Thyroid Disorders in the Neonate

Functions of the Thyroid Gland

The principal functions of the thyroid gland are to synthesize, store, and release the thyroid hormones thyroxine (T ₄ ) and triiodothyronine (T ₃ ) into the circulation. The major secretory product of the thyroid is T ₄ . Thyroidal secretion of T ₃ accounts for only about 20% of its production. The remaining 80% is derived from peripheral deiodination of T ₄ . Therefore, T ₄ acts as a prohormone for T ₃ , because T ₄ has negligible intrinsic metabolic activity in most tissues. Most of the physiologic effects of thyroid hormone are mediated by T ₃ through its interaction with the thyroid response element on DNA.

Neurologic Effects

Prenatal and postnatal maturation of the brain, retina, and cochlea is thyroid hormone dependent. Thyroid hormone modulates expression of thyroid hormone–responsive target genes at precise times during development, controlled by an interplay of deiodinases, thyroid receptor expression, transporters, cofactors, and transcription factors. T ₃ promotes the neural differentiation of embryonic stem cells at the dendritic level, and both T ₃ and T ₄ impact cerebral vascular development. Genes that control neural migration are also regulated by thyroid hormone.

As normal levels of thyroid hormone are essential for neuronal migration, myelination, and other structural changes in the fetal brain, congenital thyroid hormone deficiency results in cretinism (severe mental retardation) if not treated. This effect is prevented by thyroid hormone replacement early in life. Early detection of congenital hypothyroidism occurs through newborn screening, which was initiated in the 1970s. Intellectual development is normal in children with congenital hypothyroidism who are treated early and aggressively. The degree of mental retardation in cretinism is related to the severity and duration of the hypothyroid state of the infant. The brain is susceptible to a lack of thyroid hormone during its rapid growth and maturation. Defective growth and permanent damage do not occur if hypothyroidism begins after morphologic maturation of the brain is completed (after a postnatal age of 3 years).

Basal Metabolic Rate

Thyroid hormone stimulates basal metabolic rate primarily by increasing ATP production for metabolic processes and by maintaining ion gradients (Na/K ⁺ and Ca ²⁺ ), which consume ATP. Thyroid hormone is a key driver of thermogenesis. It uncouples oxidative phosphorylation in mitochondria and reduces activity of shuttle molecules that transfer reducing equivalents into the mitochondria. Thyroid hormone also increases sensitivity to catecholamine effect, which is required for maintenance of core body temperature.

Clinically, the calorigenic action of thyroid hormone affects circulation by increasing heart rate, stroke volume, and cardiac output. The pulse pressure is widened mainly by a decrease in the diastolic pressure and by some elevation in the systolic pressure. Circulation time is also shortened.

Protein and Lipid Metabolism

Negative nitrogen balance occurs in hyperthyroidism unless the patient is protected by adequate caloric intake to provide for the increased energy requirements. Hypothyroidism results in increased serum total cholesterol and low-density lipoprotein (LDL) cholesterol. Thyroid hormone stimulates the expression of LDL receptors and in hypothyroidism the number of hepatic LDL receptors is reduced, leading to the decreased clearance of circulating LDL. Apolipoprotein B and lipoprotein (a) are also increased in hypothyroidism.

Carbohydrates, Liver Function, Water Balance, and Calcium Metabolism

The rate of gluconeogenesis, glucose absorption, and use is increased by thyroid hormone. In hypothyroidism, the glucuronic acid conjugation mechanism of the liver may be impaired. In infants, hyperbilirubinemia associated with primary hypothyroidism is almost entirely indirect; in hypothalamic-pituitary hypothyroidism, it is both direct and indirect. Retention of water in the extracellular compartment occurs in hypothyroidism, producing deposition of myxedematous fluid in soft tissue.

In hyperthyroidism, calcium balance tends to be negative. Urinary and fecal calcium excretion is enhanced. Demineralization of bone also occurs. The efflux of calcium from the bones leads to higher plasma ionized calcium and phosphate and lower circulating 1,25(OH) ₂ D ₃ , which in turn results in decreased calcium absorption from the intestine.

Growth and Skeletal Development

A principal action of thyroid hormone is its effect on growth and skeletal development. These effects may be tissue specific and synergistic with other hormones. Prenatal growth is highly dependent on nutrition and insulin secretion. Postnatal linear growth is dependent on thyroid hormone and growth hormone (GH), which are mediated through insulin-like growth factor type 1 and its receptor. Similar synergistic effects between thyroid hormone and growth hormone can be observed in skeletal maturation. When primary hypothyroidism occurs, dental eruption, linear growth, and skeletal maturation are retarded. Retardation of skeletal maturation may be severe and is associated with immature skeletal proportions and facial contours, which contribute to the characteristic body configuration of hypothyroidism (long torso compared to short length of arms and legs). Ossification of cartilage is also disturbed in hypothyroidism, leading to epiphyseal dysgenesis in radiographs of the ossifying epiphyseal centers ( Fig. 88.1 ). Growth rate and adult height are normal in children with congenital hypothyroidism who are diagnosed in early infancy by newborn screening and treated appropriately.

Iodine Metabolism

Iodine is supplied to the body mainly through dietary intake. Although some organic iodine compounds, including T ₄ and T ₃ , can be absorbed unchanged from the gastrointestinal tract, most are reduced and absorbed as inorganic iodide. One-fourth to one-third of ingested iodide is taken up by the thyroid. Iodine can be absorbed readily from the skin, lungs, and mucous membranes. Application of iodine-containing ointment or lotion to the skin, common during procedures with premature or sick infants, causes very high levels of iodide in circulation and promptly blocks thyroid hormone release from the thyroid gland.

Iodide-trapping involves an active transport process through a sodium/iodide symporter that requires oxidative phosphorylation. Iodine uptake through the sodium/iodide symporter is a major rate-limiting step in thyroid hormone biosynthesis, and when it is defective, it is a rare cause of congenital goitrous hypothyroidism. The iodide pump is present at both the basal and apical surfaces of follicular cells. At the basal cell surface, the pump concentrates iodide in the cells by transporting them from the extracellular space. At the apical cell surface, the pump pushes iodide into the follicular lumen as a secondary reservoir. The mechanism is capable of maintaining intrathyroidal iodide concentration at a 20- to 100-fold higher level than that of serum. Some anions—bromide (Br ²⁻ ), nitrate (NO ₂ ²⁻ ), thiocyanate (SCN ²⁻ ), perchlorate (ClO ₄ ), and technetium pertechnetate (TcO ₄ ²⁻ )—are capable of competitively inhibiting iodide transport.

Iodide is immediately oxidized to an active form for iodination of thyroglobulin (TG) by a peroxidase enzyme system. Thyroglobulin, a glycoprotein, is synthesized by the ribosomes of the follicular cells. Iodination of TG (organification) appears to occur at the cell colloid-lumen interface. Almost all the iodine taken up by the thyroid is rapidly incorporated into the 3′ and the 5′ positions of the many tyrosyl residues of TG to form monoiodothyronine (MIT) and diiodothyronine (DIT). Once it is organically bound to tyrosyl residues, iodine can no longer be readily released from the thyroid. Defects in iodide oxidation or organification can be seen in several types of goitrous congenital hypothyroidism.

Synthesis of Triiodothyronine and Thyroxine

The synthesis of T ₃ requires the coupling of an MIT and a DIT molecule; T ₄ is formed by the coupling of two DIT molecules. These reactions occur within the structure of TG and involve oxidative processes, probably catalyzed by thyroid peroxidase as well.

Secretion of Triiodothyronine and Thyroxine

Secretion of T ₄ and T ₃ into the circulation requires the liberation of these moieties from TG. Thyroglobulin molecules pass from the lumen of the follicles into the follicular cells (endocytosis), where colloid droplets are ingested by lysosomes and undergo proteolysis. After proteolysis of TG, the freed MIT and DIT are deiodinated by iodotyrosine deiodinase, and the liberated iodide is recycled by the thyroid for reiodination of new TG. Congenital hypothyroidism can result from both abnormal TG synthesis or defect in the deiodination of freed iodotyrosines, which results in iodine depletion through urinary losses.

Serum Protein Binding and Transport

The thyroid is the only source of T ₄ , and its blood concentration is 50-100 times greater than that of T ₃ . T ₄ and T ₃ secreted into the circulation are transported by loose attachment, through noncovalent bonds, to three plasma proteins, which include thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin. TBG has the highest affinity for thyroid hormone and carries about 70% of T ₄ in plasma. TTR and albumin have lower affinity than TBG, but together they still provide significant binding capacity because of their higher plasma concentration. The free T ₄ (FT ₄ ) concentration more accurately indicates the metabolic status of the individual than total T ₄ or T ₃ does, because only the free hormones can enter the cells to exert their effects. If the capacity of thyroid binding proteins is increased or decreased, a concurrent change in the concentration of total hormones will follow, but the concentration of free hormones will be maintained.

Monodeiodination of Thyroxine

Monodeiodination of T ₄ occurs in many tissues through the action of three distinct deiodinase enzymes. Type I and II deiodinase through is found in peripheral tissues such as the liver and kidney. Deiodination at the 5′ position of T ₄ in peripheral tissues generates T ₃ , the iodothyronine that mediates the metabolic effects of thyroid hormone. Eighty percent of circulating T ₃ is produced by the monodeiodination of T ₄ . However, the relative serum levels of T ₄ and T ₃ do not reflect the intracellular proportions of the hormones. The tissue distribution of T ₃ may differ greatly from that of T ₄ from tissue to tissue. The plasma half-life of T ₃ is 1 day, compared with 6.9 days for T ₄ . However, the plasma half-life of T ₄ is much shorter (3.6 days) in neonates. Most T ₃ is localized in cells, whereas T ₄ is found mainly in the extracellular space. The metabolic effects of T ₃ are mediated through binding to specific receptors in the DNA response element that regulates transcription. T ₃ also interacts with membranous, mitochondrial, and cytosolic binding sites.

Neural tissue requires T ₄ (and does not bind T ₃ ). Thyroid hormone availability to neurons mainly takes place through astrocytic delivery. T ₄ is taken up by astrocytes at the blood–brain barrier, and T ₄ is converted to T ₃ by astrocytic type II deiodinase; T ₃ is then transported to neurons by transmembrane transporters. Type III deiodinase regulates peripheral deiodination of T ₄ at the 5 position on the thyronine molecule instead of 5′ and generates reverse T ₃ (rT ₃ ). Serum rT ₃ concentration parallels that of T ₃ in normal circumstances but not in fetal life, starvation, or patients with severe nonthyroidal illnesses (e.g., euthyroid sick syndrome, non-thyroidal illness syndrome). Reverse T ₃ is generally metabolically inactive, although weak nuclear binding activity has been reported.

Regulation of Thyroid Function

Control of thyroid hormone secretion is centered in the hypothalamic-pituitary-thyroid axis. Basophilic cells of the anterior pituitary gland synthesize and store thyrotropin (TSH), a glycoprotein capable of rapidly increasing intrathyroidal cyclic adenosine monophosphate (cAMP). TSH release from the pituitary causes an increased uptake of iodine by the thyroid, accelerates iodothyronine synthesis and release, and increases the size and vascularity of the thyroid. These changes are mediated by activation of adenylate cyclase and tyrosine kinase. Human chorionic gonadotropin (hCG) weakly competes with TSH for receptors on thyroid follicular cells. Hyperthyroidism seen in patients with choriocarcinoma can be explained by this mechanism. Similarly, certain immunoglobulins—TSH-binding inhibiting immunoglobulins (TBII) and TSH receptor-stimulating immunoglobulins (TSI) found in autoimmune thyroid diseases like Graves disease compete with TSH for binding to TSH receptors.

Secretion and plasma levels of TSH are inversely related to circulating levels of FT ₃ and FT ₄ . The inhibitory feedback action of FT ₃ and FT ₄ involves a direct action of these hormones on the pituitary gland without involving the hypothalamus. Therefore, secretion of TSH is regulated directly by the ambient intrapituitary T ₃ concentration and intrapituitary deiodination of T ₄ to T ₃ by type II monodeiodinase activity.

The hypothalamus secretes thyrotropin releasing hormone (TRH) that enters the portal system to reach the pituitary and stimulate synthesis and release of TSH from thyrotrophs. TRH is under negative feedback control by thyroid hormone, but other factors like nutritional status, external temperature, and circadian cycle regulate TRH independently of thyroid hormone level.

A circadian variation of circulating TSH has been found in normal children and adults. A peak TSH concentration (≈3-4 mU/L) develops between 10:00 pm and 4:00 am and is about 50%-300% higher than the afternoon (2:00-6:00 pm ) nadir values. This nocturnal TSH surge is not directly related to sleep; it is blunted or absent in central (secondary or tertiary) hypothyroidism but maintained in primary hypothyroidism. The circadian pattern of TSH is not yet present in neonates but has been noted to be present in infants as young as 4 months of age. In children age 1 year and older, the am to pm TSH ratio can be useful in identifying mild primary hypothyroidism and in differentiating this from central hypothyroidism.

In addition to hypothalamic-pituitary regulation, the thyroid is under autoregulatory control that adjusts the degree of iodide trapping, thyroid hormone production, and release in response to changes in iodine exposure. This helps to maintain a euthyroid state despite fluctuation in dietary iodine intake.

Thyroxine (T ₄ )

The plasma pool of T ₄ constitutes a large protein-bound reservoir; this pool turns over slowly. Therefore, T ₄ measurement usually reflects the adequacy of the hormonal supply. The normal level of T ₄ is age dependent in infancy and childhood. T ₄ reaches a peak concentration shortly after birth and declines slowly, gradually approaching the adult normal range in puberty. The range of normal levels for each age group is also wide ( Fig. 88.2 ). However, it should be kept in mind that more than 99% of circulating T ₄ is bound to serum thyroid hormone–binding proteins. Any change or abnormality in the concentration of these proteins, particularly TBG, can affect the T ₄ level. Several clinical situations and pharmacologic agents can alter the levels of TBG or TTR . Certain anticonvulsants not only bind competitively to TBG but also interfere with T ₄ assays without greatly influencing the TSH level in a person with an otherwise normal thyroid reserve. These drugs include phenytoin, valproate, primidone, and carbamazepine. Other drugs, such as furosemide, salicylate, and L-asparaginase, compete with thyroid hormone for binding with plasma proteins and can alter the levels of T ₄ , T ₃ , FT ₄ , and FT ₃ .

Triiodothyronine

When TSH becomes elevated, the percentage of T ₃ produced by the thyroid gland is increased. Serum concentration of T ₃ can vary from day to day. Because of the overall small quantity of T ₃ in serum, its level may not fall below the normal range until T ₄ is critically low. Therefore, serum T ₃ is not very useful in evaluation of patients for possible hypothyroidism. T ₃ is physiologically low in the fetus and cord blood, but rises promptly after birth to levels greater than those in older children and adults.

Reverse Triiodothyronine

Hormonally inactive rT ₃ is derived primarily from deiodination of T ₄ . Serum half-life is very short, less than one-half that of T ₃ . Concentration of rT ₃ usually parallels that of T ₃ . However, rT ₃ is disproportionately high in the fetus, in the early neonatal period, and in severe nonthyroidal illness, probably reflecting altered tissue metabolism of T ₄ .

Free Hormones

Because concentrations of T ₄ and T ₃ are affected by those of thyroid hormone–binding proteins and the degree of their saturation at the binding site, the simplest approach to determine thyroid hormone levels is to measure free T ₄ (FT ₄ ) and not measure T ₄ at all. In clinical settings, FT ₄ does not depend on the T ₄ -binding capacity, because a change in such a capacity is soon compensated for by a change in the amount of T ₄ released from the thyroid. The gold standard for measuring FT ₄ in serum is by direct dialysis. Serum is placed in a dialysis cell on one side of a semipermeable dialysis membrane, with a buffer solution on the other side. T ₄ equilibrates across the membrane and bound T ₄ remains with serum. Unbound FT ₄ that crosses the dialysis membrane can then be measured by radioimmunoassay or tandem mass spectrometry. FT ₃ levels in the serum can be measured in the same dialysate as that used for FT ₄ .

Labeled analogue or antibody methods are also available to measure FT ₄ . They can be performed more rapidly and are less expensive than measurement of free hormone by direct dialysis. The principle of labeled analogue or antibody methods is that the rate of binding of labeled hormones to antibodies depends on the FT ₄ concentration during a timed incubation. They are acceptable for routine testing in children. However, these methods may not provide an accurate assessment of FT ₄ at extremes of thyroid hormone binding capacity or with significant changes in T ₄ binding protein affinity.

Measurement of FT ₃ is not currently part of standard care. In the future, FT ₃ measurements may be shown to be useful in assessing hypothyroidism. Currently, FT ₃ may be useful when the diagnosis of thyrotoxicosis is suspected and TSH is suppressed but values for T ₄ , T ₃ , or both are normal.