Chapter XV.3. Thyroid Disorders
Maya Y. Matsumoto
November 2022

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The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition Dr. Melanie L. Shim. This current third edition chapter is a revision and update of the original author’s work.

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 free T4, undetectable TSH. Thyroid stimulating immunoglobulin assay is positive.

She is diagnosed with Graves disease. She is treated with methimazole 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 methimazole is adjusted as indicated to maintain a euthyroid state. Two years after diagnosis, she goes into remission and methimazole is discontinued.


The hypothalamic-pituitary-thyroid axis regulates production and maintains peripheral concentrations of the biologically active thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Thyrotroph cells of the anterior pituitary release thyroid stimulating hormone (TSH). TSH is a 31-kDa hormone composed of a beta-subunit unique to TSH and alpha-subunit common to other glycoprotein hormones including luteinizing hormone (LH), follicle stimulating hormone (FSH), and human chorionic gonadotropin (hCG). Pulsatile, diurnal 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 exclusively synthesized by the thyroid gland as a component of the large (660-kD) precursor thyroglobulin molecule. Iodine is a rate-limiting substrate, which must be actively transported into the thyroid follicular cell by a plasma membrane sodium/iodide symporter (a protein that simultaneously transports two molecules). Iodide trapping, thyroglobulin synthesis, and iodothyronine secretion are all stimulated by TSH. The iodothyronines are transported in blood bound to the thyroxine-binding globulin (TBG), transthyretin (prealbumin), and albumin.(1) Only small amounts of T4 and T3 are free or unbound. Only free hormone is available for transport into 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 and kidneys. Only small amounts of T3 are secreted by the thyroid gland in euthyroid subjects ingesting adequate iodine. Normally, T4 is deiodinated to both T3 (outer ring deiodination) and rT3 (inner ring deiodination). The T3 mediates the predominant effects of thyroid hormones via binding to nuclear thyroid hormone receptors (TRH-alpha, TRH-beta). These steroid hormone receptors function as transcription factors modulating thyroid hormone-dependent gene expression in multiple target tissues upon binding to T3 (1,2,3,4,5).

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 synthesis of thyroglobulin, T4, and T3 occur. Adequate quantities of iodide are essential for fetal thyroid hormone synthesis. Thus, the fetus is reliant on transplacental transfer of maternal T4 and small amounts of T3 to supplement fetal thyroid function, particularly during the first trimester of pregnancy. Maturation of the fetal hypothalamic-pituitary-thyroid system continues to develop throughout the second half of gestation but does not reach full maturity until term. At birth, approximately 30% to 50% of T4 within cord blood is of maternal origin, demonstrating the importance of maternal thyroid hormones in fetal development up until birth. Thus, adequate maternal iodine intake and a euthyroid state throughout pregnancy is essential. In term infants, following delivery, there is a postnatal surge of TSH which returns to normal by 2 to 3 days. T3 and T4 concentrations increase up to 6-fold, peaking at 24 hours after birth and gradually declining to levels characteristic of infancy over the first 5 to 7 days of life. Normal thyroid function parameters vary with age (6).

Table 1. Thyroid Disorders in Children can be categorized as follows:


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 is an important cause of cognitive impairment 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 the physiologic principle that primary hypothyroidism results in neonatal TSH hypersecretion. Screening tests are usually carried out with dried blood spot samples collected via heel-prick. In some areas T4 is measured initially, and TSH is measured in samples with the lowest 10% of T4 results. However, most newborn screenings in the United States use direct TSH screening with reflex testing of T4 if TSH levels are elevated. The preferred time for blood sampling in term infants is 48 hours to 4 days after birth; however, many newborns are now discharged from the hospital before 48 hours. Early measurement increases the frequency of infants demonstrating a modest elevation of TSH concentrations due to the physiological neonatal TSH surge; thus, increasing the number of false-positive results. However, blood should still be obtained for testing prior to discharge in these infants (2,7,8). The incidence of congenital hypothyroidism approximates 1 in 3000 to 4000 births. Etiologies include thyroid dysgenesis and thyroid dyshormonogenesis, which account for approximately 80% and 10% of all cases, respectively, as well as hypothalamic-pituitary (TSH) deficiency, and transient hypothyroidism (usually iodine, drug, or maternal antibody induced) (2,7).

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. Mutations in genes involved with thyroid development (e.g., PAX8, TSHR, FOXE1, NKX2.1, NXK2.5) have been identified in approximately 2% of cases. 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. Infants with no thyroid gland have no circulating thyroglobulin (2,7).

Dyshormonogenesis, or the inborn errors of thyroid hormone synthesis, secretion, and utilization, largely follows an autosomal recessive pattern of inheritance but may rarely follow an autosomal dominant pattern. The most common defect involves deficiency of thyroid peroxidase 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 (9,10).

The placenta is permeable to thionamide drugs used to treat maternal hyperthyroidism [e.g., propylthiouracil (PTU), methimazole] and TSH receptor antibodies (TRAbs). If present in the maternal circulation, these agents may cross the placenta and alter the activity of fetal thyroid follicular cells leading to a transient congenital hypothyroidism. The presence of a goiter in an infant is supportive evidence of antithyroid drug-induced 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 or a previously affected offspring. The presence in maternal or neonatal blood of a high level of TSH receptor-blocking antibody is strong supportive evidence (8,11).

Confirmatory diagnosis of congenital primary hypothyroidism is based on measurement of T4 (low) and TSH (high). Optional studies include ultrasound and radionucleotide scan of the thyroid. Physical examination of neonates may reveal one of several early and subtle manifestations of hypothyroidism, including a large posterior fontanelle, prolonged jaundice, macroglossia, umbilical hernia, hypotonia, or goiter (7,8). For neonates with congenital hypothyroidism, prompt initiation of oral levothyroxine treatment (starting dose 10-15 mcg/kg/day) is essential with the goal of normalizing T4 levels within 2-weeks and TSH levels within 1 month. Delayed institution of treatment (greater than 45days) and persistently low T4 concentrations and high TSH concentrations during the first year of life are clearly associated with diminished cognitive potential (8).

Hashimoto thyroiditis (autoimmune hypothyroidism, chronic lymphocytic thyroiditis) is an autoimmune, inflammatory process causing most euthyroid goiters and nearly all cases of hypothyroidism in childhood and adolescence (8,12). Prevalence studies have found that as many as 1% to 2% of 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 4:1 with a peak age of onset in mid-puberty. It is rare in very young infants. About half of Hashimoto thyroiditis cases are associated with a family history of some type of autoimmune thyroid disease; however, the specific mode of inheritance is not known. Increased risk is associated with the presence of other autoimmune disorders, including Type 1 diabetes and celiac disease, as well as with various syndromes such as Turner syndrome (8,12). Thyroid inflammation and damage result from self-directed humoral and cell-mediated immunity, which lead to lymphocytic infiltration and hyperplasia of the gland. Antibody markers of the destructive process include anti-thyroglobulin (anti-Tg) and anti-thyroperoxidase (anti-TPO) 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, and/or hypothyroidism with or without thyromegaly. Most 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 (8,13). Signs of hypothyroidism are only present in about 2% of patients with positive antibodies and may include 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. Most children are euthyroid initially (normal T4 and TSH). The incidence of hypothyroidism (low T4 and high TSH) amongst children with anti-Tg and/or anti-TPO antibodies is approximately 20%. It is common to have high antibody titers (8,14,15).

Treatment involves replacement with levo-thyroxine (1-6 mcg/kg/d depending on age) to normalize TSH and T4. Replacement therapy should continue with monitoring every 4 to 6 months 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 (8,12,14,15).

Graves disease (autoimmune hyperthyroidism) is the autonomous production of excessive thyroid hormones by a usually enlarged thyroid gland that is not under pituitary control. It is the most common cause of hyperthyroidism in children and accounts for 10% to 15% of all thyroid disorders in children. There is a high familial incidence and female predominance of the disease. The peak incidence occurs during adolescence but may also present in children under the age of 5 years.

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. The disease is thought to be multifactorial and may in fact be a part of a spectrum of the same disease process as Hashimoto thyroiditis, supported by the prevalence of Graves disease in children with a family history of autoimmune diseases including Hashimoto thyroiditis (14,15).

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 40% of children with Graves disease manifest ophthalmopathy (also known as thyroid eye disease or TED), this problem is not as severe as in adults. Lid retraction and stare are the most common, whereas paresis of extraocular muscles is 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 some 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 thyroid ablation. The mainstay of medical management is antithyroid mediation with methimazole which effectively decreases the production of T4 and T3 by the thyroid gland. Propylthiouracil (PTU), an antithyroid medication commonly used in adults has similar activity to methimazole with additional blockade of peripheral deiodination of T4 to T3; however, PTU is contraindicated in children due to its association with severe hepatotoxicity and hepatic failure in pediatric patients (16). Minor side effects of methimazole including skin rashes and arthralgias are common, occurring in approximately 20% of patients. More severe side effects are uncommon but may include Stevens-Johnson syndrome and agranulocytosis. Most side effects arise within 6 months of starting methimazole therapy and tend to be dose-related. Thus, initial therapy should be started with a low dose (0.2 mg/kg/d) and titrated up as needed. 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 20% to 30% over 2 years. The addition of beta-blockers is recommended to help control associated symptoms, especially tachycardia (>100 bpm) until biochemical hyperthyroidism has been sufficiently suppressed with methimazole (1 to 2 months). Medical therapy is typically pursued for at least two years before surgical or ablative therapy is considered. However, 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 (7,14,15,17).

There is about a 25% chance that a nodule found in a child will be malignant. There is increased risk for thyroid cancer in children with a history of radiation exposure, thyroid disease (e.g., Hashimoto thyroiditis), and some genetic syndromes. Basic thyroid function tests are usually normal. Thyroid scans using I-123 or Tc-99m pertechnetate are helpful in the evaluation of a thyroid nodule when TSH levels are found to be low. A "cold" area (no isotope uptake/signal, hypofunctioning) on scan increases the suspicion of malignancy while "hot" (increased isotope uptake/signal hyperfunctioning) nodules are almost invariably benign. Needle biopsy is the most simple and direct method to help determine the architecture of a thyroid nodule and has been shown to have 94% sensitivity and 100% specificity in identifying thyroid malignancy (7,18,19).

Papillary cancer is the most common malignant thyroid tumor in children. These tumors often consist of a mixture of papillary and follicular elements. Pure follicular carcinomas are the next most common type of malignant thyroid tumor seen followed by medullary carcinomas which 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 I-131 followed by appropriate surveillance (7,18,19).


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. Wassner AJ, Smith JR. Chapter 579. Thyroid Development and Physiology. In: Kliegman RM, St. Geme JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 21st edition. 2020, Elsevier, Philadelphia, PA. pp:2912-2914.

2. Alarcon, G, Veronica F, Joshua T. Thyroid Disorders. Pediatr Rev. 2021;42(11):604-618. doi:10.1542/pir.2020-001420

3. Carvalho DP, Dupuy C. Thyroid Hormone Biosynthesis and Release. Mol Cell Endocrinol. 2017;458:6-15. doi:10.106/j.mce.2017.01.038

4. Van der Spek AH, Fliers E, Boelen A. The Classic Pathways of Thyroid Hormone Metabolism. Mol Cell Endocrinol. 2017;458:29-38. doi:10.1016/j.mce.2017.01.025

5. Ortiga-Carvalho TM, Sidhaye AR, Wondisford FE. Thyroid Hormone Receptors and Resistance to Thyroid Hormone Disorders. Nat Rev Endocrinol. 2013;10(10):582-591. doi:10.1038/nrendo.2014.143

6. LaFranchi SH. Thyroid Function in Preterm/Low Birth Weight Infants: Impact on Diagnosis and Management of Thyroid Dysfunction. Front Endocrinol. 2021;12:666207. doi:10.3389/fendo.2021.666207

7. Rivkees S, Bauer AJ. Chapter 3. Thyroid Disorders in Children and Adolescents. In: Sperling MA, Majzoub JA, Menon RM, Stratakis CA (eds). Sperling Pediatric Endocrinology, 5th edition, 2021. Elsevier, Philadelphia, PA. pp:395-424.

8. American Academy of Pediatrics, Rose SR, Section on Endocrinology and Committee on Genetics, American Thyroid Association, Brown RS, Public Health Committee, Lawson Wilkins Pediatric Endocrine Society. Update of Newborn Screening and Therapy for Congenital Hypothyroidism. Pediatrics. 2006;117(6):2290-2303. doi:10.1542/peds.2006-0915

9. Wassner AJ. Congenital Hypothyroidism. Clin Perinatol. 2018;45:1-18. doi:10.1016/j.clp.2017.10.004

10. Wémeau JL, Kopp P. Pendred Syndrome. Best Pract Res Clin Endocrinol Metab. 2017;31(2):213-224. doi:10.1016/j.beem.2017.04011

11. Eng L, Lam L. Thyroid Function During the Fetal and Neonatal Periods. Neoreviews. 2020;21(1):e30-e36. doi:10.1542/neo.21-1-e30

12. Hanley P, Lord K, Bauer AJ. Thyroid Disorders in Children and Adolescents: A Review. JAMA Pediatr. 2016;170(10):1008-1019. doi:10.1001/jamapediatrics.2016.0486

13. Unnikrishan AG. Hashitoxicosis: A Clinical Perspective. Thyroid Res Pract. 2013;10(Suppl S1):5-6. https://www.thetrp.net/text.asp?2013/10/4/5/106803

14. Quintanilla-Dieck L, Khalatbari HK, Dinauer CA, et al. Management of Pediatric Graves Disease: A Review. JAMA Otolaryngol Head Neck Surg. 2021;147(12):1110-1118. doi:10.1001/jamaoto.2021.2715

15. Léger J, Oliver I, Rodrigue D, Lambert AS, Coutant R. Graves’ Disease in Children. Ann Endocrinol. 2018;79:647-655. doi:10.1016/j.ando.2018.08.001

16. Rivkees SA, Mattison DR. Propylthiouracil (PTU) Hepatotoxicity in Children and Recommendations for Discontinuation of Use. Int J Pediatr Endocrinol. 2009;2009:132041. doi:10.1155/2009/132041

17. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016;26(10):1343-1421. doi:10.1089/thy.2016.0229

18. Paulson VA, Rudzinski ER, Hawkins DS. Thyroid Cancer in the Pediatric Population. Genes. 2019;10(9):723. doi:10.3390/genes10090723

19. Chan CM, Young J, Prager J, Travers S. Pediatric Thyroid Cancer. Adv Pediatr. 2017;64:171-190. doi:10.1016/j.yapd.2017.03.007


Answers to questions

1. False
2. False
3. True
4. False
5. False
6. True


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