Pediatric Annals

Thyroiditis and Acquired Hypothyroidism

Stephen LaFranchi, MD

Abstract

Autoimmune thyroid disease can result in either goiter formation or thyroid atrophy, or hypothyroidism or hyperthyroidism. This article focuses on chronic lymphocytic thyroiditis (CLT) and acquired hypothyroidism.

Hashimoto first described CLT in 1912 when he reported four patients with a goiter characterized histologically by diffuse infiltration of lymphocytes and plasma cells, fibrosis, and follicle atrophy. Chronic lymphocytic thyroiditis or Hashimoto's thyroiditis is the most common childhood cause of goiter and hypothyroidism in iodine sufficient areas. Mounting evidence points to a failure in immune surveillance in genetically predisposed individuals producing defects in both the cellular (T cell) and humoral (B cell) arms of the immune system resulting in inflammatory destruction of the thyroid gland. This process is often insidious and may be detected by serendipitous discovery of a goiter or by recognition of growth failure or deterioration in school performance as early clinical features.

Chronic lymphocytic thyroiditis may also be part of other polyglandular syndromes or associated with chromosomal disorders. The diagnosis is usually clear by measurement of thyroid function tests and antithyroid antibody determinations. Treatment will restore the euthyroid state and may decrease goiter size. Evidence from some long-term follow-up studies shows that some children may recover from the inflammatory thyroiditis and hypothyroidism. While not necessarily requiring life-long thyroid treatment, these individuals will need life-long observation of their thyroid function.

EPIDEMIOLOGY

During childhood, CLT most commonly affects adolescent females. It is uncommon before the age of 3, but it can present at any age. In a study of 5179 children between 11 and 18 years of age in Arizona, Utah, and Nevada, 3.9% had goiters while 1.2% had clinical features and laboratory or histologie evidence on biopsy for CLT1 This study reported a 2:1 female preponderance, as is typical for most autoimmune disorders. A family history of some type of thyroid disorder has been reported in 30% of affected children.

Interestingly, the high areas of endemic goiter in the United States (Great Lakes, Northwest, and Appalachia), where up to 70% of the population had goiters, experienced a marked decrease with the institution of iodine prophylaxis in 1924- However, certain coal-rich counties in Kentucky still report a goiter prevalence as high as 35%, which can no longer be attributed to iodine deficiency. Studies have shown an increasing frequency of gram negative bacteria in the ground water which may act as a goitrogen. Further, a high proportion (one third to one half) of these children have antithyroid antibodies and subclinical hypothyroidism.2 Both immunologie and environmental factors may play a role in this example of endemic goiter.

Further studies, such as thyroid imaging, are not necessary unless there is a specific concern, such as a palpable solitary nodule. In the setting of a suspicious clinical picture, but negative antithyroid antibodies with or without an abnormality in thyroid function tests, it may be more difficult to prove the diagnosis of CLT. One option is to observe the patient over time, treat hypothyroidism if present, and repeat thyroid antibody tests in 6 to 12 months; a small proportion of initially negative patients will turn positive.

In the child with a goiter but negative thyroid autoantibodies, another option is to carry out a thyroid uptake and scan, using either radioiodine (preferably I23I-iodide or 125-I iodide) or WmTc pertechnetate. With CLT, the uptake is usually normal (unless Hashi tóxicos is is present) and the gland is variably enlarged, with a patchy or "moth-eaten" appearance in two thirds of children. While thyroid uptake of radioiodide is normal, oxidation and organi' fication of radioiodide is defective, and there is no attachment to the tyrosyl residues of thyrogloblin. Administration of…

Autoimmune thyroid disease can result in either goiter formation or thyroid atrophy, or hypothyroidism or hyperthyroidism. This article focuses on chronic lymphocytic thyroiditis (CLT) and acquired hypothyroidism.

Hashimoto first described CLT in 1912 when he reported four patients with a goiter characterized histologically by diffuse infiltration of lymphocytes and plasma cells, fibrosis, and follicle atrophy. Chronic lymphocytic thyroiditis or Hashimoto's thyroiditis is the most common childhood cause of goiter and hypothyroidism in iodine sufficient areas. Mounting evidence points to a failure in immune surveillance in genetically predisposed individuals producing defects in both the cellular (T cell) and humoral (B cell) arms of the immune system resulting in inflammatory destruction of the thyroid gland. This process is often insidious and may be detected by serendipitous discovery of a goiter or by recognition of growth failure or deterioration in school performance as early clinical features.

Chronic lymphocytic thyroiditis may also be part of other polyglandular syndromes or associated with chromosomal disorders. The diagnosis is usually clear by measurement of thyroid function tests and antithyroid antibody determinations. Treatment will restore the euthyroid state and may decrease goiter size. Evidence from some long-term follow-up studies shows that some children may recover from the inflammatory thyroiditis and hypothyroidism. While not necessarily requiring life-long thyroid treatment, these individuals will need life-long observation of their thyroid function.

EPIDEMIOLOGY

During childhood, CLT most commonly affects adolescent females. It is uncommon before the age of 3, but it can present at any age. In a study of 5179 children between 11 and 18 years of age in Arizona, Utah, and Nevada, 3.9% had goiters while 1.2% had clinical features and laboratory or histologie evidence on biopsy for CLT1 This study reported a 2:1 female preponderance, as is typical for most autoimmune disorders. A family history of some type of thyroid disorder has been reported in 30% of affected children.

Interestingly, the high areas of endemic goiter in the United States (Great Lakes, Northwest, and Appalachia), where up to 70% of the population had goiters, experienced a marked decrease with the institution of iodine prophylaxis in 1924- However, certain coal-rich counties in Kentucky still report a goiter prevalence as high as 35%, which can no longer be attributed to iodine deficiency. Studies have shown an increasing frequency of gram negative bacteria in the ground water which may act as a goitrogen. Further, a high proportion (one third to one half) of these children have antithyroid antibodies and subclinical hypothyroidism.2 Both immunologie and environmental factors may play a role in this example of endemic goiter.

Figure 1. In children with an inherited genetic predisposition to CLT, an apparent failure of suppressor T-cell lymphocyte function results in autoimmune thyroid damage by antibodymediated, complement-mediated, and natural killer cellmediated cytotoxicity.

Figure 1. In children with an inherited genetic predisposition to CLT, an apparent failure of suppressor T-cell lymphocyte function results in autoimmune thyroid damage by antibodymediated, complement-mediated, and natural killer cellmediated cytotoxicity.

Table

TABLEIThyroid Autoantlbodles Produced in Chronic Lymphocytic Thyroiditls

TABLEI

Thyroid Autoantlbodles Produced in Chronic Lymphocytic Thyroiditls

In an attempt to demonstrate a genetic predisposition to the immunologie defect leading to CLT, studies have shown an association with certain human leukocyte antigen (HLA) haplotypes. There is a higher frequency of HLA-DH and HLA-DrS with goiter and thyroiditis (2.25 increase in relative risk), while the atrophie variant of CLT is associated with HLA-Dr3. Recent studies looking at class II major histocompatibility antigens show nearly a fivefold increased risk in association with DQW7.3

TABLEZChronic Lymphocytic Thyroiditis: Classification of Clinical Disorders

TABLEZ

Chronic Lymphocytic Thyroiditis: Classification of Clinical Disorders

Figure 2. A 10-year-old boy with acquired hypothyroidism. a) & b) Before treatment; note the short stature (108 cm, less than the third percentile), immature upper-to-lower body proportions 61/47 cm = 1.30 [normal= 1.0O]), subdued facial expression, generalized myxedema, protuberant abdomen, and prominent buttocks, c) After 4 months of thyroid hormone therapy; note the increase in height 4 cm), loss of myxedema, and bright facial expression.

Figure 2. A 10-year-old boy with acquired hypothyroidism. a) & b) Before treatment; note the short stature (108 cm, less than the third percentile), immature upper-to-lower body proportions 61/47 cm = 1.30 [normal= 1.0O]), subdued facial expression, generalized myxedema, protuberant abdomen, and prominent buttocks, c) After 4 months of thyroid hormone therapy; note the increase in height 4 cm), loss of myxedema, and bright facial expression.

IMMUNOLOGIC PATHOGENESIS

While the exact pathogenesis of CLT remains unknown, there is strong circumstantial evidence pointing to an autoimmune origin involving both the cellular and humoral arms of the immune system.4 Cellular immunity is mediated by T lymphocytes, the cells that play a major role in graft -versus- host reactions, delayed hypersensitivity reactions, and direct cytotoxicity. Subsets of T lymphocytes (thymus derived) include:

* suppressor T lymphocytes, which limit the immune reaction to foreign antigens,

* helper T lymphocytes, which, together with suppressor T lymphocytes, interact with B cells bursa derived), which differentiate into plasma cells and secrete immunoglobulins (IgG1 IgM, IgA1 IgD, IgE) that act as antibodies, and

* effector T lymphocytes, which can cause direct cytotoxicity if not regulated by suppressor T lymphocytes.

Table

TABLE 3Cllnlcal Symptoms and Signs of Hypothyroidism Associated With Chronic Lymphocytic Thyroiditis

TABLE 3

Cllnlcal Symptoms and Signs of Hypothyroidism Associated With Chronic Lymphocytic Thyroiditis

Figure 3. Growth chart of patient in Figure 2; growth was normal until age 6 years, when the hypothyroidism was acquired and the growth rate declined.

Figure 3. Growth chart of patient in Figure 2; growth was normal until age 6 years, when the hypothyroidism was acquired and the growth rate declined.

Figure 1 shows the mechanisms by which the proposed defect in cell-mediated immunity results in damage to the thyroid gland and thyroiditis. A genetically determined defect in immune surveillance, perhaps linked to the HLA haplotypes described previously, results in failure of suppressor T lymphocytes to destroy a "forbidden" clone of T lymphocytes directed against thyroid antigens.5 Effector T lymphocytes may produce cytotoxicity directly by natural killer cell-mediated cytotoxicity, while helper T lymphocytes interact with B cells to produce antibodies against a variety of thyroidal components resulting in antibody-dependent cell-mediated cytotoxicity.6 A third mechanism is facilitated by complement production and is termed complementdependent, antibody-mediated cytotoxicity.

A wide spectrum of humoral thyroid autoantibodies are produced in CLT7; these are listed in Table 1 . Antithyroglobulin antibodies are not cytotoxic while antimicrosomal (antiperoxidase) antibodies fix complement and are cytotoxic to the thyroid follicle cells in vitro.7 The type, timing, and predominance of the antibodies produced may determine which clinical disorder is produced. For example, if thyroid' stimulating hormone (TSH) receptor antibodies are produced initially, this will result in an early thyrotoxic phase, so-called Hashitoxicosis. Alternatively, inflammation of the gland may result in discharge of T4 and T3 stored in colloid, resulting in a short-lived thyrotoxic phase that is not the result of antibody stimulation of the thyroid gland. In general, CLT tends to fall into one of two categories: atrophie autoimmune thyroiditis or goitrous autoimmune thyroiditis. Studies in adults report an association between TSH-binding inhibitory immunoglobulin and the atrophie form of CLT; however, this association has not been established in children.9

CLINICAL MANIFESTATIONS

Depending on the type and predominance of autoimmune antibodies produced and their course of action, different clinical thyroid disorders may result. A classification of clinical disorders associated with CLT is presented in Table 2. In approximately 5% to 10% of children with CLT, TSH-receptor stimulating immunoglobulin is the initial predominant antibody produced, resulting in hyperthyroidism as the presenting clinical disorder, Hashitoxicosis. The clinical symptoms and signs are indistinguishable from Graves' disease, except for the absence of exophthalmous and other signs of ophthalmopathy. Generally, the clinical thyrotoxic course is much shorter than with Graves' disease, lasting only weeks to a few months. Of course, this can only be appreciated in retrospect. In some cases, the thyrotoxic phase appears to result from more severe thyroiditis with inflammatory changes leading to indiscriminate discharge of stored T4 and T3. This disorder is characterized by absent radioiodine uptake in the face of hyperthyroidism, in contrast to the elevated uptake seen in Graves' disease and Hashitoxicosis. Hyperthyroidism and Graves' disease are discussed more fully in the article Thyrotoxicosis in Childhood" by Dr Thomas P. Foley, Jr (see pp 43-49).

Approximately two thirds of children with CLT will present with a goiter, so-called goitrous autoimmune thyroiditis. The goiter may be produced by an autoimmune antibody, which causes inflammatory lymphocytic infiltration of the thyroid, or by elevated serum TSH concentrations, which occurs when hypothyroidism is present. Thyroid growth stimulating antibody appears to be a likely candidate for the autoimmune antibody contributing to goiter formation in some children with CLT.10 The majority of these children will have no specific clinical manifestations of hypothyroidism. Thus, an asymptomatic goiter is the most common clinical presentation for CLT. The goiter is often discovered during neck palpation carried out during a physical examination performed for other reasons. Typically, the thyroid gland is diffusely enlarged, though it may be asymmetric. The goiter has a firm, rubbery consistency, and the surface is pebbly or bosselated due to accentuation of the normal lobular architecture. Markedly accentuated lobules may feel like distinct nodules and therefore may be mistaken for thyroid neoplasms. The goiter is not painful, although pressure symptoms such as dysphagia and mild tenderness on palpation may be present. Adjacent cervical lymph nodes may be easily palpable; they are of normal consistency and freely mobile.

Children with goitrous autoimmune thyroiditis may be biochemically euthyroid (normal serum T4 and TSH), have compensated hypothyroidism (normal ?*, elevated TSH)1 or have overt hypothyroidism (low T4, elevated TSH). The exact proportion of each category varies with reports, but the majority of children in general practice will iall into the first two categories.

A smaller proportion of children will present with clinical features of hypothyroidism, but without any palpable thyroid gland. The diagnosis of CLT is confirmed by the presence of thyroid autoantibodies. These children most likely have the atrophie autoimmune thyroiditis form of CLT, which is always associated with clinical and biochemical hypothyroidism. In adults with atrophie autoimmune thyroiditis, a greater proportion will have some form of thyroid growthblocking antibodies present,8 but this has not been demonstrated in children with atrophie autoimmune thyroiditis.9 Atrophie autoimmune thyroiditis does not appear to be a later stage of goitrous autoimmune thyroiditis. Children with euthyroid or hypothyroid goiter or atrophie autoimmune thyroiditis will not develop hyperthyroidism later in their clinical course.

Table

TABLE 4Autoimmune Polyglandular Syndromes

TABLE 4

Autoimmune Polyglandular Syndromes

The clinical features of hypothyroidism in CLT are typically insidious in onset. The most important effect is on growth; any child with a slow growth rate who is falling across percentile lines should be evaluated for hypothyroidism. Sluggish intellectual performance is often first detected by the child's teacher. Other clinical symptoms and signs are listed in Table 3. Children and parents are sometimes aware of a swelling in the neck, facial puffiness, and cold intolerance. While these children are myxedematous, and weight for height is increased, they usually are not significantly obese. The vast majority of obese children are not hypothyroid. Generally, a fairly dramatic change in body habitus and alertness, plus a catch-up in growth, will be seen within a short time after treatment is started, as illustrated by the patient in Figure 2. The same patient's growth chart is shown in Figure 3. If hypothyroidism is longstanding before diagnosis and initiation of treatment (ie, several years), however, not all the growth potential may be recovered, and final adult height may be below that expected for the child's genetic potential."

Two other clinical features, galactorrhea and sexual pseudoprecocity, are interesting endocrine effects manifested by a small number of children with primary hypothyroidism. Galactorrhea is the result of low serum T, levels leading by way of negative feedback to elevated hypothalamic thyrotropin-releasing hormone (TRH), which is the releasing hormone for both TSH and prolactin. With thyroxine replacement, both the elevated prolactin and galactorrhea will resolve. Sexual psuedoprecocity is manifested by breast development and sometimes vaginal bleeding in girls and enlargement of the penis and testes in boys. While these features suggest precocious puberty, short stature and delayed skeletal maturation (bone age) separate these children from those with true sexual precocity.

The exact mechanism of psuedoprecocity is unknown. Serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations are elevated. These glycoproteins consist of alpha and beta chains, the alpha chain being identical to that in TSH. An initial theory suggested that with increased alpha chain formation to produce more TSH, some might "spill over" to produce more FSH and LH, but with the development of alpha chain assays, elevated serum alpha chain formation has not been found. A more recent study suggests that elevated serum prolactin concentrations produce resistance to LH gonadal stimulation, perhaps leading to hypothalamic gonadotropinreleasing hormone production and stimulation of pituitary FSH and LH secretion and subsequent gonadal enlargement and pseudoprecocity.12 As with galactorrhea, thyroxine replacement will tower serum gonadotropins into the prepubertal range and the clinical features of sexual precocity will regress.

Lastly, if computed tomography or magnetic resonance imaging of the brain is performed in children with hypothyroidism (usually carried out to look for a pituitary lesion to explain growth retardation before the results of thyroid function tests are known), enlargement of the sella turcica may be discovered. This is the result of pituitary thyrotropin cell hypertrophy; it rarely causes any local pressure symptoms and signs and again is reversible with thyroxine replacement. If severe, an empty sella, thought to result from hypophyseal vessel infarction, may occur.13 Neurosurgical intervention is not indicated.

Chronic lymphocytic thyroiditis may be part of a more general autoimmune polyglandular syndrome. Awareness of" these associations will aiert the physician to the development of other autoimmune endocrinopathies in the patient or other family members. Because certain autoimmune endocrinopathies are more commonly seen together, Neufeld et al]4 classified them into three types (Table 4). Type I requires the presence of two of three major features - hypoparathyroidism, Addison's disease, or mucocutaneous candidiasis (often referred to as the HAM syndrome). Chronic lymphocytic thyroiditis, seen in approximately 10% of such children, should be screened for with a laboratory assessment of thyroid function and anrithyroid antibodies. A variety of other autoimmune problems, as listed in Table 4, may also be associated with this syndrome. Type II patients are usually identified by the detection of Addison's disease, associated with either CLT or insulindependent diabetes melhtus (IDDM). This combination of endocrinopathies, referred to as Schmidt's syndrome, more commonly presents in adulthood. Type III patients have CLT without Addison's disease, and they also have either IDDM or pernicious anemia, but no other distinguishing clinical features or known HLA linkages. The association of autoimmune endocrinopathies in children with IDDM emphasizes the importance of screening for CLT. Approximately 20% of diabetic children will have thyroid autoantibodies, and 5% will have a thyroid function abnormality.14

Table

TABLESDiagnostic Tests In Chronic Lymphocytic Thyroldltls

TABLES

Diagnostic Tests In Chronic Lymphocytic Thyroldltls

Chronic lymphocytic thyroiditis is also seen in increased frequency with chromosome abnormalities, including Turner's and Klinefelter's syndrome and Down syndrome. In one report in girls with Turner's syndrome, 18% had a goiter, 41% had antithyroid antibodies (predominantly antimicrosomal antibodies), 8% had overt hypothyroidism, and 8% had compensated hypothyroidism.15 In a study of Down syndrome children, 28% had antithyroid antibodies (again, predominantly antimicrosomal antibodies), 7% had overt hypothyroidism, 14% had compensated hypothyroidism, and 5% had hyperthyroidism; overall, 47% of Down syndrome children had evidence of antithyroid antibodies or thyroid disease.16 These studies again emphasize the importance of screening these children for autoimmune thyroiditis.

Table

TABLEÓThyroiditis and Acquired Hypothyroidism: Differential Diagnosis

TABLEÓ

Thyroiditis and Acquired Hypothyroidism: Differential Diagnosis

DIAGNOSTIC EVALUATION

The diagnosis of CLT is based on a compatible clinical presentation plus a constellation of confirmatory laboratory tests (Table 5). The laboratory hallmark of thyroiditis is the presence of thyroid autoantibodies. The two commercially available tests measure antimicrosomal (antiperoxidase) antibodies and antithyroglobulin antibodies; with improved assay sensitivity and specificity, elevated titers of these two types of antibodies are found in 90% to 95% of children with CLT. Measuring serum total T4 and T3 resin uptake (taking into account any changes in binding proteins), or free T4, plus TSH will determine whether the patient has overt hypothyroidism (low T4, elevated TSH), compensated hypothyroidism (normal T4, elevated TSH), or is euthyroid. If hyperthyroidism is suspected, measuring total T3, which may be proportionally more elevated than T4, may aid in the diagnosis. It is important to keep in mind that the normal range for serum T4 and T3 is higher in infants and children as compared to adults. With a compatible clinical picture and positive thyroid autoantibodies, there is no difficulty in making the diagnosis.

Table

TABLE 7Recommended Treatment Dosages

TABLE 7

Recommended Treatment Dosages

Further studies, such as thyroid imaging, are not necessary unless there is a specific concern, such as a palpable solitary nodule. In the setting of a suspicious clinical picture, but negative antithyroid antibodies with or without an abnormality in thyroid function tests, it may be more difficult to prove the diagnosis of CLT. One option is to observe the patient over time, treat hypothyroidism if present, and repeat thyroid antibody tests in 6 to 12 months; a small proportion of initially negative patients will turn positive.

In the child with a goiter but negative thyroid autoantibodies, another option is to carry out a thyroid uptake and scan, using either radioiodine (preferably I23I-iodide or 125-I iodide) or WmTc pertechnetate. With CLT, the uptake is usually normal (unless Hashi tóxicos is is present) and the gland is variably enlarged, with a patchy or "moth-eaten" appearance in two thirds of children. While thyroid uptake of radioiodide is normal, oxidation and organi' fication of radioiodide is defective, and there is no attachment to the tyrosyl residues of thyrogloblin. Administration of potassium perchlorate will lead to a high discharge of the accumulated radioiodide, a "positive perchlorate discharge test."

Thyroid ultrasound, which can assess thyroid size and parenchymal density, may also prove to be a useful ancillary diagnostic test. In one study of biopsy proven CLT, 95% of patients had a picture of scattered thyroid hypoechogenicity.17 Further studies are necessary in children with CLT. Fine-needle aspiration of the thyroid is not routinely recommended for the diagnosis of CLT, but it may be useful if a cyst or neoplasm is being considered.

In the presentation of a goiter or of hypothyroidism without a goiter and negative antithyroid antibodies, if the ancillary tests mentioned above do not provide evidence supporting the diagnosis of CLT, then other etiologies must be considered (Table 6). Subacute thyroiditis, a relatively rare disorder in children, may present with a goiter and a hypothyroid phase. The clinical hallmark of subacute thyroiditis is painful swelling of the thyroid gland preceded by nonspecific "viral syndrome" symptoms (fever, sore throat), with a lymphocytosis and elevated sedimentation rate. Initially, the inflammatory damage results in autonomous release of thyroid hormone and a thyrotoxic phase. The thyrotoxic phase is followed by a euthyroid, then hypothyroid phase, each lasting a few weeks or so, and then usually by a return to a euthyroid state, depending on the degree of tissue damage.

In regard to the childhood onset of congenital forms of hypothyroidism, radioiodine uptake and scan will usually diagnose thyroid aplasia or hypoplasia and locate an ectopie gland. The inborn errors beyond a trapping defect are usually suspected by an increased radioiodine uptake and large gland on scan. Goitrogen ingestion is often obvious by history. When the goitrogen is iodide, it will block radioiodide uptake and cryptic cases can be suspected in the face of a low uptake; elevated serum iodine concentrations will identify this goitrogen. Worldwide, iodine deficiency is the foremost cause of endemic goiter; iodine supplementation in salt and food preservatives has eliminated this as a cause in the United States. Other environmental goitrogens, such as ground water bacteria, have been suspected as a cause of endemic goiter in Kentucky, as described in the section on epidemiology.

TTiyroid hormone resistance, an autosomal dominant disorder, is characterized clinically by a family history of goiters, and euthyroid or hypothyroid features in the fece of elevated serum T^ or T3 concentrations. These individuals are often mistakenly diagnosed as having Graves' disease. The key laboratory finding separating these patients from those with Graves' disease is a normal TSH (not suppressed below the lower range of normal with a sensitive TSH assay); this constellation of clinical and laboratory features should lead the clinician to the correct diagnosis. Goiter and hypothyroidism may be found in disorders that infiltrate the thyroid gland, such as cystinosis or histiocytosis X; generally, the primary cause is evident when the hypothyroidism develops. The clinician should bear in mind, however, that CLT is more common than all these disorders.

Lastly, so-called simple or colloid goiter occurs about as often as goiter owing to CLT; however, hypothyroidism never results from a simple or colloid goiter.

MANAGEMENT

Children with hypothyroidism resulting from thyroiditis should be started on thyroxine replacement. The dose of replacement thyroxine decreases on a weight basis with age, although it approximates 100 ^g/m^/day. Recommendations for thyroxine doses by age are presented in Table 7. While the need to treat children with compensated hypothyroidism (normal T4, elevated TSH) is somewhat controversial, replacement therapy is recommended for the following reasons. First, it may be difficult to know if the "normal T4 concentration" is truly normal for that particular child. Second, there is some evidence that suppression of TSH may "put the gland at rest," slow the autoimmune inflammatory process, and allow a greater chance for recovery to a euthyroid state. Third, one can predict with confidence that a goiter in the face of an elevated TSH concentration will decrease in size with thyroxine suppression of TSH. Lastly, one can always discontinue therapy at a later time in life and recheck thyroid status. Children who are euthyroid at presentation will most likely remain euthyroid and so do not require thyroxine therapy.

The issue of whether to treat children with a euthyroid goiter resulting from CLT is also controversial. Most studies show that as many untreated as treated children with euthyroid goiter will experience a decrease in goiter size over time'; this probably represents the natural course of CLT rather than a treatment effect. Further, there appears to be no consistent effect of thyroxine treatment on antithyroid antibody titers or the histologie appearance of thyroiditis, as obtained by fine-needle biopsy.18

Children on treatment should be monitored every 6 to 1 2 months. The aim of replacement therapy is to produce normal growth and development. Children with a significant rail-off in growth at diagnosis should experience gradual catch-up in growth. Serum T4 or free T, and TSH should be monitored at regular intervals, with the aim to keep the T4 in the upper half of the normal range and the TSH suppressed to the lower range of normal. Overtreatment, as assessed by an abnormally high T4 and suppression of TSH below the range of normal, should be avoided as this may advance skeletal maturation too rapidly and compromise final adult height, and may lead to long-term decreased bone mineral density. Periodic evaluation of skeletal maturation by a bone age x-ray, every year or two until growth is complete, may help in the decision to adjust the thyroxine dose.

Once hypothyroidism develops and treatment is started, the question of whether this is a permanent change and whether lifelong therapy is necessary undergoes révaluation. Studies examining the natural course of Viypothyroidism resulting from CUT now show that approximately 20% of children will recover to a euthyroid status.19 In a report of 46 children with fine-needle biopsy-proven CLT, evaluation at a mean 6.5 years later showed that:

* of 24 initially euthyroid subjects, 80% were still euthyroid, 12% had developed compensated hypothyroidism, and 8% were overtly hypothyroid,

* of 16 children with initial compensated hypothyroidism, 56% had reverted to a euthyroid state, 12% remained with compensated hypothyroidism, and 31% had developed overt hypothyroidism, and

* of six initially hypothyroid children, 17% each had reverted to a euthyroid or compensated hypothyroid state, while 67% remained with overt hypothyroidism.20

Once thyroxine replacement is started, it is best to continue therapy until the child stops growing and passes puberty. If one wishes to assess the permanency of the initial hypothyroid state, treatment should be discontinued for 6 weeks and serum T4 or free T4 and TSH determined. If these are normal, the child can remain off treatment. All children with CLT, however, whether on treatment or ??? should be advised to continue life-long monitoring to assure a euthyroid state.

REFERENCES

1. Rallison ML, Brawn BM, Keating R, Rail JE, Tyler FH. Occurrence and natural history of chronic iymphocytlc thyroid it U in childhood. ; Fidiaci-, 1975;86:675-682.

2. Gallan E, Looksey RC, Ugan JS, Gettar, GS, Monwlvo JS, Pino JA. TKc Kentucky Appalachian goiter revisited. In: Abstracts of the 60th meeting oí the American Thyroid Association; September 19-22, 1984; New York, NY. ?-T.

3. Badenboop K, Schwari G, Walfish PG, Drummond V, Usadel KH, Bottaao Gf Susceptibility to thyroid autoimmune disease: molecular analysis of HLA-D region genes identities new markers for goitrous Hashimoioi thyroiditis. } Clin Endocrino/ Mítab. 1990;71;113M137.

4. Weetman AP, McGregor AM. Autoimmune thyroid disease; development« in our understanding. Endacr Rev 1984;5:309-355.

5. litakaM, AguagoJF, Iwatani Y, Row S'Y, Volpe R. Studiesof the effect of suppressor T lymphocytes on the induction of antlthyroid microsomal antibody-secreting cell* in autoimmune thyroid disease. } Clin Endocrinoí Mtub. ?98T;66:708-714.

6. Mackeniie WA, Schwanz AE, Friedmen EW, Davies TF. Intrathyroidal T cell clono irom patients with »maimmune thyroid disease. J Clin Endocrmol Meiob, 1987-^4:818· 824.

7. Fisher DA, Pandran MR, Garitón E. Autoimmune thyroid disease: an expanding spectrum. ftdiûcr Clin Nora Am. 1987:34:907-918.

8. Chiavato L, Vihi P, Santini F, et al. Incidence of antibodies blocking lhyiotrapln effect In vitro in patients with euthyroid or hypothyroid autoimmune thyroldltis. } CIm Endocrmol Mttafe. 1990:71:40-45.

9. Matsuura N, Konishl J, Yurl K, et a!. Comparison of atrophie and goitrous auto-immune thyroiditis in children: clinical, laboratory and TSH-receptor antibody studies, EurJ Pediatr. 1990; 149:529-533.

10. van dei Gaag RD. Drexhage HA, Wiersinga WM, et a). Further studies on thyroid growth stimulating immunoglohulins in euthyroid nonendetnlc goiter, j CIm EnàotrmA Meiab. 1985 i60:972 -979.

11, Rivkees SA, Bode HH, Ctawfocd JD, Lone-tetm K"*™th. in juvenile acquired hypothyroidism: the failure to achieve normal adult stature- N Engi J Mid. 1988;3I8:599-602.

12. Castro-Magana M, Ángulo M, Canas A, Sharp A, fijenres B. Hypothalamic-pituitary gonadal axis in boys with primary hypothyroidism and macroorchidism. } Pcdiarr. 1988;122:397-402.

13. LaFranchi SH, Harina CE, K ta i ni PL. Primary hypothyroidisro. empty sella, and hypopituitarism. J ftdìarr. 1986;108;57Ì-57Ì.

14. Neufeld M, MacLaren N, Blizzard R. Autoimmune polyglandu lar syndromes. Miatr Ann. I980i9;154-162.

15. Crune irò de Papendieck L, lorcansky S, Coco R. High Incidence of thyroid disturbances in 49 children with Turner syndrome. } ftdiotr. 1987;! 11:258-261.

16. Pueschel SM, Peizallo JC. Thyroid dysfunction in Dann syndrome. AmJ Dis Child, 1 985-,139:636-639.

17. Gutekunsi R, Hafermann W, Mansky T. Scriba PC. Ultrasonography related to clinical and laboratory findings in lymphocytic thyroiditis. Acca Endocnnol (Copenh). 1989;! 21: 1 19-135.

18. Hayashi Y1 Tamal H, Fukata S, et al. A lung term clinical, Immunologi cai, and histológica! fallow-up study of patients with goitrous chronic lymphocytic thyroiditis. J Clin Endocmoí Metab. 1985;6I:1172-1178.

19. Sitiar CA, Qaii R, David R- Juvenile autoimmune lhyroiiiuis: hormonal status at presentation and after long-term follow-up. Am } Du Cfiiid. 1986:140:877-880.

20. Maenpaa J, Raatikka M, Rasanen J. Taskinen E, Wager Q Natural course of juvenile autoimmune thyroiditis. J Pedían. 1985; 107: 898-904.

TABLEI

Thyroid Autoantlbodles Produced in Chronic Lymphocytic Thyroiditls

TABLE 3

Cllnlcal Symptoms and Signs of Hypothyroidism Associated With Chronic Lymphocytic Thyroiditis

TABLE 4

Autoimmune Polyglandular Syndromes

TABLES

Diagnostic Tests In Chronic Lymphocytic Thyroldltls

TABLEÓ

Thyroiditis and Acquired Hypothyroidism: Differential Diagnosis

TABLE 7

Recommended Treatment Dosages

10.3928/0090-4481-19920101-07

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