Congenital Hypothyroidism

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1 PEDIATRIC ENDOCRINE EMERGENCIES Malcolm S. Schwartz D.O., F.A.C.O.P. Congenital Adrenal Hyperplasia Congenital Hypothyroidism

2 I have no Conflicts of Interest

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5 Congenital Hypothyroidism Historical perspective 30 BCE Vitruvius described the occurrence of goiter in the Alps 1527 Paracelsus described relationship between hypothyroidism and mental retardation 1850 Curling described sporadic congenital hypothyroidism with autopsy findings 1896 Pendred described goiter with deafness 1897 Osler describes thyroid deficiency and sporadic cretinism

6 Congenital Hypothyroidism Historical perspective 1891 use of thyroid extract 1972 early treatment prevents MR 1972 filter paper assay 1974 first congenital hypothyroidism newborn screening

7 Timeline of Newborn Screening in New Jersey 1960s to MS/MS PKU CH GAL Hgb MSUD CAH BIO CF 4FAO 2UCD 6OA 29 HRSA NBS Advisory Panel NSARC

8 Thyroid Embryology The thyroid is the first endocrine gland to develop in the embryo, starting during the third week of gestation. The thyroid derives from an epithelial proliferation of the floor of the pharynx: a thickening between the first and second pharyngo-bronchial pouches (later the foramen cecum) becomes the thyroid diverticulum. [As we discuss this you can imagine that, at each point in the discussion, something can go wrong that would ultimately affect thyroid function in the newborn infant.]

9 Thyroid Embryology By seven weeks the thyroid gland has attained its final shape and has reached its final location in the neck. The thyroglossal duct has normally degenerated and disappeared.

10 Thyroid Anatomic Abnormalities Anatomic abnormalities may lead to later clinical problems if 1.the gland is missing (Athyreosis) 2.both lobes are absent (not so rare) 3.the gland is dysgenetic (i.e., it does not develop normally) 4.the gland is ectopic 5.it remains at the base of the tongue (lingual thyroid) 6.thyroid cells remain along the downward tract of the gland 7.the gland does not descend far enough, or descends too far 8.the gland is hypoplastic 9. one lobe is absent (rare) 10.the thyroglossal duct fails to degenerate and disappear

11 Example 1: Failure of descent lingual thyroid Significance: a lingual thyroid may be a person s only thyroid tissue. A child may be hypothyroid at birth or may become hypothyroid as the increasing demand for thyroid hormone cannot be met. An enlarging lingual thyroid may cause dysphagia or may be an incidental finding in an otherwise apparently normal child. Treatment: Suppression of TSH with exogenous thyroid hormone will cause the lingual thyroid to shrink.

12 Example 2 : failure of the thyroglossal duct to degenerate A midline mass may appear at any time anywhere from just below the base of the tongue to just above the normal location of the thyroid. The mass may be cystic if the duct fails to atrophy, or solid if there are thyroid tissue remnants. Since the thyroglossal duct is attached to the base of the tongue, the mass moves upward in the neck when the tongue is protruded from the mouth. Significance: a solid mass might simulate metastases from a primary cancer site; a cystic lesion might become infected.

13 Congenital Hypothyroidism Synthesis of Thyroid Hormones Iodide Tyrosine T/S ratio MIT DIT T 4 T 3 Thyroglobulin

14 Once we have the anatomic thyroid gland, that gland must produce thyroid hormones. Here is the most simplistic view of Thyroid Hormone Synthesis Iodine (actually, iodide) is taken up by thyroid gland, attaches to tyrosine (residues) to form T 3 (tri-iodo-thyronine) and T 4 (thyroxine) which are released into the circulation.

15 Thyroid Hormone Synthesis A little more detail synthesis of T 4 There is also mono-iodotyrosine Note that the synthesis process takes place with tyrosine residues attached to thyroglobulin.

16 Thyroid Hormone Synthesis More detail.. Iodide (I - ) taken up by thryoid follicular cells is oxidized to iodine (I 0 ) by thyroid peroxidase within those cells. The most common synthesis defect occurs at this point. In the follicle lumen iodine binds to tyrosyl residues on thyroglobulin to form MIT and DIT which can be conjugated as follows: MIT+DIT T 3 (tri-iodo-thyronine) DIT+DIT T 4 (thyroxine) DIT+MIT reverse T3 (inactive) T 3 and T 4 are released into the circulation. Failure of any of these steps to occur can lead to hypothyroidism in an infant with an anatomically normal gland.

17 Congenital Hypothyroidism Metabolism of Thyroid Hormones T 4 T 3 TBG TBPA

18 Development of Human Thyroid Function Hormone levels throughout gestation Note: 1. the thyroid can concentrate iodine by 10 weeks. 2. thyroid hormones begin to appear by the end of the first trimester, 3. thyroxine-binding globulin appears by weeks, and 4. feedback control mechanisms are functioning by the end of the second trimester Wolf-Chaikoff effect: Iodine excess causes hypothyroidism by inhibiting iodide organification and T 4 and T 3 synthesis. Normal people escape from this effect. People with abnormal thyroid glands (e.g. autoimmune thyroiditis) can become hypothyroid if given iodine for more than a few days. The excess iodine could come from OTC products, such as cough medicines, some dietary supplements, drugs such as amiodarone, or radiographic contrast.

19 Control of Thyroid Hormone Synthesis and Release Negative Feedback A classic negative feedback system controls synthesis and release of thyroid hormone: When free T 3 and T 4 levels are low, their suppressive effect on the hypothalamus and pituitary is removed. Thyrotropin- Releasing Hormone (TRH) then stimulates release of thyrotropin (aka TSH = thyroid stimulating hormone), which in turn activates T 3 and T 4 synthesis and release. Conversely, when free T 3 and T 4 are high, release of TRH and TSH is inhibited. Peripheral conversion of T 4 to T 3 is also regulated, e.g., in response to illness.

20 Relation of Maternal, Placental and Fetal Thyroid Hormones Note: 1. Some maternal T 4 and T 3 are delivered to the fetus. [Delivery of T 3 is especially important for brain development in the hypothyroid infant.] 2. T 4 can be de-iodinated to the more active T 3 by the mother, placenta and fetus. 3. T 4 can also be de-iodinated to the inactive reverse T 3 by the mother, placenta and fetus.

21 Placental Transfer

22 Development of Human Thyroid Function More details near birth Note that premature infants tend to have lower levels of T4 and T3 than term infants, and may have various forms of hypothyroxinemia (low T 4 ) without hypothyroidism (normal TSH) This fact, especially in the sick premature infant, can lead to uncertainty about whether or not these infants need thyroid replacement therapy. This has more than academic interest.

23 And some definitions: Problems at the level of the thyroid gland are called primary. Problems at the level of the pituitary gland are called secondary. Problems at the level of the hypothalamus are called tertiary.

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27 Congenital hypothyroidism Differential diagnosis (with rate of occurrence) 1. Something intrinsically wrong with the thyroid primary hypothyroidism Dysgenetic (ectopic, hypoplastic); usually random: 1/4,000 births Synthesis (enzyme) defect; autosomal recessive inheritance; 1/40, Something wrong with the pituitary ( secondary hypothyroidism ) or hypothalamus ( tertiary hypothyroidism ): 1/100, Transient hypothyroidism (1/40,000) where an otherwise normal thyroid gland is temporarily suppressed, mimicking primary hypothyroidism: drug induced maternal antibodies that block the infant s TSH receptor; resolves as antibodies disappear. These antibodies can be measured.

28 Congenital Hypothyroidism Congenital Hypothyroid Causes Thyroid dysgenesis 1:4000 Agenesis Ectopic gland Thyroid Dyshormonogenesis 1:30,000 Hypothalamic-Pituitary 1:100, or 3 0 Hypothyroidism Transient Hypothyroidism 1:40,000

29 Congenital Hypothyroidism Clinical signs and symptoms at birth [Why is this page blank?] This page is blank because most babies with congenital hypothyroidism appear completely normal at birth. That s why we have a screening program! However

30 However, if you look very closely at babies in the nursery you might find that some babies with congenital hypothyroidism have a large posterior fontanel (greater than 1 cm) a goiter (in a baby with a hormone synthesis defect) Less than 5% of babies with congenital hypothyroidism are diagnosed by clinical exam. (That s why we have a screening program!) The posterior fontanel is usually almost closed in the normal term infant. A large posterior fontanel reflects delayed skeletal maturation in utero that correlates with the degree of fetal hypothyroidism. A bone age X-ray after birth has prognostic value regarding the baby s potential for intellectual development.

31 There are some clinical clues that appear gradually over weeks to months, and eventually will make the baby s condition obvious: in the newborn period prolonged physiologic jaundice (more than 7 days) gradually progressive symptoms Weight change feeding difficulties; choking sluggishness; lack of interest; little crying large abdomen; umbilical hernia; constipation hypothermia; cold/mottled skin retarded growth/development By the time these clinical signs lead to a diagnosis, there may have been irreversible intellectual impairment. (That s why we have a screening program!)

32 Congenital Hypothyroidism Thyroid Hormone Effects Metabolism Nutrients Inorganic Ions Growth and Development Neurological Function

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35 You and many others in the in the US and around the world use these time-dependent normal values every day to screen newborn infants (4.1 million in the US in 2004*) for congenital hypothyroidism. About 1 in 4000 babies has congenital hypothyroidism. The goal is to prevent avoidable outcomes like those shown here: 6 months 17 years 48 years * Social comment: of these, 1.5 million were born to unmarried women.

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40 Congenital Hypothyroidism Thyroid Function Tests Serum Thyroid and pituitary Hormones TSH T 4 T 3 Free T4 Free T 3 TRH Stimulation T 3 Uptake X

41 TRH Stimulation Test

42 Congenital Hypothyroidism Radiologic Studies Bone age Thyroid Imaging Ultrasound Radioisotope Scanning and Uptake T C 99 M I 123

43 Congenital Hypothyroidism Bone Age

44 Congenital Hypothyroidism Bone Age

45 Congenital Hypothyroidism Tests for Underlying Etiology Serum Antithyroid Antibodies Anti-Thyroglobulin Anti-Thyroid Peroxidsase (TPO) Perchlorate Discharge

46 THYROID DISORDERS OF CHILDHOOD Free T ng/dl 0.5 ng/dl 0.8 ng/dl

47 Congenital Hypothyroidism Why screen? Most cases are asymptomatic When symptoms develop, damage may have already occurred Early treatment can prevent mental retardation As early as possible Subsequent normal growth Severe in utero hypothyroidism is more likely associated with mild developmental problems despite adequate treatment

48 SCREENING US, Canada, western Europe, Israel, Japan, Australia and New Zealand have developed programs Latin and South America, Eastern Europe, Africa and Asia in process Approximately 1250 cases in US & 7000 cases worldwide detected

49 Screening States vary in their use of T4, TSH or both as primary screen After 24 hours of life Statistical detection of lowest 10% T4 Secondary TSH TSH >20 mciu/ml needs secondary confirmation with venous blood

50 Congenital Hypothyroidism Screening Program Filter Paper <1.8 SD below MEAN T 4 Presumptive Hypothyroidism TSH TSH Reported and repeated TSH T4 TSH T 4

51 Congenital Hypothyroidism Most common presentation Telephone call from the state newborn screening follow up program FT baby born 5 days ago had a presumptive positive for congenital hypothyroidism: T4 low TSH > 100 What do I do? (even if it is Friday before Memorial Day)

52 Initial Steps for a Presumptive Positive Immediate consultation with a pediatric endocrinologist Send serum for free T4, and TSH as directed by endocrinologist If treatment is needed it should be initiated immediately in discussion with consultant

53 Severe Congenital Hypothyroidism Mental Prognosis vs. Age When Adequate Treatment Initiated Total Group 4 months 4-6 months 7-12 months 12 months < >90

54 School Performance and IQ Levels Children Treated with Congenital Hypothyroidism Progress through the first four years of school Patients (n=74) % Control Subjects (n=279) IQ (9-10 YOA) Repeated Grades 12.1% 16.1% Special Class 6.9% 6.1% Tutoring 12.1% 9.7% No Problems 68.9% 68.1% From New England Congenital Hypothyroidism Collaborative 1990 Heyerdahl,M.D. et al 1991; T in upper reference range 4 Glourieux, J., LP s, et al 1992;Severity of CH is significant

55 Rovet et. al. 80 children followed until 9 years of age Sibling and classmate matched controls At 6 years of age statistically significant 8 point difference in McCarthy At 9 and > 13 years, 9 point difference in WISC-R and WISC-IIIIII

56 Congenital Hypothyroidism Congenital Hypothyroidism Treatment Age Newborn (full term) 1-3 months 3-6 months 6-10 months Maintenance Levothyroxine (mcg/kg) (50 mcg/day) Follow clinical status monthly and thyroid function tests until stable. Then every 3-4 months

57 Congenital Hypothyroidism Outcome The earlier the treatment the better Correlation between in utero hypothyroidism and poorer outcome Complete agenesis vs. ectopic Specific learning difficulties Visuospatial deficits Memory and attention problems

58 [Note: the earlier the infant is treated, the better prognosis for intellectual development. After six weeks untreated, the prognosis becomes much worse. If treatment is started in a case where the diagnosis is uncertain it should be continued for 3 years until brain development is essentially complete.]

59 Congenital Adrenal Hyperplasia Adrenal Insufficiency

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64 Embryology of the Genetalia

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72 STEROID PATHWAYS 21 Hydroxylase defect

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81 Congenital Adrenal Hyperplasia Screening Program 17 OHP Filter Paper 17 OHP Borderline Results: 17OHP ng/ml <1250 g to 160 >1250 to<1750 g. 90 to 135 >1750 to 2250 g. 65 to 90 >2250 g. 50 to 90 Repeat 17 OHP 17 OHP Presumptive Positive Results: 17OHP ng/ml <1250 g. - > 160 >1250 to<1750 g. > 135 >1750 to 2250 g. > 90 >2250 g. > 90 Presumptive CAH If unclear do ACTH Stimulation Test

82 GLUCOCORTICOID REPLACEMENT A. Hydrocortisone 25 mg IV bolus B. Infusion of Hydrocortisone 50 mg / M 2 / 24 hours IV C. Hydrocortisone mg / M 2 / 24 hours P.O. HYPOGLYCEMIA 25 % Dextrose 1ml /kg IV followed by 10% Dextrose IV

83 MANAGEMENT OF ADRENAL INSUFFICIENCY Sodium 2-6 meq /kg/ day Hyperkalemia and acidosis rarely treated

84 If you are not sure or THE RESULTS ARE UNCLEAR: Treat Treat TREAT

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