Endocrine

Hypothyroidism

Introduction

The actions of thyroid hormone are crucial to ensuring the proper development of the neonatal brain. Deficiency of thyroid hormone in the fetal and neonatal period can result in severe intellectual disability; therefore, early detection of the most common etiology, congenital hypothyroidism (CH), via the newborn screen, and subsequent treatment reduces the neurological devastation of this treatable condition. The AAP issued a detailed algorithm in 2006 describing when to screen, which tests to screen with, interpretation of the test results, and when and how treatment should be initiated.

The actions of thyroid hormone on brain development occur even prior to birth. Maternal thyroid hormone is essential for fetal cortical development, and decreased levels of thyroid hormone in mid-gestation can adversely affect fetal brain development2,4. In the fetus, hormone synthesis begins and steadily increases around 18th-20th week of gestation. After birth, TSH increases to 50-80 mU/L by week 1. T4 and T3 mirror this pattern of peaking early before stabilizing. Thus, it is cricital to recognize the timing of testing when interpreting the results.

There are many causes of CH, several of which will be discussed in this review.

Pediatric acquired hypothyroidism also exists as a significant and distinct entity. Acquired hypothyroidism in children and adolescents can present in a number of ways, including decreased growth velocity, poor school performance, fatigue, and decreases in energy level.

Congenital Hypothyroidism

Incidence and Risk Factors:

The overall incidence of CH in the United States has been steadily increasing since 1991, although this increase is not uniform and differs from state to state.  Overall, from 1991-2000, the incidence of CH increased 30.4%. The reasons for this increase are unclear, but some theories have been suggested. Compared to whites, Hispanic infants have an odds-ratio of CH of 2.01 (1.77-2.08). World epidemiologic data suggests that the incidence in females is nearly twice that of males, but in the US, the gender ratio incidence is closer to 1.56, suggesting that our screening may be picking up transient CH instead of classic CH9. Again, this is why it is critical to understand the rise and fall of TSH in the early days of life.

Etiology:

Permanent hypothyroidism can often be confirmed if 1) thyroid scan shows dysgenesis, 2) initial TSH<50mU/L, and there is no increase in TSH during the neonatal period, or 3) TSH increases once therapy is ceased6. Permanent hypothyroidism can be primary, central, or peripheral.

Permanent primary hypothyroidism

Approximately 80-85% of overt hypothyroidism is due to thyroid dysgenesis, a term which includes athyreosis (thyroid tissue not present), hypoplasia (too little thyroid tissue), and ectopy (thyroid tissue is in the wrong location) and may be identified with a radioactive iodine uptake test or ultrasound. Of these, ectopy represents the largest portion of overt hypothyroidism cases; subclinical hypothyroidism is most often caused by thyroid hypoplasia. Other causes of CH are rare, with case reports describing dysfunction in virtually every part of the thyroid hormone synthesis pathway7,8.

Permanent central hypothyroidism:

This is due to defects of TSH production. As a result, there is often concomminant hypopituitarism, and low TSH. This is criticul because every other common variant of neonatal hypothyroidism presents with an elevated TSH. Further, one should evaluate for other midline defects (cleft lip/palate, septo-optic dysplasia) if central hypothyroidism is suspected6.

Permanent peripheral hypothyroidism:

In peripheral hypothyroidism, there is resistance to thyroid hormone, usually secondary to a defect in the thyroid hormone receptor. These patient often present in a euthyroid state, but are rarely hypothyroid. One example of this is Refetorr's syndrome6.

Transient hypothyroidism

The AAP Guideline from 2006 define transient CH as abnormal screening values (low T4, elevated TSH) resulting from one of the causes of transient hypothyroidism but normal serum T4 and TSH concentrations on a subsequent serum test at 1-2 months of age, at which point a pediatricion should consider starting medications3. The accepted causes of transient CH are as follows1,9:

  • Exposure to maternal thyrotropin receptor blocking antibodies (TRBAbs):

This condition is due to maternal autoimmune thyroid dysfunction, including Graves disease and Hashimotos thyroiditis. Maternal IgG antibodies cross the placenta, resulting in congenital hypothyroidism, but the severity is likely based on maternal antibody concentration6. This condition resolves with disappearance of the maternal antibodies, which occurs between 3-6 months given a 4 week half-life of IgG. TRBAbs accounts for 1-2% of all cases of CH.

  • Exposure to antithryoid drugs: 

In maternal Graves disease, the goal of therapy is to maintain T4 levels in the upper limit of normal. PTU is a drug affecting the metabolism of thyroid hormone which is used during pregnancy. PTU crosses the placenta, and can cause transient decreases in fetal thyroid hormone production.

  • Iodine deficiency:

This is the most common cause of transient CH worldwide, but is less common in the US and developed countries.

  • Iodine excess:

The Wolff-Chaikoff effect describes the transient inhibition of T4 synthesis by excessive plasma concentrations of inorganic iodine, with effects lasting 10 days. Studies have demonstrate an increased risk of transient CH with use of iodine containing antiseptics in hospitals9.

Signs and Symptoms:

Nonspecific and often asymptomatic, but include irritability, poor feeding, hypotonia, and constipation. With the institution of newborn screens, untreated CH is rarely seen, however it could manifest as:

  • Lethargy
  • Hoarse cry
  • Feeding difficulty (often needing to be awakened to feed)
  • Constipation
  • Macroglossia
  • Umbilical hernia
  • Large fontanelles
  • Hypotonia
  • Dry skin
  • Hypothermia
  • Prolonged Jaundice
  • Palpable goiter

300px-Jaundice_in_newborn.jpg
https://en.wikipedia.org/wiki/Congenital_hypothyroidism

Treatment:  

See Table 1 for the AAP 2006 Management Guidelines. Briefly, this includes a repeat of the initial screening tests, patient interview with family history, thyroid hormone replacement therapy, frequent follow-up testing, and an assessment of the permanence of the hypothyroidism.3

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Click HERE to access an algorhythm to interpret thyroid function tests.

Acquired Hypothyroidism

Prevalence and Risk Factors: 

While the incidence of congenital hypothyroidism has been well described and documented in the literature, there are fewer estimates of the incidence of acquired hypothyroidism in the pediatric population. A Scottish study published in 2000 estimated the overall prevalence of pediatric acquired hypothyroidism to be 0.135%, with a male-to-female ratio of 1:2.8, based on analysis of a national database which reported thyroxine prescriptions10. This is almost certainly an underestimate, as a significant number of children can have subclinical hypothyroidism or euthyroid Hashimoto’s thyroiditis not requiring thyroxine treatment.  Risk factors include a personal or family history of autoimmune conditions, including type 1 diabetes mellitus and celiac disease. There is also a significant association with Downs syndrome and Turner syndrome. Thus, the AAP recommends testing patients with Downs syndrome for TSH levels at 6 months, 12 months, and annually.

Etiology:  

The most common cause of pediatric acquired hypothyroidism is chronic autoimmune thyroiditis (Hashimoto’s), and is often associated with other autoimmune diseases. This is most commonly suspected on the basis of thyroid goiter or thyroid function tests suggestive of hypothyroidism plus evidence of anti-thyroid peroxidase antibodies (TPO Ab). Many patients can in a euthyroid state; in these cases, TSH and antibody levels have poor predictive value in terms of progression of thyroid dysfunction in the individual patient11.  

Patient with Hashimoto’s thyroiditis may actually present in thyrotoxicosis due to a large release of thyroid hormone from injured thyroid cells12.

Other causes of acquired hypothyroidism in children include hypothyroidism secondary to head and neck malignancies requiring radiation and atypical presentations of Graves’ disease.

Signs and symptoms:

Many patients will be asymptomatic. Those with overt hypothyroidism may have fatigue, decreased growth velocity, goiter, or pubertal delay.

Treatment: 

In patients who are overtly hypothyroid or who meet TSH criteria, treatment with levothyroxine is the standard therapy. Dosage will depend on age and body surface area. The goals of therapy are to restore normal development, including growth velocity. Neonates should be treated to quickly bring them to euthyroid state by normalizing TSH and T4 within 1 month of life. Pediatricians may start with 10-15ug/kg of levothyroxine crushed up in breast milk or formula. THe child should be maintained with a TSH 0.5-2.0mU/L during the first 3 years of life for optimal outcomes3,6,13.

Summary and Conclusion

Thyroid hormone is essential for proper neurological development. Congenital hypothyroidism can be detected through universal newborn screening, and proper therapy can improve and sometimes reverse neurointellectual outcomes. The 2006 AAP Guidelines for screening and management of CH should be followed to improve CH outcomes.

While CH has many causes, the most common cause is thyroid agenesis. While the incidence of CH appears to be increasing, there are several confounding factors (increases in newborn screening, variations in classification of transient CH) that make it difficult to determine the exact cause.

Acquired hypothyroidism is rare, but is most often associated with autoimmune dysfunction. Identification of these patients and restoration of thyroid hormone can restore normal sexual development as well as height velocity.

References:

1. Olivieri, A., Corbetta, C., Weber, G., Vigone, M. C., Fazzini, C., & Medda, E. (2013). Congenital hypothyroidism due to defects of thyroid development and mild increase of TSH at screening: data from the Italian National Registry of infants with congenital hypothyroidism. The Journal of clinical endocrinology and metabolism, 98(4), 1403–8.

2. Morreale de Escobar, G., Obregon, M. J., & Escobar del Rey, F. (2004). Role of thyroid hormone during early brain development. European journal of endocrinology / European Federation of Endocrine Societies, 151 Suppl 3, U25–37.

3. Rose, S. R., Brown, R. S., Foley, T., Kaplowitz, P. B., Kaye, C. I., Sundararajan, S., & Varma, S. K. (2006). Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics, 117(6), 2290–303.

4. Bernal, J., Guadaño-Ferraz, A., & Morte, B. (2003). Perspectives in the study of thyroid hormone action on brain development and function. Thyroid : official journal of the American Thyroid Association, 13(11), 1005–12.

5. Hinton, C. F., Harris, K. B., Borgfeld, L., Drummond-Borg, M., Eaton, R., Lorey, F., … Pass, K. a. (2010). Trends in incidence rates of congenital hypothyroidism related to select demographic factors: data from the United States, California, Massachusetts, New York, and Texas. Pediatrics, 125 Suppl 2, S37–47.

6. Bona G, De Luca F, Monzani A, eds. Thyroid diseases in childhood: recent advances from basic science to clinical practice. Cham: Springer, 2015.

7. Waller DK, Anderson JL, Lorey FW, Cunning- ham GC. Risk factors for congenital hypothyroidism: an investigation of infant’s birth weight, ethnicity, and gender in Cali- fornia, 1990–1998. Teratology. 2000;62(1): 36–41

8. Nagasaki, K., Asami, T., Ogawa, Y., Kikuchi, T., & Uchiyama, M. (2011). A study of the etiology of congenital hypothyroidism in the Niigata prefecture of Japan in patients born between 1989 and 2005 and evaluated at ages 5-19. Thyroid : official journal of the American Thyroid Association, 21(4), 361–5.

9. Parks, J. S., Lin, M., Grosse, S. D., Hinton, C. F., Drummond-Borg, M., Borgfeld, L., & Sullivan, K. M. (2010). The impact of transient hypothyroidism on the increasing rate of congenital hypothyroidism in the United States. Pediatrics, 125 Suppl 2, S54–63.

10. Hunter, I. (2000). Prevalence and aetiology of hypothyroidism in the young. Archives of Disease in Childhood, 83(3), 207–210.

11. Radetti, G., Gottardi, E., Bona, G., & Corrias, A. (2006). The natural history of euthyroid Hashimoto’s thyroiditis in children. The Journal of pediatrics…, 827–832.

12. Nabhan, Z. M., Kreher, N. C., & Eugster, E. a. (2005). Hashitoxicosis in children: clinical features and natural history. The Journal of pediatrics, 146(4), 533–6.

13. LaFranchi S. Evaluation and management of neonatal Graves’ disease. Up to Date. 2016; 5839;9.