0021-972X/90/7203-0523$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society

Vol. 72, No. 3 Printed in U.S.A.

CLINICAL REVIEW 19 Management of Congenital Hypothyroidism DELBERT A. FISHER Professor of Pediatrics and Medicine, UCLA School of Medicine, Harbor-UCLA Medical Center, Torrance, California 90509

discharged within 1 day. Early measurement increases the prevalence of infants demonstrating a modest elevation of blood spot TSH concentrations due to the physiological neonatal TSH surge; thus early screening for CH increases false positive results. In most programs the false positive to confirmed CH case ratio is 2-3/1. In California the effect of early hospital discharge of mother and infant increased this ratio from 2.5 to 1 to about 5 to 1. The ratio will vary, however, depending on the threshold value established for a significant TSH elevation by the individual program.

Detection by newborn screening

Newborn screening for congenital hypothyroidism (CH) now is routine in the United States and Canada and is conducted in most countries of western Europe and Scandinavia as well as Japan, Israel, Australia, and New Zealand (1, 2). Newborn CH screening is being developed in several areas of eastern Europe, South America, Asia, and Africa, but most infants in these geographic areas are not being screened. It is estimated that 10 to 12 million infants worldwide are now being screened yearly for congenital hypothyroidism. The impact of these screening programs is remarkable. Newborn screening has essentially eliminated CH as a significant cause of mental retardation in most industrialized societies. Due to screening, treatment usually has been initiated within 45 days of birth and IQ values in treated infants measured at 5-7 yr of age have been normal (1, 3,4). The prevalence of CH approximates 1 in 4000 births. The etiologies include thyroid dysgenesis (aplasia, hypoplasia, ectopy), 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 the total CH cases. Newborn CH screening tests are usually carried out in dried blood spot samples collected via skin puncture. In North America, T4 is measured initially and TSH is measured in samples with the lowest 10-20% of T4 results. In other areas of the world direct TSH screening has been commonly employed. In general the threshold value for a significant TSH elevation is 20-25 mU/L (20-25 ix\J/ mL). The most effective CH screening occurs when screening samples are obtained at 3-5 days after birth. However, most mother-newborn diads are discharged from the hospital within 3 days of delivery and some are

Evaluation of infants with presumptive positive screening results A positive screening report for CH in a newborn demands prompt evaluation of the infant, including a history, physical examination, and laboratory testing. A careful maternal health, dietary, and drug ingestion history should be obtained. A history of autoimmune thyroid disease in the family suggests the possibility of transient CH, either drug or maternal TSH receptor autoantibody induced. Recurrent CH in the same sibship also suggests maternal autoantibody-mediated disease. A history of familial congenital thyroid disease suggests thyroid dyshormonogenesis which usually is transmitted as an autosomal recessive trait. There is an increased prevalence of CH in infants with Down syndrome, and an increased prevalence of associated congenital anomalies has been suggested in infants screening positive for CH. These anomalies include congenital heart disease, trisomy 18 or 21, spina bifida, Pierre Robin syndrome, spastic diplegia or quadraplegia, and metabolic disorders (1). The mechanisms and significance of these associations remain unclear. Physical examination may reveal one of several early and subtle manifestations of hypothyroidism including a large posterior fontanelle (>1 cm diameter), prolonged jaundice (hyperbilirubinemia > 7 days), macroglossia, hoarse cry, distended abdomen, umbilical hernia, hypotonia, or goiter. Less than 5% of infants are diagnosed on clinical grounds before the screening report, but 15-

Received August 15, 1990. Address requests for reprints to: Delbert A. Fisher, M.D., Professor of Pediatrics and Medicine UCLA School of Medicine, Harbor-UCLA Medical Center, 1000 West Carson Street, RB-1, Torrance, California 90509. 523

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FISHER

20% of infants have suggestive signs when carefully examined at age 4-6 weeks, after the screening results have been reported (1, 2). The diagnosis of CH is confirmed by plasma or serum measurements of T4 and TSH concentrations. In the neonatal period (2-6 weeks) serum T4 and TSH levels below 84 nmol/L (6.5 g/dL) and above 7 mU/L (7 /*U/ mL), respectively, suggest CH. In infants with proven CH, 90% have TSH levels above 50 mU/L (50 MU/mL) and 75% have T4 concentrations below 84 nmol/L (6.5 Mg/dL) (1, 2). Notably, some 25% of CH infants have T4 levels in the 84-165 nmol/L (6.5 to 13 ixg/dL) range, usually with clearly elevated TSH concentrations (>30 mU/L; >30 juU/mL). A few infants will manifest serum levels of T4 in the low normal range (84-165 nmol/L;

JCE & M • 1991 Vol 72 • No 3

genesis have elevated serum thyroglobulin levels which relate to the mass of residual thyroid tissue and degree of stimulation. However, the ir levels usually do not exceed 1000 pmol/L (660 ng/mL) (1, 5). Very high levels (>1000 pmol/L) may be observed in infants with CH due to defective thyroxine synthesis not involving the capacity for thyroglobulin production (5). Serum calcitonin levels also are low in CH infauts with thyroid agenesis but offer no advantage over tie thyroglobulin measurement in diagnosis (1). These approaches are summarized in Fig. 1. Normal thyroid function test results in infants 2 to 6 weeks of age are summarized in Table 1. A bone age measurement (x-ray examination of the knee and foot) also is useful as a sign of possible intrauterine hypothyroidism.

6.5-13 Mg/dL) with only modest TSH elevations (7-30

mU/L; 7-30 /*U/mL). The latter infants may require repeat examinations in order to establish a diagnosis of CH. Serum T 3 or rT 3 concentrations have limited practical value in the diagnosis of CH. All infants with abnormal test results should undergo radionuclide scanning is possible, using either technetium or 123I. Radioiodine 123 is preferred, if available; technetium is trapped by thyroid follicular cells but not organified. Use of radioiodine provides greater isotope concentration, and allows later scanning (2-24 h) with lower background radioactivity and improved discrimination. The confirmation of an ectopic thyroid gland provides a definitive diagnosis of thyroid dysgenesis. The absence of uptake of radioisotope suggests thyroid agenesis, but some infants may have low radioisotope uptake and a nondetectable gland by scan due to a TSH receptor defect, iodide trapping defect, or TSH receptor blockade by maternal TSH receptor blocking antibody (TBA). These infants or the mother should have blood drawn for measurement of TBA if there is a history of maternal autoimmune thyroid disease. Thyroid ultrasound will confirm thyroid gland agenesis (1). A normal radioisotope scan and/or a palpable or ultrasound positive thyroid gland in the presence of hypothyroidism indicates impaired thyroid hormone synthesis. This can be due to blockade by drugs, to a TSH or TSH receptor defect, or to an inborn defect in thyroid hormone synthesis. Also, we have seen infants with mild to moderate TBA-mediated transient CH and normal thyroid scan results. Thyroid gland function in these infants is conditioned by the titer and affinity of the TSH receptor blocking antibody. The maternal and family histories should be carefully reviewed in such cases. A serum thyroglobulin measurement may be helpful in infants with absent uptake or normal scans. A very low or absent serum thyroglobulin level indicates thyroid agenesis in an infant with absent radioisotope uptake, and suggests a defect in thyroglobulin synthesis in infants with a normal imaging study (1, 5). Infants with thyroid dys-

Treatment of affected infants Initial evaluation, using one or more of the diagnostic modalities as outlined in Fig. 1, should be accomplished promptly and should require no more than 2-5 days. In the absence of facilities or funds to conduct scanning, ultrasound, TBA bioassay, or thyroglobulin measurements, treatment should be instituted as soon as the diagnosis is confirmed. The goal of newborn CH screening is the institution of early, adequate thyroid hormone replacement therapy. It h\ now clear from animal studies that most of the brain call thyroid hormone is derived from local T4 to T 3 conversion; approximately 70% of the T 3 in the cerebral cortex of perinatal rats is derived via local T4 monodeiodination (1). Thus, the preferred thyroid hormone preparation for treatment of infants with CH is Na-L-T4. Since the focus of screening is early and adequate treatment, the dosage of T4 should be such that the serum T4 concentration is normalized as quickly as possible. We cannot known where the baseline T4 value in a given individual infant falls in the normal distribution of serum T4. Thus, to guarantee adequate hormone to all infants, it is desirable to maintain the serum T4 in the upper half of the normal range during therapy. Moreover, 10-20% of normal endogenous thyroid hormone secretion consists of T3. In Ir^pothyroid subjects maintained on optimal levels of exogenous T4 the biological effect of this secreted T 3 is compensated by a 10-20% increase in serum T 4 concentration and a decreased serum T 3 /T 4 concentration ratio. Finally, the 97% upper limit of serum T4 levels in hypo;hyroid infants often ranges to 130 nmol/L (10 jig/dL). For these reasons the target range for the total T4 concentration is 130-260 nmol/L (10-16 ng/dL). This assumes a normal serum T4-binding globulin (TBG) concentration. This can be confirmed by measuring a normal ran^e T 3 resin uptake or TBG level at the time of the first posttreatment T4 measurement.

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525

CLINICAL REVIEW Positive Newborn CH Screening Test

Serum T4, TSH Measurements

AbnormaI

Norma.1

Thyroid Scan

i Absent Uptake

Norms 1

Ultrasound

TBA Measurement

Negative

Normal GJand

Positive

TH Synthetic Defect or Drug Effect

Negative

Absent

Tgb Synthetic Defect

No Thyroid Tissue

TBA Measurement

Tgb Measurement

Present

Ectopic

Transient CH

TSH Receptor or TH Synthetic Defect, Iodine BIockade

Positive

Transient CH

Thyroid Agenesis

Ectopic Thyroid Gland

FIG. 1. Possible initial approaches to a newborn infant with a presumptive positive test result for CH from a screening laboratory. All such infants require measurements of serum T4 and TSH concentrations. Those infants with low T4 and elevated TSH concentrations can be further screened by a thyroid scan using technetium or radioiodine 123. Finding an ectopic gland provides a definitive diagnosis. Infants with absent uptake or a normally appearing thyroid gland by scan can be evaluated further by ultrasound scanning and measurements of TBA and serum thyroglobulin (Tgb) concentrations. Infants with TBA-induced transient CH may have a normal scan if their CH is partially compensated. This initial evaluation should be accomplished within 2-5 days. TABLE 1. Normal thyroid function parameters in infants aged 2 to 6 weeks" Serum constituent

Concentration

T4 T3 Free T4, FT4* TSH T4-binding globulin, TBG Thyroglobulin0

84-210 nmol/L (6.5-16. 1.5-4.6 nmol/L (100-300 ng/dL) 12-28 pmol/L (0.9-2.2 ng/dL) 1.7-9.1 mU/L (1.7-9.1 MU/mL) 160-750 nmol/L (1.0-4.5 mg/dL) 15-375 pmol/L (10-250 ng/mL)

"Data from Nichols Institute reference values unless indicated otherwise. 6 Measured by direct dialysis. 0 Thyroglobulin from Vulsma et al., N Engl J Med. 1989;321:13-6.

Alternatively, a direct free T4 measurement can be used and should be maintained in the upper half of the normal range for the method. The New England Congenital Hypothyroidism Collaborative has emphasized the importance of maintaining the serum T 4 concentration above 103 nmol/L (8 Mg/dL) throughout the first year of

treatment to avoid IQ deficits (6). To rapidly normalize the serum T4 concentration in the CH infant, an initial dose of Na-L-T4 of 10 to 15 /xg/ kg-day is recommended (7, 8). For the average term infant of 3-4.5 kg we prescribe an initial dose of 50 ng (0.050 mg) daily (7). This dose increased the total serum T4 concentration to the upper half of the normal range within 1-2 weeks (8). Serum TSH concentrations in most treated infants with CH usually remain relatively elevated despite normalized levels of T4 or free T4 (1, 7-9). The relative elevation of serum TSH is more marked during the early months of therapy but can persist to some degree through the second decade of life (9). Raising the total serum T4 value to the 130 to 206 nmol/L (1016 Mg/dL) range or the free T4 to the upper half of the normal range during the first 1-2 yr of treatment lowers the serum TSH concentration below 20 mU/L (20 ixU/ mL) in 80-90% of CH infants. In the remainder, the serum TSH remains above 20 mU/L (20 ix\J/mL). In

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FISHER

these infants, raising the serum T 4 level to the 155-206 nmol/L range (12-16 ng/6L) usually will lower the TSH value to less than 20 mU/L (20 fiU/mL) (1). Untoward serum TSH elevations or thyrotoxic signs and symptoms should be avoided. The elevated serum TSH level relative to T4 concentration in CH infants is due to a resetting of the feedback threshold for T 4 suppression of TSH release in infants with CH. This resetting occurs in utero, but the mechanism remains obscure. Individual T4 doses are adjusted at 4- to 6-week intervals during the first 6 months and at 2-month intervals during the 6- to 18-month period to maintain serum T 4 levels in the 130-206 nmol/L (10-16 jug/dL) range. Physical growth and development of infants with CH usually is normalized by early adequate therapy, and infants with a delay in bone maturation at the time of diagnosis will normalize their bone age by 1-2 yr of age (1). As indicated, IQ values and mental and motor development also are normalized in most infants with CH. However, low normal or occasionally low IQ values have been reported in a small subset of CH children with very low serum T4 and delayed bone maturation at birth (1, 7). It is not yet clear whether therapy was or was not early or adequate enough in such infants, but most were on a relatively low dose of replacement T4. Rovet and colleagues (10) have observed that increasing the dose of replacement T4 from 7-9 /ug/kg-day to 8-10 /ug/kg-day increases the childhood IQ of CH infants by 4-5 points. The investigators also have noted a significant 5-10 point lower mean IQ in infants in whom there was a 4-week delay in time of onset of treatment and more severe hypothyroidism manifested by a delayed bone age and/ or higher serum TSH level at the time of diagnosis (10). This and earlier information suggests that infants with marked thyroid hormone deficiency, if untreated, will lose 3-5 points of IQ monthly during the first 6-12 months of life (1, 10). Thus, the most critical period of thyroid dependency of the human central nervous system is the first year of postnatal life. It is possible that this critical period extends for a few weeks in utero, but IQ values are normalized even in most athyroid infants by early adequate postnatal treatment. This may relate, in part, to limited but measurable maternal to fetal T4 transfer in utero and increased activity of the brain 5'iodothyronine deiodinase in the hypothyroid fetus. Such transfer may protect the brain of most athyroid CH fetuses but may be inadequate in a few infants. The time required to normalize serum T4 concentrations during therapy with Na-L-T4 in infants with CH has varied from an average of 74 days from the time treatment was begun using a 7-9 ixg/kg • day T4 dose, to 31 days for an 8-10 /ig/kg-day dose, to less than 3 weeks for a 10-15 /ug/kg-day T4 dose (6, 8). Assuming a 3-week average delay in starting treatment, the average age for

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normalization of the seru:n T4 level would approximate 3 months, 2 months, and 1V2 months, respectively, for a 7-9, 8-10, and 10-15 jug/^g-day T4 dose. Such delay is undesirable. The untoward effect of a 3-month delay in treatment on IQ values was demonstrated before the advent of newborn screening programs.

Hypothalamic-pituitary hypothyroidism Infants with organic TSH deficiency are relatively uncommon with a prevalence in the 1:50,000 to 1:150,000 range (1, 2). These infants are not usually detected in newborn thyroid screening programs since all programs are designed to screen for hyperthyrotropinemia. However, some programs, which use initial T4 measurements to reduce the number of TSH specimens to be assayed, report T4 values and report infants with low blood spot T4 and low (