Congenital Hypothyroidism

At a Glance

The thyroid gland produces 2 related hormones, thyroxine (T4) and triiodothyronine (T3), which play a critical role in thermogenic and metabolic homeostasis. T4 and T3 are normally synthesized and released in response to a combined hypothalamic pituitary signal mediated by thyroid stimulating hormone (TSH) from the anterior pituitary and thyrotropin releasing hormone from the hypothalamus. There is a negative feedback from thyroid hormone concentration, primarily T3, to TSH production, causing total T4, total T3, free T4, and free T3 concentrations to move in opposition to TSH concentrations.

Congenital hypothyroidism is a thyroid dysfunction present at birth. It occurs in its severest form in approximately 1 out of 4,000 births each year. The prevalence is higher in iodine deficient areas. Untreated congenital hypothyroidism can lead to growth failure, permanent mental retardation, and goiters. Treatment consists of a daily dose of thyroxine (L-T-4) by mouth. Children treated appropriately with thyroxine develop normally.

Hypothyroidism present at birth can have multiple causes, some genetic and some not. Causes of hypothyroidism at birth may be iodine deficiency, most commonly seen in underdeveloped nations; a defect in the development of the thyroid gland (i.e., aplasia, hypoplasia, or an ectopic thyroid gland), often referred to as dysgenesis, which is rarely a familial disorder and is the most common cause of congenital hypothyroidism; presence of maternal antibodies, usually resulting in a transient neonatal hypothyroidism until maternal antibodies are cleared; TSH resistance; or genetic defects in T3 or T4 synthesis, which are usually recessive.

Genetic defects in T3 or T4 synthesis may be either an iodine trapping disorder, a defect in organification, iodothyrosine deiodinase deficiency, or a mutation of thyroglobulin, the protein that provides the hormone precursor. Rarely, a hemangioma that expresses type III deiodinase that inactivates T3 and T4 preventing formation of reverse T3 can cause hypothyroidism in infants.

Actual symptoms may be absent or very mild, since the baby gets some thyroid hormone from the mother. T4 crosses the placental barrier. TSH and T3 do not. If symptoms are present, they may include excessive sleeping, reduced interest in nursing, poor muscle tone, a low or hoarse cry, infrequent bowel movements, exaggerated jaundice, and low body temperature. In more severe cases, physical findings may include distorted facial features, an umbilical hernia, or a large tongue.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Nearly the entire developed world performs newborn congenital hypothyroidism screening. However, the design of the screen varies between North America, where iodine deficiency is rare, and the rest of the screening world where iodine deficiency is more common. Most North American screening programs initially measure T4 and reflex to TSH. The reflex threshold is usually set at the tenth percentile.

If TSH is high and total T4 is low on samples from the second or third day after birth, congenital hypothyroidism is suspected. Time of sampling must be known, whether TSH or total T4 is used as the initial screen. Total T4 levels in newborns in the first 48 hours typically increase 2 to 3 times higher than levels seen in adults and then return to cord blood levels within 5 or 6 days. TSH spikes in the neonate during the first 24 hours. The TSH spike is less marked in premature infants. Advantages of total T4 as the first line screening test are the fact that total T4 is less affected by the TSH newborn surge seen if samples are collected within the first 24 hours and total T4 is more sensitive to the rare case of central hypothyroidism than TSH.

In Europe, and much of the remainder of the world exclusive of North America, TSH is the primary screening assay and abnormal results are reflexed to total T4. Initial TSH screening has an advantage over total T4 screening in areas of iodine deficiency.

Interpretation of newborn thyroid function tests, regardless of the order of testing, requires an understanding of the interaction between maternal and fetal iodine, thyrotropin releasing hormone, antithyroid medications, and any IgG antibodies present, TSH receptor blocking antibodies present in the mother, even when the mother is receiving adequate replacement therapy, can cause transient hypothyroidism in infants.

It should be noted that both total T4 and TSH in dried whole blood spots are stable for months when stored with a desiccant. The filter paper must meet guidelines.

Free T4 is not usually a part of the testing cascade for congenital hypothyroidism, since the testing of blood spots on filter paper requires significant dilution that may exceed the analytical reportable range of free T4.

(SeeTable 1)

Table I.

Test Results Indicative of the Disorder
Total T4 TSH
Low, in combination with an elevated TSH, should be followed up with free T4 and TSH in mother and infant and thyroperoxidase antibody in mother Elevated, in combination with a decreased total T4, should be followed up with free T4 and TSH in mother and infant and thyroperoxidase antibody in mother

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

In screening programs using TSH as the initial screen, it is particularly important to rule out maternal ingestion of antithyroid medications or the use of iodine antiseptic solutions at delivery as a cause of a transient TSH rise.

It is possible for heterophilic antibodies to cross the placenta and interfere. Most thyroid testing today is performed by either immunoassay in which labelled and unlabeled ligands compete for a limited number of antibody sites or immunometric assays in which an antibody is bound to a solid surface rather than an antibody. Cross reactivity of autoantibodies or heterophilic antibodies can affect diagnostic accuracy of these competitive binding-based tests.

The term heterophilic antibodies is often loosely applied to relatively weak antibodies with multiple activity sites known as autoantibodies seen in auto immune disorders; broadly reactive antibodies induced by infections or exposure to therapy containing monoclonal mouse antibodies (HAMA); or human anti animal immunoglobulins produced against well defined, specific antigens following exposure to therapeutic agents containing animal antigen or by coincidental immunization through exposure to animal antigens.

The latter, Human Anti-Animal Antibodies (HAAA), are strong reactors. HAMA and HAAA affect immunometric assays more than they affect simple competitive immunoassays. In immunometric assays, HAMA and HAAA can form a bridge between the capture and signal antibodies.

What Lab Results Are Absolutely Confirmatory?

Measurement of total T4 and/or TSH performed on filter paper eluates is not diagnostic, but rather a screen. Abnormal results must be further explored with the usual quantitative methods (i.e., free T4 and TSH in both the infant and mother and, additionally, thyroperoxidase antibody in the mother).

There is testing available to establish the etiology of congenital hypothyroidism. Presence of a thyroid gland may be established by radioactive iodine, which can differentiate congenital absence of the gland from a defect in organification; serum thyroglobulin analysis, which is quite sensitive to residual functioning thyroid tissue; or ultrasonography. Percholate discharge testing and I123 uptake can suggest an inborn metabolic error. Urinary iodine can identify specific gene mutations or clarify suspected iodine exposure or deficiency. Molecular testing is now available for many of the inborn metabolic defects. TSH receptor antibody in the mother and in the infant indicates the presence of an autoimmune disease in the mother. Some of these tests need to be performed prior to initiation of thyroxine replacement therapy.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The transient nature of a congenital hypothyroidism can best be confirmed by retesting at about 2 years of age.

In cases of transient hypothyroidism caused by transplacental passage of TSH receptor blocking antibodies from the mother to the infant, treatment with thyroxine is still indicated, even though the condition will be temporary. The presence of blocking antibody in the neonate inhibits the action of infant TSH and results in a lowered free T4 level. Thyroxine replacement therapy, in this case, can be tapered once the maternal antibodies have been degraded. This usually takes 3 to 6 months.

In many cases, it is not possible to determine whether the hypothyroidism is permanent or transient at the time of diagnosis of congenital hypothyroidism. TSH below 100 mIU/L, male sex of the infant, prematurity, exposure to iodine or dopamine, or pseudohypoparathyroidism are factors that present a greater likelihood the hypothyroidism is transient. All congenital hypothyroid patients are treated for their hypothyroidism. The transient nature of the disorder is then ruled in or out by removing the patient from therapy and retesting.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

The use of total T4 levels reflexed to TSH testing for neonatal congenital screening can produce false negatives in infants with ectopic thyroid glands who may have thyroxine concentrations above the tenth percentile cut-off. However, the threshold cannot easily be lowered to improve the sensitivity, since false positives would then be encountered.

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