrast, hyperthyroidism refers only to the subset of diseases associated with thyrotoxicosis, which are due to hormone overproduction (increased biosynthesis) and secretion by the thyroid gland itself (Table 9.4). Most adolescent and young adult patients have thyrotoxicosis caused by hyperthyroidism, especially
Graves disease. However, some may have thyrotoxicosis caused by thyroid gland inflammation causing a release of stored thyroid hormone (but not accelerated synthesis) or from ingestion of exogenous thyroid hormone. The ability to diagnose accurately hyperthyroidism and differentiate it from thyrotoxicosis is critical as disease management differs and antithyroid drugs have no role in the treatment of thyrotoxicosis without hyperthyroidism.
- Graves disease is the most common cause of hyperthyroidism in the United States and is the focus of most of this section. Only 5% of patients with Graves disease are younger than 15 years. However, hyperthyroidism becomes more common with age, particularly in women, affecting approximately 2% of women. The prevalence in females increases dramatically during late adolescence and young adult ages, with a peak at approximately 25 years.
- Graves disease is the most common autoimmune disorder in the United States and is associated with a five to ten times greater prevalence in women.
Causes of Thyrotoxicosis and Hyperthyroidism
- Graves disease: For practical purposes, almost all hyperthyroidism in adolescents is caused by Graves disease. Graves hyperthyroidism is caused by TSAbs that bind and activate the thyrotropin receptor, leading to thyromegaly and the hypersecretion of thyroid hormone. Lymphocytic infiltration of the thyroid is present, hence its classification as a form of thyroiditis (Table 9.1). Lymphocytic infiltration and the accumulation of glycosaminoglycans in the orbital connective tissue and skin cause the extrathyroidal manifestations of Graves ophthalmopathy and dermopathy (Weetman, 2000). Girls are affected four to five times more frequently than boys, although no gender difference is noted below 4 years of age (Lavard et al., 1994; Zimmerman and Lteif, 1998).
- Transient thyrotoxicosis due to the release of preformed thyroid hormones from a damaged gland:
- Painless sporadic thyroiditis
- Painless postpartum thyroiditis
- Painful subacute thyroiditis
These forms of thyrotoxicosis are self-limited because the thyroid gland contains a limited quantity of preformed hormone. It is hypothesized that painless postpartum thyroiditis and painless sporadic thyroiditis may result from thyroid autoimmunity (Pearce et al., 2003). Because painful subacute thyroiditis is often preceded by a prodome of infectious symptoms, a viral etiology has been proposed, although definitive evidence is lacking. In practice, the precipitating insult of transient thyroiditis in any individual patient is usually unknown, but care is unaffected as thyrotoxicosis is self-limited and supportive therapies are nonspecific. These forms of transient thyroiditis should be distinguished from acute or suppurative thyroiditis, which refer to infections (usually bacterial) of the thyroid gland that often require antibiotic therapy, but are usually not associated with the derangement of thyroid function (Huang, 2006).
- Toxic nodular goiter: Single adenoma or multiple nodules
- Ectopic thyroid tissue (e.g., struma ovarii [ovarian teratoma-containing thyroid tissue])
- Inappropriate TSH secretion—pituitary tumor
- Exogenous iodide intake
- Thyroid cancer
The presentation of Graves disease in adolescence may be insidious and a careful history will often reveal a several month history of progressive symptoms (Table 9.5). A goiter is palpable in most cases, with diffuse enlargement that is smooth, rubbery, and nontender. Extrathyroidal manifestations such as ophthalmopathy and dermopathy are rarer than in adults and tend to be less severe (Zimmerman and Lteif, 1998). In adolescents, prolonged hyperthyroidism from Graves disease may accelerate linear growth and bone maturation (Buckler et al., 1986; Wong et al., 1999). Commonly, patients have a family history involving a wide spectrum of autoimmune thyroid diseases, such as Graves disease, Hashimoto thyroiditis, or postpartum thyroiditis, among others.
- TSH and free T4: Thyrotoxicosis is recognized by an elevation of serum free T4with a decreased or suppressed serum TSH (typically <0.1 µU/mL). Free T4
may be normal in early disease or in iodine-deficient patients, so a determination of free T3 should be added if TSH is suppressed and the serum free T4 is normal.
- Duration of disease: Once biochemical derangement has been documented, it is helpful to address the duration of thyrotoxicosis to facilitate the differentiation of Graves disease from painless thyroiditis. Onset may be documented by prior laboratory studies or inferred from the history.
- More than 8 weeks: For thyrotoxicosis that has been present for >8 weeks, Graves is by far the most likely etiology. In such patients, the constellation of thyrotoxicosis, goiter, and orbitopathy is pathognomonic for Graves and no additional laboratory or imaging tests are necessary to confirm the diagnosis.
- Less than 8 weeks: If thyrotoxicosis has been present for <8 weeks, and if thyromegaly is subtle and eye changes are absent, an 123I uptake should be performed to address the possibility of transient thyrotoxicosis secondary to painless sporadic thyroiditis or painful subacute thyroiditis. The RAIU in these conditions will be low, distinguishing them from the more common Graves disease (Table 9.4). Hyperfunctioning nodules must be large to cause hyperthyroidism (typically 2–3 cm or more in diameter), so radioiodine thyroid scanning should be reserved for patients in whom a discrete nodule(s) is palpable. 123I uptake will localize to the hyperfunctioning nodule(s) and radionuclide signal in the surrounding tissue will be low secondary to TSH suppression. Thyrotoxicosis factitia can be recognized by a low RAIU and serum thyroglobulin in the presence of thyrotoxicosis and a suppressed TSH.
Therapy for hyperthyroidism (Graves disease) includes medical therapy with antithyroid drugs and definitive therapy with 131I or surgery.
Medical Therapy (Antithyroid Drugs)
Medical therapy is usually the primary modality for adolescent patients.
- Symptomatic end-organ therapy with a β-blocker (e.g., propranalol):The cardiovascular manifestations of hyperthyroidism are generally well-tolerated in the young, so this measure is needed only if symptoms are significant.
- Antithyroid medications:The thionamide derivatives, Tapazole (MMI) and propylthiouracil (PTU), are the most commonly used antithyroid drugs (Cooper, 2005; Franklyn, 1994). Both block thyroid hormone biosynthesis and PTU, when used at doses more than 450 to 600 mg/day, also inhibits the extrathyroidal activation of T4 to T3 (Klein et al., 1994). The recommended pediatric starting dose is 0.5 to 1.0 mg/kg/day for MMI and 5 to 10 mg/kg/day for PTU. For adolescent patients, the following rule of thumb is helpful in the determination of a starting dose:
- Because of its longer half-life, MMI can be administered qd or b.i.d, compared with the t.i.d dosing of PTU, so it is our first choice for initial therapy except for those patients who are pregnant (MMI administration during pregnancy has been associated with aplasia cutis) and those who present with severe hyperthyroidism. For severely hyperthyroid patients, PTU is the preferred thionamide because of its ability to inhibit T4to T3 conversion and a combination of high-dose PTU (up to 1,200 mg/day divided q6 hours) and inorganic iodine (SSKI three drops PO b.i.d for 5–10 days) will speed up biochemical correction (Davies, 2003).
- Response to antithyroid drugs and monitoring:After the free T4 has fallen to the upper half of normal range, the dose of antithyroid drug should be decreased by one half or one third. Patients should be counseled that clinical response often lags behind biochemical correction,
usually starting 2 to 4 weeks into therapy. Further dose adjustments are guided by serial thyroid function tests, initially relying upon the free T4. After pituitary TSH secretion recovers from suppression, TSH normalization is the goal of maintenance therapy. For any patient on antithyroid drug, we monitor thyroid function tests every 3 months and also 3 weeks after dose adjustment. Physical examination should focus upon heart rate, puberty, linear growth, and vision.
- Side effects:Antithyroid drugs are usually well tolerated, but side effects are more common in children than in adults (Lazar et al., 2000; Rivkees et al., 1998).
- Common side effects include pruritus, fever, rash, and urticaria. Less common side effects include gastrointestinal distress and change in taste sensation, and production of insulin autoantibodies, causing hypoglycemia.
- Agranulocytosis (defined as a granulocyte count <500/µl) is a serious idiosyncratic reaction that can occur with either MMI or PTU (Cooper et al., 1983). For this reason, a baseline white blood cell count should be obtained before the initiation of antithyroid drugs, and teens and their parents should be counseled that fever, sore throat, or other serious infections warrant the immediate cessation of antithyroid drugs, the notification of the physician, and a determination of white blood cell count with differential.
- Hepatitis is another serious but rare adverse reaction associated with the thionamides, so symptoms suspicious of hepatitis (jaundice, right upper abdominal pain, etc.) similarly warrant the immediate discontinuation of drug and medical evaluation including liver function tests.
- Remission:Reports of long-term remission rates in children and adolescents are variable, ranging anywhere from 30% to 60% (LaFranchi, 2005; Raza, et al., 1999; Rivkees et al., 1998; Shulman et al., 1997). If a patient has a normal serum TSH concentration for 6 months to 1 year on a minimal dose of antithyroid medication (5 mg/day of Tapazole or 50 mg/day of PTU), a trial off medication may be offered. Antithyroid drugs can be discontinued and TSH concentrations monitored at monthly intervals. If hyperthyroidism recurs, antithyroid medications should be resumed or definitive therapy provided.
- “Block and replace” strategy:Some authors have advocated a “block and replace” strategy of high-dose antithyroid medication (to suppress all endogenous thyroid secretion) combined with levothyroxine replacement. One report described a lower recurrence rate with this approach, but all subsequent studies have failed to duplicate this finding (Hashizume et al., 1991; Lucas, et al., 1997; McIver et al., 1996). For the purpose of simplifying the patient's regimen and minimizing the risk of adverse drug reactions, we prefer monotherapy with a single antithyroid medication.
- Subclinical hyperthyroidism:The term “subclinical hyperthyroidism” refers to patients who have a subnormal serum TSH (usually between 0.1 and 0.3 µU/mL) but normal concentrations of both free T4 and free T3. These patients are generally asymptomatic. The differential diagnosis is the same as for overt thyrotoxicosis. In adults older than 60 years, subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation, but the adverse sequelae of untreated subclinical disease in adolescents are not defined (Marqusee et al., 1998). No consensus exists as to the indications for therapy but, assuming there are no specific risk factors such as a history of cardiac disease, asymptomatic adolescents with subclinical hyperthyroidism can be followed without treatment. Thyroid function tests should be obtained every few months with the expectation that TSH suppression that is due to transient thyroiditis will resolve spontaneously and that which is due to Graves disease or autonomous secretion will declare itself over time.
The two options for the definitive treatment of Graves disease are radioiodine (131I) and thyroidectomy. Both are likely to result in lifelong hypothyroidism and there is disagreement in the literature as to their indications. Some centers use them as first-line treatment for pediatric hyperthyroidism (Clark et al., 1995; Moll and Patel, 1997; Ward et al., 1999). However, as a remission of Graves disease occurs in a significant percentage of adolescents, we recommend the long-term use of antithyroid medications until young adulthood. If patient noncompliance prevents the successful treatment of thyrotoxicosis or if both antithyroid medications must be discontinued secondary to serious drug reactions, definitive therapy is appropriate.
- Radioiodine (131I) ablative therapy: Therapeutic administration of 131I is the definitive treatment of choice in adults. Several studies support that the incidence of secondary malignancy in children or adolescents treated with 131I is not increased, but these study populations are relatively small and the carcinogenic effects of radiation to the thyroid are higher in young children than in adults (Read et al., 2004; Lafranchi, 2005; Baverstock et al., 1992; Nikiforov et al., 1996). This argues for continued study and, for children and teenagers who fail antithyroid medication, the provision of an 131I dose adequate to destroy all thyroid follicular cells. Efficacy is dependent on both thyroid uptake and mass, so we perform an 123I RAIU before treatment and prescribe an 131I dose which will provide approximately 200 µCi/g estimated weight into the gland at 24 hours (limited to a maximum of 11 mCi total into the gland at 24 hours).
At some point in young adulthood, it is appropriate to revisit the option of definitive therapy for those individuals on medical therapy. For young adults with persistent hyperthyroidism, 131I is our definitive treatment of choice. We perform an RAIU before treatment with the goal of delivering approximately 8 mCi of 131I into the gland at 24 hours. For glands larger than three times normal size, approximately 11 mCi is required (Alexander and Larsen, 2002). Definitive therapy typically results in permanent hypothyroidism, but allows for a simpler regimen of medication and laboratory monitoring (daily levothyroxine and a yearly TSH measurement). Additionally, prior definitive therapy simplifies the management of female patients during pregnancy.
- Surgery: Thyroidectomy is rarely used electively for the definitive therapy of Graves disease in the United States, except for patients with massive thyromegaly (more than eight times normal size) or for patients who have coexisting cytologically abnormal thyroid nodules. A recent meta-analysis of the pediatric literature reported that thyroidectomy relieved hyperthyroidism in 80% (subtotal thyroidectomy) to approximately 97% (total thyroidectomy) of children with Graves disease, but the
overall complication rates included a 2% incidence of permanent hypoparathyroidism, a 2% incidence of vocal cord paralysis, and a 0.08% mortality (Rivkees et al., 1998). On the basis of these data, the authors suggest that thyroidectomy be considered only for patients who have persistently failed medical management, or those whose parents or physicians do not wish to proceed with radioiodine therapy. The experience of the individual surgeon is the primary determinant of thyroidectomy morbidity and so referral to a surgeon with a low personal complication rate and extensive experience with subtotal thyroidectomy is required, if this is the desired procedure (Sosa et al., 1998). 131I therapy is an acceptable alternative if the surgical options are undesirable in a given community. 131I is recommended for all patients who have recurrence following surgery because of the high complication rate of secondary thyroidectomy (Waldhausen, 1997).
Approximately 0.6% of infants born to mothers with a history of Graves disease will develop neonatal hyperthyroidism due to the transplacental passage of TSI. This can occur even after successful definitive treatment with 131I or thyroidectomy, secondary to the persistence of maternal autoantibodies. The care of such women must be coordinated between a high-risk obstetrician and an endocrinologist. Fetal heart rate and growth should be monitored by regular prenatal ultrasonography, and the measurement of antithyrotropin receptor antibodies during at-risk pregnancies is recommended as a predictor for the development of fetal/neonatal Graves disease (Laurberg et al., 1998). Health care providers should be aware that maternal antithyroid medication use near delivery or the cotransfer of maternal thyrotropin receptor–blocking immunoglobulins may delay the appearance of neonatal hyperthyroidism (McKenzie and Zakarija, 1992; McKenzie and Zakarija, 1983). For high-risk infants, such as those born to mothers with high levels of TSAbs or those with a history of an affected sibling, the authors recommend thyroid function tests at birth, and at 1 and 2 months of age. An additional set of laboratory work at 1 week of age is indicated for infants who have been exposed to maternal antithyroid drugs in the third trimester.
- Prevalence: The frequency of nodular thyroid disease increases with age. Thyroid nodules are therefore common in adults (lifetime risk of 5% to 10%), but are rare in children (estimated frequency of. 05% to 1.8%) (Mazzaferri 1993; Rallison et al., 1975; Trowbridge et al., 1975). The condition affects more women than men. Although nodular disease of the thyroid is common, malignancy of the thyroid occurs in only 0.004% of the American population annually (12,000 new cases per year). In comparison to the 5% to 10% cancer prevalence cited for adults, early pediatric series reported a 40% to 60% prevalence of thyroid cancer in children with thyroid nodules (Rallison et al., 1975; Schlumberger et al., 2002; Trowbridge et al., 1975). More recent studies estimate the cancer prevalence of pediatric thyroid nodules to be 5% to 33% (Al-Shaikh et al., 2001; Arda et al., 2001; Khurana et al., 1999; Lafferty and Batch, 1997).
- Causes: High doses of neck irradiation increase the risk of developing thyroid nodules (Cooper et al., 2006). Thyroid nodules are also associated with several genetic disorders including multiple endocrine neoplasia type 2, familial nonmedullary thyroid cancer, the PTEN hamartoma tumor syndromes (Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome), and familial adenomatous polyposis. Other risk factors are described in subsequent text. In the authors' experience, most children and adolescents with thyroid nodules present without these risk factors.
- Clinical Presentation: Thyroid nodules may be detected on routine physical examination, as an incidental finding on radiographic studies, or brought to medical attention by the patients or their family. Regardless of how a thyroid nodule is discovered, all nodules of significant size should be evaluated for the possibility of malignancy.
- Evaluation: Because thyroid cancer prognosis depends in part upon tumor size, the early identification of differentiated thyroid cancer is the primary goal in the evaluation of nodular thyroid disease. Once a nodule has been detected, the medical history should include inquiry into prior neck irradiation, determination of whether there is a family history of thyroid cancer, and if there are extrathyroidal manifestations suspicious of other syndromes associated with thyroid cancer (see preceding text). A complete review of systems should include symptoms of thyroid dysfunction and neck compression (dysphagia, hoarseness, pain, etc.). Physical examination should include palpation of both the thyroid gland and the cervical lymph nodes. Nodules that are hard, large, adherent to adjacent structures, or associated with lymphadenopathy should heighten the suspicion of cancer.
- Factors suggesting a malignant diagnosis are as follows (Hegedus, 2004):
- High suspicion
- Family history of medullary thyroid carcinoma or multiple endocrine neoplasia
- Rapid tumor growth
- Hard or firm nodule
- Fixation of the nodule to adjacent structure
- Paralysis of vocal cords
- Regional lymphadenopathy
- Distant metastasis
- Moderate suspicion
- Age younger than 20 years or older than 70 years
- Nodule more than 4 cm or partially cystic
- Symptoms of compression such as dysphagia, dysphonia, hoarseness, dyspnea, and cough
- History of neck irradiation
- Factors suggesting a benign diagnosis are as follows:
- Family history of autoimmune disease (e.g., Hashimoto thyroiditis)
- Family history of benign thyroid nodule or goiter
- Thyroid hormonal dysfunction—either hypo- or hyperthyroidism
- Pain or tenderness associated with nodule
- Soft, smooth, and mobile nodule
- Laboratory evaluation: The initial laboratory evaluation should include thyroid function testing (serum
TSH) to screen for autonomous/hyperfunctioning nodule(s). Diffuse thyromegaly and/or hyperthyrotropinemia warrant the measurement of antithyroid antibodies to diagnose possible chronic autoimmune thyroiditis. However, it is important to realize that the diagnosis of autoimmune thyroid disease does not exclude the possibility of coexistent thyroid cancer, illustrated by the report of autoimmune thyroiditis in 18% (7 of 39) of pediatric patients with papillary thyroid cancer cited by one study (Gupta et al., 2001).
- Imaging studies and ultrasonography: Because >90% of thyroid nodules are cold by thyroid scanning and therefore require biopsy, the author recommends that 123I thyroid scanning/scintigraphy to detect benign hyperfunctioning nodules should be reserved for patients with suppressed serum TSH concentrations (Schlumberger et al., 2002). For all others, ultrasonography is the most cost-effective imaging modality to confirm the presence of a thyroid nodule. Because of limitations of physical examination alone, thyroid ultrasonography should be performed in all adolescents with suspected thyroid nodules before any attempt at biopsy. Cytology should be obtained in all patients before considering surgery and ultrasound-guided fine-needle aspiration is the procedure of choice because it improves the diagnostic accuracy of fine-needle aspiration guided by palpation alone and reduces the likelihood of accidental penetration into the trachea or the great vessels (Marqusee et al., 2000).
- Suggested Approach for the Evaluation and Management of Thyroid Nodules: The serum TSH concentration should be measured before endocrine consultation for nodular thyroid disease. If the patient's serum TSH concentration is suppressed, an 123I scan should be obtained to address the possibility of a hyperfunctioning nodule. The hyperfunctioning nodule might be treated with radioiodine, but alternatives include no treatment, surgery, and ethanol injection. If the serum TSH is normal or high, the patient should be triaged directly to a center with experience in the management of thyroid nodules and cancer, and any thyroid nodule ≥1 cm in diameter requires biopsy by ultrasound-guided fine-needle aspiration. Categorization of biopsy interpretations into cytologic risk categories facilitates the discussion on surgical approach, based on the likelihood of malignancy associated with the patient's specific category and an individual assessment of the child's operative risks. If surgery is indicated, referral to a surgeon with extensive experience in pediatric thyroidectomy and a low personal complication rate is paramount, regardless of the degree of resection (Sosa et al., 1998). Adolescents with thyroid nodules <1 cm or with benign cytology should be followed up chronically by serial ultrasonography every 6 to 12 months, and ultrasound-guided fine-needle aspiration should be repeated if significant interval growth or other concerning sonographic features develop. Clinical practice guidelines were published in Cooper et al, 2006 by the American Thyroid Association (www.thyroid.org/professionals/publications/documents/Guidelinesthy2006.pdf and the American Association of Clinical Endocrinologists (www.aace.com/pub/pdf/guidelines/thyroid_nodules.pdf).
For Teenagers and Parents
http://www.magicfoundation.org/www/docs/114/thyroid_disorders.html. Information from the Magic foundation on thyroid disorders.
http://www.tsh.org. Thyroid Foundation of America information on thyroid disease; also has links to many more sites.
http://www.thyroid.org. Home page of the American Thyroid Association.
http://www.endocrineweb.com/thyroid.html From Endocrine Web page, information on many thyroid problems with information on thyroid hormone, tests, disease states, and more.
http://www.nlm.nih.gov/medlineplus/thyroiddiseases.html. The National Institutes of Health search area on thyroid diseases.
http://www.thyroid.about.com/health/thyroid/library/weekly/aa0421001.html. Thyroid 101 with basic information about all thyroid diseases.
For Health Professionals
http://familydoctor.org/flowcharts/514.html. Flowchart on neck swelling evaluation from the American Academy of Family Physicians.
http://www.thyroid.org. The American Thyroid Association website with helpful updates on a variety of topics, including patient information sheets, thyroid hormone assays, and ongoing diagnostic and management controversies.
http://www.aacc.org/AACC/members/nacb/LMPG/. The National Association of Clinical Biochemists provides Guidelines for Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease.
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