Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter XV.2. Thyroid Disorders
Melanie L. Shim, MD
June 2002

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A previously healthy 14 year old female complains of a fast heart rate, weight loss, and fatigue over the past 2 months. Her family history is significant for a grandmother and aunt with Hashimoto thyroiditis.

Exam: VS T 37, HR 110, R 22, BP 120/50. On exam, she is comfortable without diaphoresis. She has a mild tachycardia without murmurs or gallop. She is found to have a smooth goiter with a bruit, a mild tremor, and exaggerated DTRs.

Labs: Elevated T4, undetectable TSH. Thyroid stimulating immunoglobulin assay is positive.

She is diagnosed with Graves' disease. She is treated with PTU (propylthiouracil) after which her thyroid function normalizes. Clinically, there is resolution of her tachycardia, weight loss, and fatigue, and her goiter decreases in size. Her thyroid function is monitored routinely and the dose of PTU adjusted as indicated to maintain a euthyroid state. Two years after diagnosis, she goes into remission and PTU is discontinued.


The hypothalamic-pituitary-thyroid axis regulates production and maintains peripheral concentrations of the biologically active thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Pituitary thyroid stimulating hormone (TSH) secretion is modulated by the stimulatory effect of hypothalamic thyrotropin releasing hormone (TRH) and the inhibitory (negative feedback) effects of T4 and T3 influencing both TRH and TSH secretion. The major secretory product of the thyroid gland is T4. It is synthesized as a component of the large (660-kD) precursor thyroglobulin molecule. Iodine is the rate-limiting substrate, which must be actively transported in to the thyroid follicular cell by a plasma membrane sodium/iodide pump. Iodide trapping, thyroglobulin synthesis, and iodothyronine secretion are all stimulated by TSH. The iodothyronines are transported in blood bound to the thyroid hormone-binding proteins, thyroid hormone-binding globulin (TBG) and transthyretin (prealbumin). Thyroid hormones also bind to albumin and lipoproteins with lesser affinity (1,2).

Only small amounts of T4 and T3 are free or unbound. This free hormone is available to tissues. T4 serves largely as a prohormone and is deiodinated in peripheral tissues by several iodothyronine monodeiodinase enzymes to active T3 or biologically inactive reverse T3 (rT3). The major source of circulating T3 is peripheral conversion from T4, largely by the liver. Only small amounts of T3 are secreted by the thyroid gland in euthyroid subjects ingesting adequate iodine. Normally, T4 is deiodinated to both T3 and rT3. The T3 mediates the predominant effects of thyroid hormones via binding to the 50-kD nuclear protein receptors, which function as transcription factors modulating thyroid hormone-dependent gene expression (1,2).

During the first trimester of gestation, the thyroid gland arises from the foramen caecum at the base of the tongue and migrates caudally to the neck site. By 12 weeks gestation, iodine trapping and T4 and T3 synthesis occur. Adequate quantities of iodide are essential for fetal thyroid hormone synthesis. The placenta imposes a relative barrier to the thyroid hormones and is impermeable to TSH, so the fetal hypothalamic-pituitary-thyroid system develops largely autonomous of the maternal system. The placenta is permeable to thionamide drugs used to treat maternal hyperthyroidism, which could result in fetal and early postnatal hypothyroidism. In term infants, following delivery, there is a postnatal surge of TSH which returns to normal by 2-3 days. T3 and T4 concentrations increase 2 to 6 fold, peaking at 24 to 36 hours after birth and gradually declining to levels characteristic of infancy over the first 4-5 weeks of life. Normal thyroid function parameters vary with age (1,2).

Thyroid Disorders in Children:

Primary hypothyroidism:
. . . . . 1. Congenital
. . . . . 2. Autoimmune (Hashimoto thyroiditis)
. . . . . 3. Iodine deficiency
. . . . . 4. Iatrogenic (goitrogen ingestion, radiation)
. . . . . 5. Transient (transplacental passage of antithyroid drugs, maternal transfer of antibodies)

Secondary hypothyroidism:
. . . . . 1. Central hypothyroidism (TSH deficiency)

Primary hyperthyroidism:
. . . . . 1. Autoimmune (Graves' disease)
. . . . . 2. Neonatal Graves' disease (transplacental passage of TSH receptor-stimulating antibody)
. . . . . 3. Factitious (ingestion of excess thyroid hormone)

Secondary hyperthyroidism:
. . . . . 1. Hyperthyrotropinemia (TSH excess)

Other thyroid disorders:
. . . . . 1. Thyroid nodules (benign vs. malignant)
. . . . . 2. TBG deficiency or excess
. . . . . 3. Synthetic defects - hormones or carrier proteins
. . . . . 4. Euthyroid Sick Syndrome

Congenital hypothyroidism (3) is an important cause of mental retardation that can be prevented with early identification and treatment. Newborn screening for congenital hypothyroidism is now routine in most industrialized societies. It is based on physiologic principle that primary hypothyroidism results in neonatal TSH hypersecretion. Screening tests are usually carried out with dried blood spot samples collected via skin puncture. In some areas T4 is measured initially, and TSH is measured in samples with the lowest 10-20% of T4 results. In other areas, direct TSH screening has been used. The preferred time for blood sampling is 3-5 days after birth. However, many newborns are now discharged from the hospital before 3 days of age. Early measurement increases the prevalence of infants demonstrating a modest elevation of TSH concentrations due to the physiological neonatal TSH surge; thus increasing the number of false-positive results (4). The prevalence of congenital hypothyroidism approximates 1 in 4000 births. Etiologies include thyroid dysgenesis, thyroid dyshormonogenesis, hypothalamic-pituitary (TSH) deficiency, and transient hypothyroidism (usually iodine, drug, or maternal antibody induced); the proportions approximate 75%, 10%, 5%, and 10%, respectively, of all cases of congenital hypothyroidism.

Thyroid dysgenesis describes infants with ectopic or hypoplastic thyroid glands as well as those with total thyroid agenesis. It is usually sporadic, with a 2:1 female preponderance. Ectopic glands may be located anywhere from the base of the tongue, along the thyroglossal duct, laterally, or as distant as the myocardium. A normal or near normal circulating level of T3 in the presence of low T4 suggests the presence of residual thyroid tissue, and this can be confirmed by a thyroid scan. A measurable level of serum thyroglobulin indicates the presence of some thyroid tissue; athyroid infants have no circulating thyroglobulin.

Dyshormonogenesis, or the inborn errors of thyroid hormone synthesis, secretion, and utilization, follows an autosomal recessive pattern of inheritance. The most common defect involves deficiency of thyroperoxidase enzyme, which is responsible for organification of iodide. When present with sensorineural hearing loss it is known as Pendred syndrome. Other defects may involve iodide trapping, coupling of tyrosyl rings, abnormal thyroglobulin synthesis, or deiodination of iodothyronines.

Transient congenital hypothyroidism may result from goitrogenic agents and transplacentally derived TSH receptor-blocking maternal autoantibodies. The presence of a goiter in an infant is supportive evidence of antithyroid drug- or goitrogen- induced transient hypothyroidism. Maternal TSH receptor-blocking antibody-induced hypothyroidism should be suspected in any case in which the mother has a history of autoimmune thyroid disease. The presence in maternal or neonatal blood of a high level of TSH receptor-blocking antibody is strong supportive evidence.

Confirmatory diagnosis of congenital primary hypothyroidism is based on measurement of T4 (low) and TSH (high). Optional studies include ultrasound and radionucleotide scan. Physical examination may reveal one of several early and subtle manifestations of hypothyroidism, including a large posterior fontanelle, prolonged jaundice, macroglossia, hoarse cry, distended abdomen, umbilical hernia, hypotonia or goiter. Fewer than 5% of infants are diagnosed on clinical grounds before the screening report, but 15-20% of infants have suggestive signs when carefully examined at age 4-6 weeks, after the screening results have been reported. For infants with congenital hypothyroidism, prompt initiation of levo-thyroxine (75-100-ug/m2/d) treatment is essential. Delayed institution of treatment (>45days) is clearly associated with diminished mean IQ.

Hashimoto thyroiditis (autoimmune hypothyroidism, chronic lymphocytic thyroiditis) is an autoimmune, inflammatory process causing 55-65% of all euthyroid goiters and nearly all cases of hypothyroidism in childhood and adolescence (5,6). Prevalence studies have found that as many as 1.2% of school-aged children have chronic lymphocytic thyroiditis as defined by an enlarged thyroid gland and detectable thyroid antibodies in the serum. Females predominate at a ratio of 2:1 with a peak age of onset in mid-puberty. It is rare under 4 years of age. The specific mode of inheritance is not known, but there is a high familial incidence. Thyroid inflammation and damage result from self-directed humoral and cell-mediated immunity. Antibody markers of the destructive process include anti-thyroglobulin and anti-thyroperoxidase antibodies. One or both of these antibodies are present in virtually all patients with chronic lymphocytic thyroiditis, but they are not specific for this disorder and may be found in other autoimmune diseases such as Graves' disease, Addison's disease, and Type 1 diabetes.

The initial presentation of Hashimoto thyroiditis can usually be categorized as thyromegaly with euthyroidism, toxic thyroiditis, or hypothyroidism with or without thyromegaly. The majority of patients are asymptomatic and present with an enlarged thyroid gland. The gland may be symmetrically or asymmetrically enlarged with a bosselated (cobblestone) texture. Toxic thyroiditis (Hashitoxicosis) is a transient, self-limited form of hyperthyroidism occurring in less than 5% of patients. If hypothyroidism is present, there may be a history of poor growth, fatigue, constipation, mild weight gain, dry skin and cold intolerance.

The initial screening of thyroid function should include measurement of serum free T4, TSH, and anti-thyroid antibodies. Again, most children are euthyroid initially (normal T4 and TSH). The incidence of hypothyroidism (low T4 and high TSH) is 3-13% and compensated hypothyroidism (normal T4 and high TSH, signifying possible impending hypothyroidism) occurs in up to 35%. In addition, serum T3 concentration should be determined if the patient appears to have hyperthyroidism.

Treatment involves replacement with levo-thyroxine (50-100 ug/m2/d) to normalize TSH and T4. Long-term follow-up studies indicated that chronic lymphocytic thyroiditis resolves in 50% of children. Replacement therapy should continue until the patient has achieved final adult height. At that time, a trial without medication may be considered. If a child has positive antibodies but is euthyroid, replacement therapy is not necessary, however thyroid function should be monitored regularly. Children with transient toxic thyroiditis can be treated with propranolol.

Graves' disease (autoimmune hyperthyroidism) is the autonomous production of excessive thyroid hormones by a usually enlarged thyroid gland that is not under pituitary control (7,8,9). It is the most common cause of hyperthyroidism in children. There is a high familial incidence, and females predominate in a 3:1 ratio. The peak incidence occurs during adolescence.

Graves' disease arises from autoimmune processes, which include production of immunoglobulins against antigens in thyroid, orbital tissues, and dermis. Thyroid-stimulating immunoglobulins (TSI) are present in nearly all patients. These antibodies bind to the TSH receptors on the thyroid cells and have a stimulatory (TSH-like) effect. TSI, like TSH, stimulates thyroid follicular cell growth to cause thyromegaly. Anti-thyroglobulin and anti-thyroperoxidase antibodies are also found in many patients, but in lower levels than in Hashimoto thyroiditis. Graves' disease and Hashimoto thyroiditis may in fact be a part of a spectrum of the same disease process.

The sustained state of an increased metabolic rate results in enhanced energy expenditure to cause a catabolic state. Clinical features include nervousness, irritability, palpitations, tachycardia, tremor, increased appetite with weight loss, diarrhea, difficulty sleeping, heat intolerance, poor school performance, irregular periods, and rapid height velocity. Most patients will have a goiter. Even though up to 50% of children with Graves disease manifest ophthalmopathy, this problem is not as severe as in adults. Lid retraction and stare are the most common, whereas chemosis (conjunctival swelling), lid eversion, and paresis of extraocular muscles are found predominately in adults. Graves dermopathy (pretibial myxedema) in children is virtually nonexistent.

The thyroid hormone profile characteristically shows elevated T4 and T3 levels, accompanied by very low or undetectable levels of TSH. In 15-20% of cases, the T3 level is elevated with a normal level of T4 (T3 toxicosis). This represents an early stage of thyrotoxicosis, prior to the elevation of T4.

The three forms of treatment for Graves' disease are medical, surgical, and radioactive iodine ablation. The mainstay of medical management is antithyroid mediations with methimazole or propylthiouracil. Both are equally effective at decreasing the production of T4 and T3 by the thyroid gland, but propylthiouracil also blocks the peripheral deiodination of T4 to T3. Side effects are infrequent, but include skin rashes, arthritis, hepatitis and agranulocytosis. Evidence suggests that with antithyroid medication alone, remission of Graves' disease (defined as being euthyroid for 1 year after stopping medications), occurs at a rate of 25% over 2 years. If medical treatment must be discontinued because of side effects, frequent relapses, or inability of comply with the treatment schedule, thyroid ablative therapy or thyroidectomy should be implemented (10).

Thyroid cancer in children (11). There is about a 30% chance that a nodule found in a child will be malignant. In children who have had other forms of cancer there is a 50-fold increased risk of thyroid cancer secondary to the use of radiation therapy. Basic thyroid function tests are usually normal. Thyroid scans using 123I or 99m Tc-pertechnetate are helpful in the evaluation of a thyroid nodule. A "cold" area (hypofunctioning) on scan increases the suspicion of malignancy while "hot" (hyperfunctioning) nodules are almost invariably benign. Needle biopsy is the most simple and direct method to help determine the architecture of a thyroid nodule.

Papillary cancer is the most common malignant thyroid tumor in children (60-80%). These tumors often consist of a mixture of papillary and follicular elements. Pure follicular carcinomas comprise about 10-15% of cases (12). Medullary carcinomas account for less than 7% of all thyroid cancers and may be sporadic, familial (autosomal dominant), or part of one of the multiple endocrine neoplasia syndromes. Malignant or suspicious lesions require surgical intervention and post-operative ablation with 131I followed by appropriate surveillance.


Questions

1. True/False: The major secretory product of the thyroid gland is T3.

2. True/False: A low T4 and low TSH at newborn screening suggests thyroid dysgenesis.

3. True/False: Most patients with Hashimoto thyroiditis present with a goiter and are asymptomatic.

4. True/False: Graves' ophthalmopathy is more severe in children than in adults.

5. True/False: Graves' disease occurs equally among males and females.

6. True/False: Papillary carcinoma is the most common type of thyroid cancer in children.


References

1. Fisher DA. Disorders of the thyroid in the newborn and infant. In: Sperling MA (ed). Pediatric Endocrinology. 1996, Philadelphia: W.B. Saunders Co, pp. 51-70.

2. Burrow GN, Fisher DA, Larson PR. Maternal and fetal thyroid function. New Engl J Med 1994;331(16):1072-1078.

3. Sobel EH, Saenger P. Hypothyroidism in the newborn. Pediatr Rev 1998;11:15-20.

4. Saslow JG, Post EM, Southard CA. Thyroid screening for early discharged infants. Pediatrics 1996;98:41-44.

5. Slatosky J, Shipton B, Wahba H. Thyroiditis: differential diagnosis and management. Am Fam Phys 2000;61:1047-1052.

6. Foley TP. Disorders of the thyroid in children. In: Sperling MA (ed). Pediatric Endocrinology. 1996, Philadelphia: W.B. Saunders Co, pp. 171-194.

7. Lavin N. Thyroid disorders in children. In: Lavin N (ed). Manual of Endocrinology and Metabolism. 1994, Boston: Little, Brown and Co, pp. 415-444.

8. Kraiem Z, Newfield RSL. Grave's disease in childhood. J Pediatr Endocrinol Metab 2001;14(3):229-243.

9. Hopwood NJ, Kelch RP. Thyroid masses: approach to diagnosis and management in childhood and adolescence. Pediatr Rev 1993;14:481-486.

10. Rivkees SA, Sklar C, Freemark M. The management of Graves disease in children, with special emphasis on radioiodine treatment. J Clin Endocrinol Metab 1998;83(11):3767-3771.

11. Feinmesser R, Lubin E, Segal K, et al. Carcinoma of the thyroid in children. J Pediatr Endocrinol Metab 1997;10(6):561-568.

12. Schlumberger MJ. Papillary and follicular thyroid carcinoma. New Engl J Med 1998;338:297-306.


Answers to questions

1.F, 2.F, 3.T, 4.F, 5.F, 6.T


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