The Thyroid: Pathophysiology and Thyroid Function Testing

Chapter 55

The Thyroid

Pathophysiology and Thyroid Function Testing

The thyroid is a butterfly-shaped gland located in the front of the neck, just above the trachea. The fully developed thyroid gland in a human is composed of two lobes connected by a thin band of tissue, the isthmus, which gives the gland the appearance of a butterfly. The gland is closely attached to the trachea in the anterior aspect of the neck. Anatomically and embryologically, the thyroid gland is two glands in one: the thyroid follicular cells produce thyroid hormones and the parafollicular (or C) cells secrete calcitonin.21

Thyroid Gland: Structural and Functional Ontogeny

Embryologically at day 24, the thyroid gland develops from an anterior outpouching of the foregut. From this thyroid diverticulum, the thyroid gland descends, and the process is usually complete at 7 weeks. Failure of descent can produce (1) a lingual thyroid gland (located at the base of the tongue), (2) an ectopic gland, or (3) a hypoplastic or aplastic gland. Coincident with thyroid development, the parafollicular (C cells) cells (producing calcitonin) develop.

The fetus is dependent on the transplacental passage of maternal thyroid hormone for the first half of gestation.26,29,65,225 Although only minute amounts of maternal thyroid hormone cross the placenta, maternal hypothyroidism in the first 20 weeks of gestation may adversely impact fetal central nervous system (CNS) development, leading to neuropsychologic impairment in infants and children.178 Worldwide, the most common cause of hypothyroidism during pregnancy is iodine deficiency. Conversely, in developed countries, where iodine fortification is widespread, the most common cause of primary hypothyroidism is Hashimoto thyroiditis (chronic autoimmune thyroiditis/inflammation of the thyroid gland).

Hypothalamic thyrotropin-releasing hormone (TRH) stimulates thyrotropin [thyroid-stimulating hormone (TSH)], which in turn stimulates thyroid hormone synthesis. By 10 weeks, fetal thyroid follicles and thyroxine synthesis are demonstrable. By the mid second trimester, maturation of the hypothalamic-pituitary-thyroid axis occurs, so that by 20 weeks, the fetus is becoming responsible for its own production of thyroid hormone. Thyroxine-binding globulin (TBG) and thyroxine are first detectable in fetal serum at 8 to 10 weeks’ gestation and increase thereafter until they plateau at 35 to 37 weeks (Figure 55-1). Thyroxine [tetraiodothyronine (T4); see Table 55-1 for nomenclature and abbreviations) and TSH rise until birth, with T4 near ≈10 µg/dL and TSH reaching a concentration of 7 to 10 mIU/L. Beginning at ≈30 weeks, T4 is converted to triiodothyronine (T3) by increased activity of the type 1 deiodinase (D1), so that T3 concentrations rise, while reverse T3 (rT3) concentrations decline. At 30 weeks, T3 is less than 15 ng/dL; at term, T3 is ≈50 ng/dL.

Within hours of birth, TSH, T4, and T3 rise rapidly (Figure 55-2).52 Cold stress is believed to be responsible for the massive TSH surge to concentrations of 70 to 100 mIU/L. By 2 to 3 days, the TSH concentration falls in most cases to less than 20 mIU/L. Total T4 peaks near ≈17 µg/dL. T4 then falls to adult concentrations by 1 to 2 months of age. The postbirth rise in T3 results from increased thyroid gland release in response to the rising TSH concentration and increased conversion of T4 to T3 due to maturation of the type 1 deiodinase enzyme (D1).

Thyroid Gland Anatomy

The adult thyroid gland weighs between 15 and 20 g. However, in disease states, the gland can attain a weight of several hundred grams. The thyroid gland is normally bilobed, with the right lobe somewhat larger than the left lobe. In adults, the lobes are ≈2.0 to 2.5 cm thick by ≈2.0 to 2.5 cm wide by ≈4 cm high. The lobes are connected by the isthmus, which is ≈0.5 cm thick by ≈2.0 cm wide by ≈1 to 2 cm high.

Microscopically, the thyroid gland is composed of follicles or acini (Figure 55-3, A). The outside of the follicular unit/acinus is enveloped by a basement membrane. Along the inside of the basement membrane are squamous or cuboidal epithelial follicular cells. The height of the follicular cells reflects their biochemical activity: the greater their height, the more thyroid hormone synthetic activity is occurring. The basal pole of the follicular cell is oriented toward the basement membrane, and the apical pole is oriented toward the center of the follicle (Figure 55-3, B). In the center of the follicle, lined by the apical aspects of the follicular cells, is the lacuna, which contains colloid composed predominantly of thyroglobulin.

On average, follicles are ≈200 microns wide (compared with a normal red blood cell diameter of 7 microns). The parafollicular cells usually are located below the basement membrane but are not adjacent to the lumen (lacuna) of the follicle. Without immunohistochemical staining for calcitonin, the parafollicular cells are very difficult to identify.

Branches of the common carotid artery (the superior thyroid arteries) and the subclavian arteries (the inferior thyroid arteries) supply the thyroid. It is surprising to note that on a per gram basis, the thyroid gland receives more blood than the kidney: 4 to 6 mL/min/g of thyroid tissue versus 3 mL/min/g of kidney. In cases of hyperthyroidism, blood flow to the entire thyroid gland can exceed 1000 mL/min, which is ≈20% of the normal cardiac output of an adult.

Biological Function

Thyroid hormones (T4 and T3) bind to intranuclear receptors that function as transcription factors and thereby regulate gene expression. Thyroid hormones have ubiquitous effects on growth and development in the fetus, child, and adolescent, and they regulate calorigenesis and metabolic rate throughout life. At a molecular level, thyroid hormones (1) increase oxygen consumption within tissues via increased membrane transport (cycling of sodium/potassium ATPase with increased synthesis and consumption of adenosine triphosphate), (2)  enhance mitochondrial metabolism (stimulation of mitochondrial respiration and oxidative phosphorylation), (3) increase sensitivity to catecholamines with increased heart rate and myocardial contractility, (4) stimulate protein synthesis and carbohydrate metabolism, (5) increase synthesis and degradation of cholesterol and triglycerides (e.g., regulation of low density lipoprotein receptor expression by the liver), (6) increase vitamin requirements, and (7) regulate calcium and phosphorous metabolism.

Thyroid hormones maintains the basal metabolic rate and thus regulates the metabolism of endogenous and exogenous substances. Hypothyroidism impairs the excretion of many drugs, with hyperthyroidism accelerating their clearance.


Thyroid hormone is derived from the amino acid tyrosine. Thyronine is produced by substitution of a second phenol moiety for the phenolic hydrogen on tyrosine, producing a diphenyl ether having two phenol rings attached to one another through an ether linkage (Figure 55-4).

There are four possible sites for iodine attachment to thyronine at the meta positions on both phenyl rings, designated the 3, 5, 3′, and 5′ positions. The 3 and 5 positions are on the alpha (inner) ring, and the 3′ and 5′ positions are on the beta (outer) ring. The biologically important thyroid hormones are 3,5,3′,5′-tetraiodothyronine [thyroxine (T4)] and 3,5,3′-triiodothyronine (T3). Debate continues over whether T4 has any intrinsic biological activity, or whether it is a prohormone.

Iodination of tyrosine to ultimately produce T4 and T3 involves the tyrosine residues on thyroglobulin.86 An isomer of T3 is reverse T3 (rT3), in which the alpha ring is monoiodinated and the beta ring is di-iodinated, producing 3,3′,5′-L-triiodothyronine. Reverse T3 is not biologically active. Almost all rT3 is formed by the extrathyroidal conversion of T4 to rT3, and approximately 80% of T3 is formed by extrathyroidal monodeiodination of T4 to T3.

Thyroid hormone biosynthesis begins with the active transport of iodide (I) into the thyroid gland via the Na+/I (sodium-iodide) symporter (NIS, SLC5A; SLC = solute carrier; chromosome 19p12-13.2; Figure 55-5).20 Iodide transport is inhibited by lithium, which competes with sodium, but the NIS transports other anions besides iodide. In the follicular cells, the iodine concentration is 30- to 40-fold greater than the circulating concentration. When the thyroid gland is stimulated by TSH, even larger iodide concentration gradients can result. Antithyroid drugs such as propylthiouracil and methimazole inhibit iodination and coupling; this can lead to an 800-fold difference in the concentration of iodide in the thyroid gland versus the plasma.

Once in the thyroid follicular cells, cytoplasmic iodide moves into the lacuna (colloid) via pendrin (SLC26A4 gene on chromosome 7q21-34) (see Figure 55-5).88 Pendrin is a passive iodide-transporting glycoprotein identified during studies of patients with Pendred syndrome. Pendred syndrome is an autosomal recessive disorder of dyshormonogenesis that is characterized by goiter and sensorineural deafness.

Thyroglobulin (Tg) is necessary for thyroid hormone synthesis. Similar to other proteins, Tg is synthesized in follicular epithelial cells by ribosomes located on the endoplasmic reticulum (see Figure 55-5). Tg may represent up to 50% of protein synthesis in the thyroid gland and may account for 75% of glandular total protein.

The 42-exon gene encoding Tg is located on chromosome 8q24 and spans 250 kilobases. Tg is a glycoprotein homodimer of 660 kDa. A total of 134 tyrosine residues are found in the homodimer, and 25 to 30 of these residues are iodinated. However, T4 is formed only at residues 5, 1290, and 2553, and T3 is formed only at residue 2746. The Tg sedimentation coefficient of 19S is similar to that of circulating pentameric IgM, reflecting the large size of Tg. TSH is the principal stimulator of Tg synthesis. Thyroid transcription factor 1 (TTF1) interacts with the Tg promoter to stimulate Tg mRNA synthesis.

Although most Tg is secreted into the follicular lumen, a small amount of Tg is released from the follicular cells without transport into the colloid, and this Tg is not iodinated. Of consequence in autoimmune thyroid disease, iodination increases the immunogenicity of Tg. Increased dietary iodine exposure is associated with the development or expression of Hashimoto thyroiditis.112

Once in the lacuna, iodide is oxidized (“organified”) to an iodine radical by the thyroperoxidase (TPO) enzyme. Hydrogen peroxide (H2O2) serves as the terminal electron acceptor, forming H2O2.185 Hydrogen peroxide is generated at the apical membrane by the action of DUOX1 and DUOX2 (DUOX was previously known as THOX, or thyroid oxidase). DUOX is a dual oxidase that has domains analogous to the domains found in nicotinamide adenine dinucleotide phosphate (NADPH) oxidoreductases. Hypothyroidism due to DUOX mutations has been reported.130

TPO catalyzes the monoiodination of Tg tyrosines to monoiodotyrosine (MIT) (Figure 55-6). Di-iodination of tyrosine forms di-iodotyrosine (DIT) (Figure 55-6). After Tg is iodinated to form MIT and DIT, TPO catalyzes the coupling reaction to produce T4 (Figure 55-7) and T3 (Figure 55-8). In the coupling reaction, T3 (bound to Tg) is formed from one DIT and one MIT residue with the transfer of one monoiodinated phenolic group to a DIT residue. T4 (bound to Tg) is formed from two DIT residues with the transfer of one di-iodinated phenolic group to another DIT residue.

Tg, along with its T3 and T4 residues, remains in the colloid, providing a reservoir of thyroid hormone. With TSH stimulation, the apical pole of the follicular cell releases colloid into a vesicle by pinocytosis (see Figure 55-5). The follicular cell digests the intravesicular colloid containing Tg after fusion of the phagosome body with a primary lysosome. Fusion of the endocytosed Tg with the primary lysosome forms a secondary lysosome, in which digestion of Tg occurs, releasing T4, T3, MIT, DIT, and amino acids. By diffusion, the lipophilic T4 and T3 molecules exit the lysosome and cross the follicular cell plasma membrane to be captured in thyroid capillaries, where the vast majority of thyroid hormone is protein bound. Only 0.03% of total T4 is free (unbound and bioactive), and only 0.3% of total T3 is unbound and bioactive.

Within the cytoplasm of the follicular cell, the released MIT and DIT are stripped of iodine by dehalogenase (Dhal) to produce free iodide ions, which can be recycled immediately for the synthesis of new thyroid hormone.64 Two dehalogenase genes have been described: Dhal1 and Dhal1b. Normally, only negligible amounts of MIT and DIT are released from the thyroid gland into the circulation. However, loss-of-function mutations in the dehalogenase enzyme potentially lead to iodine loss in the urine and increased concentrations of DIT and MIT in the circulation.

The peripheral metabolism of thyroid hormones is very complex.191 Three homodimeric deiodinases are present: type 1 (D1), with inner and outer ring deiodinase activities found in liver, kidney, thyroid, and possibly the anterior pituitary gland (Figure 55-9); type 2 (D2), with outer ring deiodinase activity expressed in the CNS, anterior pituitary, brown fat, placenta, heart, skeletal muscle, and thyroid; and type 3 (D3), with inner ring deiodinase activity identified in CNS, liver, endometrium, and placenta. Approximately 40% of T4 is deiodinated to T3 by D1 or D2, and ≈45% is deiodinated to rT3 by D1 or D3. About 80% of circulating T3 comes from 5′-deiodination of T4; only ≈20% of T3 is released directly from the thyroid gland (Figure 55-9). Almost all circulating rT3 results from 5-deiodination of T4. By regulating the conversion of T4 to T3, the body, in part, regulates the metabolic rate.

D1 converts T4 to rT3 (via 5-deiodination) and T4 to T3 (via 5′-deiodination) (Figure 55-10). The preferred substrates for D1 are sulfated T3 (converted to 3,3′-T2 via 5-deiodination) and rT3 (converted to 3,3′-T2 via 5′-deiodination). D1 activity is stimulated by thyroid hormone through increased gene transcription. Thus, increased D1 activity promotes peripheral conversion of T4 to T3 in hyperthyroidism. Therapeutically, D1 is inhibited by propylthiouracil, which is used to treat hyperthyroidism. In contrast to the effect of thyroid hormone on D1, D2 expression is suppressed by thyroid hormone. The Km for the D1-T4 complex is approximately 1000-fold greater than the corresponding Km for D2 or D3. Regulation of the T4→T3 and T4→ rT3 conversions is dependent on the tissue distribution of D1, D2, and D3. The free T3 (FT3)-to-T4 (FT4) ratio is affected by a genetic polymorphism in the D1 gene (DIO1; the single-nucleotide polymorphism rs2235544).143

Each of the deiodinase enzymes has a single transmembrane domain. The deiodinases are attached to the inner plasma membrane (D1 and D3) or endoplasmic reticulum (D2), and the active site of the enzyme is on the cytoplasmic domain. Therefore, thyroid hormone must enter the cytoplasm of cells to be metabolized. In addition to thyroid hormone metabolism via deiodination, small amounts of T4 are glucuronidated or sulfated and excreted in the bile. Intestinal cleavage of glucuronidated T4 releases T4 that can then be reabsorbed from the intestine back into the circulation.

Until recently it was believed that both T4 and T3 entered cells by passive diffusion across the plasma membrane. However, evidence has shown that thyroid hormones cross plasma membranes using specific transporters.74 One important thyroid hormone transporter is monocarboxylate transporter 8 (MCT8).118 The solute carrier family of monocarboxylate transporters has 14 members (MCT1 through MCT14); examples of other monocarboxylates transported by these carriers are lactate and pyruvate.

It has been shown that MCT10 (SLC16A10; chromosome 6q) transports iodothyronines and aromatic amino acids across membranes, and MCT10 is likely more preferential than MCT8 in transporting T3 over T4 across plasma membranes. Organic anion transporting polypeptide 1C1 (OATP1C1) also has high affinity for thyroid hormone and may be an important component of the transport of T3 and T4.

Transport of thyroid hormone into neurons is especially critical for normal CNS development and function (Figure 55-11). OATP1C1 may be responsible for thyroid hormone uptake and release by astrocytes, although this has not yet been definitively demonstrated. Within the astrocyte, T4 is converted to T3 via D2 attached to the astrocyte membrane. T3 may exit the astrocyte via OATP1C1 to be taken up by neurons via MCT8. Within the neuron, T3 can interact with the intranuclear thyroid hormone receptor (TR), or can be converted to 3,3′-T2 via membrane-attached D3.

Although T4 is converted to T3 outside of target organs (the liver converts T4 to T3 and then releases T3 back into the circulation), target organs can also deiodinate T4 to T3 so that T3 can bind to TRs. The liver, kidney, brain, brown fat, anterior pituitary, pineal, heart, skeletal muscle, and placenta all express a 5′-deiodinase capable of deriving T3 from T4.

T3 binds to specific intranuclear TRs to exert its hormonal effects. In humans (and various animals), thyroid hormone upregulates the expression of growth hormone,110 myelin basic protein, the alpha-myosin heavy chain, and a sarcoplasmic reticulum calcium ATPase, while downregulating the expression of the TSH beta chain and the beta-myosin heavy chain. In part, suppression of TSH beta chain synthesis contributes to negative feedback.

TRs are members of the steroid hormone supergene family and serve as transcription factors that include domains for DNA binding, T3 binding, and transactivation. T3 binds to the TRs with 15-fold greater affinity than T4. The TRs form heterodimers with the retinoid X receptor (RXR) to interact with the thyroid response elements (TREs) in DNA. Monomers and homodimers of TRs can also bind to the TREs. TRs have zinc-finger structures that form alpha helices for interaction with the response elements.

Two types of TRs are known: TRα and TRβ (Table 55-2).218 TRα is encoded by the thyroid hormone receptor-alpha (THRA) gene on chromosome 17q11.2. Of its two expressed isoforms (TRα1 and TRα2), only TRα1 binds thyroid hormone. A TRα3 isoform produced by alternative splicing has also been reported. TRα1 is expressed throughout the body, but its mRNA is in highest concentrations in the heart, brain, liver, and kidneys.

TRβ is encoded by 11 exons on the thyroid hormone receptor-beta (THRB) gene on chromosome 3p24.3. Three isoforms of TRβ exist: TRβ1, TRβ2, and TRβ3. The highest concentrations of TRβ1 are found in heart, kidney, liver, and brain. Expression of TRβ2 has been identified in the anterior pituitary, hypothalamus, retina, cochlea of the inner ear, and developing brain. Defects in TRβ1 can produce resistance to thyroid hormone; defects in TRα have not been reported.

Within most cells, ≈90% of T3 is cytosolic and ≈10% is intranuclear. An exception is seen in the pituitary gland, where T3 is distributed approximately equally between the cytoplasm and the nucleus. A T3-binding protein (CTBP, or C-T3BP) has been identified that may influence the intracellular distribution of thyroid hormone; however, this protein does not exhibit receptor activity.

It is important to consider the comparative biological activity of circulating T4 and T3. On a molar basis, there is ≈100 times as much circulating T4 as T3. Typical reference intervals for T4 and T3 are 60 to 135 nmol/Land 1 to 3.5, nmol/L, respectively. The difference in T4 and T3 concentrations narrows, however, to a 10-fold excess of free (active) T4, compared with unbound T3, in the circulation. Because T3 is 4 to 15 times as biologically active as T4, the difference in effectiveness narrows further. It is debated whether the effects of T4 exceed those of T3, or whether they equally influence the tissues. Within the cells of the anterior pituitary, large intracellular amounts of T3 are derived from monodeiodination of T4, so circulating FT4 appears to be the major regulator of pituitary TSH secretion. This is an important concept that explains why TSH remains normal in the early stages of the sick euthyroid syndrome, when FT4 is normal, preventing a rise in TSH, yet the T3 is decreased.

In the pituitary, most T3 is derived from intrapituitary conversion of T4 to T3. Within target tissues, if more T3 comes from T4 (via target cell 5′-deiodination) than from the circulation itself, T4 has a major effect on tissues. Nevertheless because most T3 is derived from T4, within the circulation or within a target cell, T4 is often considered to be a prohormone in the generation of T3.

Compared with the kidney, liver, and cerebral cortex, much higher concentrations of TRs are found in the anterior pituitary gland and brown adipose tissue. In both of the latter tissues, two thirds to three quarters of the receptors are occupied by T3, with slightly more than half of the T3 derived from intracellular conversion of T4 to T3 via D2, versus T3 taken up from the circulation (derived from T4 outside the target tissue by D1 and D2). Most of the hepatic and renal T3 comes from circulating hormone. On the other hand, the vast majority of T3 in the cerebral cortex is derived intracellularly from T4 by monodeiodination of T4 to T3.


Thyroid Hormone Negative Feedback Control of TRH and TSH

Thyroid hormone synthesis and secretion are controlled by a negative feedback system involving the hypothalamus, the pituitary, and the thyroid follicular cells (Figure 55-12).30 In contrast to other hypothalamic-anterior pituitary target organ systems that utilize a negative feedback system, however, the major site of thyroid hormone feedback is at the level of the anterior pituitary thyrotrophs—not at the level of the hypothalamus.

Hypothalamic Physiology

Thyrotropin-releasing hormone (TRH; thyrotropin-releasing factor, thyroliberin, or protirelin) is encoded on chromosome 3, and the modified tripeptide L-pyroglutamyl-L-histidyl-L-prolinamide is secreted by the paraventricular nuclei (PVN) in the hypothalamus (Figure 55-13). Cyclization of the glutamate terminus is required for TRH bioactivity. The PVN are located in the anterior hypothalamus, rostral to the optic chiasm. TRH concentrations rise in thyroid hormone deficiency with TRH declining when thyroid hormone is in excess. TRH is delivered to the anterior pituitary gland via the hypothalamic-pituitary portal system.

Anterior Pituitary Thyrotroph Physiology

Thyrotrophs, the anterior pituitary cells that secrete thyroid-stimulating hormone (TSH; thyrotropin), express TRH receptors, which are G-protein–coupled receptors with seven transmembrane domains. When TRH binds to its receptor, the thyrotroph depolarizes, triggering calcium influx. Consequently, increased free cytosolic calcium activates the Ca2+-phosphatidylinositol cascade, effecting TSH release, synthesis, and glycosylation of alpha and beta TSH subunits. In relative terms, TRH has a greater effect on TSH glycosylation than hormone release.165 However, glycosylation of TSH is necessary for normal TSH bioactivity. When TRH is deficient, TSH may lack potency as the result of insufficient glycosylation, yet nonglycosylated TSH may retain much of its immunoreactivity. Therefore, immunoassays for TSH may not reflect the activity of the hormone when injury or disease results in a TRH deficiency.

TRH modifies the sensitivity of the thyrotroph to thyroid hormone negative feedback; increased TRH makes the thyrotroph less sensitive to inhibition with decreasing TRH makes the thyrotroph more sensitive to negative feedback. The mechanism for TRH control involves reduced expression of TRs in the thyrotroph following TRH stimulation. When the thyrotroph is less sensitive to negative feedback from thyroid hormone, TSH release is potentiated. Therefore, TSH secretion rises in thyroid hormone deficiency and declines in thyroid hormone excess. An inverse logarithmic relationship exists between TSH and FT4 concentrations (Figure 55-14); a 50% decline in FT4 concentration results in a 100-fold increase in TSH.

TSH is a 30 kDa heterodimeric glycoprotein that shares a subunit with luteinizing hormone (LH), follicular stimulating hormone (FSH), and human chorionic gonadotropin (hCG).174 All four hormones contain a 14.7 kDa alpha subunit (gene location: chromosome 6q21.1-q23). Each of these hormones has a unique beta subunit that is responsible for the specific activity of the hormone. The 15.6 kDa TSH beta chain is encoded by a three-exon gene located on chromosome 1p. The alpha chain contains two oligosaccharides, and the TSH beta subunit contains one oligosaccharide modification.

Thyroid Follicular Cell Physiology

The effects of TSH on the thyroid follicular cell are mediated through TSH receptor (TSHR)–G-protein–adenyl cyclase–coupled synthesis of intracellular cyclic adenosine monophosphate (cAMP).197 At supraphysiologic concentrations (100× normal), TSH will signal through the inositol-phosphate diacylglycerol cascade, activating phospholipase C (PLC) and raising intracellular calcium concentrations, with subsequent stimulation of H2O2 generation and iodide efflux into the follicular lumen.

The TSHR is a 743 amino acid, 84.5 kDa protein generated after cleavage of a 21 amino acid pre- (or leader) sequence. After post-translational glycosylation, the TSHR is ≈100 kDa. The first nine exons encode the 398 amino acid N-terminal extracellular domain. The extracellular domain contains six N-glycosylation sites that make up the TSH-binding domain. The TSHR may be in either of two conformations: the “on” conformation, with active signaling, or the “off” conformation, where signaling does not occur. TSH binding to the TSHR puts it in the “on” conformation, leading to stimulation of the thyroid gland.

Within the TSH-stimulated thyroid follicular cell, the activity of the sodium-iodine symporter increases; increased synthesis of thyroglobulin (Tg) and TPO, increased generation of hydrogen peroxide and NADPH, and pinocytosis of colloid with consequent degradation and release of T4 and T3 from Tg are also noted. Replication of thyroid follicular cells is stimulated by cAMP, phospholipase C, insulin-like growth factor-I (IGF-I), and a fibroblastic growth factor (FGF)-mediated kinase. TSH stimulation increases the size and number of thyroid follicular cells. Likewise, follicular cellular hyperplasia is seen in Graves’ disease, when an agonistic autoantibody stimulates the TSH receptor.

Thyroid Hormones in The Circulation

Both T4 and T3 are highly bound to plasma proteins in circulation. Protein-bound T4 and T3 serve as thyroid hormone reservoirs within plasma. In the thyroid gland, Tg serves as a reservoir. The unbound fraction of circulating thyroid hormone is the biologically active form, so FT4 concentrations correlate more closely with the clinical status of the patient than do total T4 concentrations.15,142 However, elevations in FT3 usually correlate with the clinical status of the patient, low FT3 concentrations do not always equate with clinical hypothyroidism, as evidenced in the sick euthyroid syndrome (see later). Similarly, elevated free concentrations of T4 or T3 do not always correlate with hyperthyroidism because of the possibility of peripheral thyroid hormone resistance syndromes and rare MCT8 loss-of-function mutations. Alterations in the concentrations of thyroid hormone–binding proteins can profoundly affect the total concentrations of T4 and T3 without significant changes in the free hormone concentrations.

T4 binds to thyroxine-binding globulin (TBG; a 54 kDa α1-globulin), thyroxine-binding prealbumin (TBPA, or transthyretin; 54 kDa), and albumin. T3 binds almost exclusively to TBG and albumin; TBPA binds only negligible amounts of T3 (Table 55-3).176 On serum protein electrophoresis, TBPA migrates in the prealbumin region (hence, its name). TBG (chromosome Xq11-23) is a 395 amino acid acidic glycoprotein with one iodothyronine-binding site. TBG has 4 heterosaccharide sidechains with 5 to 9 sialic acid moieties. As the degree of sialylation increases (an effect of estrogen), the half-life of TBG increases, thus raising TBG concentrations.

Increased concentrations of TBG raise total T4, yet FT4 remains within the euthyroid interval as the result of negative feedback (see Figure 55-12). Similarly, decreased TBG concentrations lower total T4 while maintaining normal FT4.

Causes of elevations and depressions in thyroid hormone–binding protein (TBP) are shown in Box 55-1. In congenital TBG excess (an X-linked dominant condition), male hemizygotes display threefold to fivefold elevations in TBG concentration, while female heterozygotes typically have twofold to threefold elevations in TBG. Abnormal forms of albumin (familial dysalbuminemic hyperthyroxinemia) and TBPA (familial euthyroid thyroid excess) alter the concentrations of total T4, yet do not affect FT4, total T3, or FT3. These conditions are discussed later, along with antithyroid hormone autoantibodies that raise total thyroid hormone concentrations. Isolated euthyroid hypertriiodothyroninemia (with all other thyroid parameters normal) caused by a rare form of dysalbuminemia has been reported.

Radiographic Thyroid Testing

Thyroid gland location, anatomy, and function is also assessed radiographically. For example, thyroidal uptake of radioactive iodine (I-123 or I-131) or technetium pertechnetate (99mTc-pertechnetate; TcO4) is assessed over time as an index of thyroid function.116

The degree of uptake of an exogenously administered radioactive tracer versus time reflects the activity of the thyroid gland (Figure 55-15). Radioactive iodine or technetium pertechnetate can be used. The radioactive iodine uptake (RAIU) is typically expressed as the counts measured (via scanning of the thyroid gland) divided by the total counts administered. The reference interval for the RAIU is usually 5 to 25%, which means that 5 to 25% of administered radioactive tracers are present in the thyroid gland at the time of the scan (usually at 24 hours).

In most endogenous hyperthyroid states, the RAIU is increased; in hypothyroid states, the RAIU is decreased. In thyrotoxicosis, measurement of the RAIU at 6 hours may be helpful because a hyperactive thyroid gland takes up the radioiodine at a very rapid rate and may have released some of the tracer by 24 hours. Otherwise, scanning at 24 hours alone might reveal a falsely lower measurement of the RAIU. As iodine has become more plentiful in the diet, the reference interval for the RAIU has declined.

Perchlorate Discharge

Normally, iodide is rapidly transported into the thyroid gland via the NIS. Within minutes of entry into the thyroid gland, intracellular iodide is transported into the lacunae via pendrin and undergoes oxidation, leading to iodination of tyrosine residues on thyroglobulin. DUOX and thyroperoxidase are responsible for the formation of organified iodine, and thyroperoxidase is responsible for the iodination of tyrosine. TPO couples MIT and DIT to produce T3, and DIT and DIT to produce T4. The NIS also concentrates other anions within the thyroid gland, such as thiocyanate (SCN), pertechnetate (TcO4), and perchlorate (ClO4).

The perchlorate discharge test is used to detect defects in thyroid gland iodide oxidation or iodination of Tg. Radioactive iodine is administered prior to perchlorate, and any radioiodine still in the follicular cells that has not yet been incorporated into colloidal Tg is released.227 Perchlorate does not block iodination of Tg. If the NIS has transported radioiodide into the thyroid gland, but the iodide is not yet incorporated into Tg after perchlorate administration, a supranormal amount of radioiodine is released from the thyroid gland (an increase in the perchlorate discharge of radioiodine occurs).

Causes of increased radioiodide discharge after perchlorate administration include defects in pendrin, thyroperoxidase, and DUOX. Alternatively, if an inborn error is present in the NIS (e.g., a loss-of-function mutation), release of radioiodide is not increased after perchlorate because radioiodide was not initially taken up by the thyroid gland.

Clinical Conditions

Because the signs and symptoms of thyroid dysfunction are extremely variable, thyroid function studies are often measured in clinical practice.36,41 An enlarged thyroid gland (goiter) is typically evaluated by measurement of TSH and thyroid hormones, and on the basis of (1) history, (2) physical examination, and (3) laboratory results; patients may be classified as (1) euthyroid, (2) hypothyroid, or (3) hyperthyroid.95,125,153

Patients presenting with a thyroid mass are typically euthyroid. Suspicious masses are typically followed by ultrasound-guided fine-needle aspiration of the mass with cytologic examination. A thorough discussion of all forms of thyroid cancer is beyond the scope of this chapter, although the role of Tg measurements will be examined as a tumor marker for differentiated thyroid cancers.67

If clinical findings do not suggest an abnormality in the hypothalamic-pituitary thyroid axis, laboratory evaluation is begun with measurement of TSH (Figure 55-16).4,95A If TSH is within the reference interval, thyroid dysfunction generally can be excluded. If TSH is below the reference interval, measurement of FT4 is indicated. If TSH is depressed and FT4 is elevated, the biochemical diagnosis of primary hyperthyroidism is established. Although total T3 can be measured at this point (and is expected to be greatly elevated), this value should not change the diagnosis or the initial therapy. If TSH is depressed and FT4 is within the reference interval, T3 should be measured in search of T3 toxicosis. The authors favor total T3 measurements over FT3 measurements because total T3 measurements are both more accurate and less expensive than FT3 measurements. If TSH is depressed and both FT4 and T3 are normal on more than one occasion, subclinical hyperthyroidism is diagnosed. This assumes that causes of TSH suppression such as high-dose glucocorticoids and dopamine have been excluded. If TSH is depressed, FT4 is normal, and T3 is elevated, the diagnosis of T3 toxicosis is established.50

If TSH is above the reference interval, FT4 should be measured. If FT4 is depressed, the biochemical diagnosis of primary hypothyroidism is established. Measurement of T3 (or FT3) provides no essential or additional information when hypothyroidism is a clinical consideration. Furthermore, in primary hypothyroidism, T3 declines later than T4 because elevated TSH concentrations in primary hypothyroidism stimulate T3 production more than T4 production. Whether this is due to limited availability of iodine during an attempt at increased thyroid hormone production or the increased “speed” of synthesis (T3 synthesis requires only one iodination versus two for T4 synthesis) is unknown.

If TSH is elevated and FT4 is within the reference interval on more than one occasion in an asymptomatic patient, subclinical hypothyroidism is diagnosed (assuming that heterophilic antibodies have been excluded as a cause of TSH elevation).8,145 Elevated TSH and FT4 raise the possibility of central hyperthyroidism or thyroid hormone resistance. These disorders are differentiated clinically: patients with thyroid hormone resistance usually are euthyroid or, at worst, mildly hypothyroid, however, those with true hyperthyroidism clinically manifest thyrotoxicosis (see later). Because of the log-linear relationship of TSH to FT4, FT4 usually is normal as long as TSH is between 0.5 and 10 mcIU/mL.

If hypothalamic or pituitary disease is suspected, initial testing requires measurement of both TSH and FT4 (with FT4 being more important). FT4 is used to establish the presence of the biochemical euthyroid state, hypothyroidism, or hyperthyroidism. When FT4 is low and TSH is low or normal, central hypothyroidism may be present. If FT4 is low with only a mild elevation in TSH, central hypothyroidism is still possible because of discordance in the ratio of immunoreactivity to bioactivity, with a decrement in bioactivity from abnormal TSH glycosylation from pituitary disease or TRH deficiency. In the setting of clinical hyperthyroidism, central hyperthyroidism is diagnosed with an elevated FT4 and normal or elevated TSH.


Hypothyroidism is defined as a deficiency in thyroid hormone secretion and action that produces a variety of clinical signs and symptoms of hypometabolism.73,84,198 This common disorder occurs in 2 to 15% of the population, more commonly in women than in men. The risk of developing hypothyroidism increases with age.39

Clinical symptoms suggesting hypothyroidism include (1) mental dullness (including mental retardation in children with untreated or undertreated congenital hypothyroidism), (2) somnolence, (3) increased sleeping, (4) lethargy, (5) easy fatigability, (6) hoarseness or deepening of the voice, (7) hair loss, (8) weight gain, (9) cold intolerance, (10) menstrual irregularities, (11) infertility, (12) growth failure, (13) delayed puberty in adolescents, (14) constipation, (15) muscle weakness or cramps, and (16) depressed affect or frank clinical depression.171 Physical signs compatible with hypothyroidism include (1) bradycardia, (2) decreased pulse pressure, (3) cool and/or dry skin, (4) puffy eyes, (5) loss of the outer lateral eyebrows, (6) delayed relaxation phase of reflexes (“hung-up” reflexes), (7) myopathy, (8) carotenemia, (9) occasional galactorrhea, and (10) radiologic evidence of delayed bone age in children. In cases of severe hypothyroidism, congestive heart failure or coma may develop.90 In children with untreated congenital hypothyroidism, severe growth failure and mental retardation ensue. The development of biological and biochemical processes is delayed in cases of congenital hypothyroidism. For example, affected infants often have prolonged jaundice as the result of immaturity of UDP-glucuronyl transferase.

A rare (and controversial) manifestation of Hashimoto thyroiditis is encephalopathy.216 However, no definitive clinical test is available to diagnose encephalopathy resulting from Hashimoto thyroiditis. The diagnosis is considered when encephalopathy of unknown origin is associated with autoantibodies against the thyroid gland.

Laboratory evidence compatible with hypothyroidism encompasses hyponatremia, a normocytic or macrocytic anemia, elevated creatine kinase (from myopathy), and hypercholesterolemia and/or hypertriglyceridemia [from decreased lipoprotein-lipase activity and decreased low-density lipoprotein (LDL) receptor expression]. Anatomically, stimulation of the TSH receptor can cause follicular cell hyperplasia and goiter. Goiter can also be caused by glandular infiltration (e.g., Hashimoto thyroiditis, in which the gland is heavily infiltrated by lymphocytes).

Based on TSH and FT4, the causes of hypothyroidism are classified as primary thyroid gland failure (low FT4 and increased TSH; primary hypothyroidism) or central hypothyroidism (low FT4 and usually a normal or low TSH concentration). Central hypothyroidism results from pituitary disease (secondary hypothyroidism from TSH deficiency) or hypothalamic disease (tertiary hypothyroidism from TRH deficiency).

Primary Hypothyroidism

The causes of primary hypothyroidism are classified as endogenous or exogenous (Box 55-2).38 Endogenous disorders are conditions that develop within the patient such as autoimmune thyroid gland dysfunction, inborn errors, and developmental abnormalities. Exogenous disorders are conditions that originate outside the patient such as iodine deficiency or excess, goitrogen or drug effects, and postsurgical hypothyroidism or hypothyroidism following radioactive iodine treatment.

Autoimmune Hypothyroidism

Excluding the newborn period, autoimmune thyroid disease (AITD) is the most common cause of thyroid disease and primary hypothyroidism.111,148,203 Hashimoto thyroiditis (chronic lymphocytic thyroiditis) leads to destruction of the thyroid follicular cells through a cell-mediated autoimmune process.102 Histologically, the gland is infiltrated with lymphocytes and plasma cells to the extent that secondary lymphoid follicles develop within the thyroid gland that are similar to the secondary follicles observed in normal lymph nodes. Initially, the gland is usually enlarged. Over time, with destruction of the gland, the gland can atrophy or become firm. In the rare condition of Riedel thyroiditis (Riedel disease or struma, ligneous struma, ligneous thyroiditis, chronic fibrous thyroiditis), the thyroid gland becomes fibrotic with possible attachment to adjacent structures that can produce, for example, tracheal compression.144 Subacute (viral) thyroiditis may also cause Riedel thyroiditis.31 Not all cases of Riedel thyroiditis are presaged by Hashimoto thyroiditis.

Although atrophy may occur in Hashimoto thyroiditis, atrophic thyroiditis may also occur when autoantibodies against the TSH receptor bind to the receptor and block the action of endogenous TSH. TSH receptor blocking autoantibodies can cross the placenta during pregnancy, causing transient hyperthyrotropinemia in infants (elevated TSH with a normal T4) or even transient congenital hypothyroidism. Therefore atrophic thyroiditis falls under the rubric of AITD.

The diagnosis of Hashimoto thyroiditis is supported by recognition of autoantibodies against TPO or Tg.113 Ninety percent of patients with chronic lymphocytic thyroiditis (the histologic description of Hashimoto thyroiditis) have antithyroperoxidase autoantibodies (TPOA), antithyroid microsomal autoantibodies (TMA), and/or antithyroglobulin autoantibodies (TgA), making these autoantibodies excellent markers for Hashimoto thyroiditis.182 TPOA testing was initially pursued by testing for TMA (see section on thyroid autoantibody testing). TMA testing is being replaced by specific testing for TPOA using TPO as the antigen in the immunoassay. TPOA/TMA positivity is more common at the time of diagnosis than TgA positivity with TgA usually appearing later in the disease process. TgA overall are less common than TMA or TPOA. Ultrasound has limited value and is not routinely used to detect Hashimoto thyroiditis.

In many families, AITD appears to be inherited in an autosomal dominant pattern although some family members develop Hashimoto thyroiditis and other family members develop Graves’ disease. Several genetic loci have been associated with susceptibility to Hashimoto thyroiditis (or AITD): HLA-DR, CTLA-4, CD40, FCRL3, Tg, the TSH receptor, PTPN22, and the IL-2 receptor. However, no single Mendelian locus explains the apparent autosomal dominant pattern of inheritance of AITD.66 It is most appropriate to describe AITD as polygenic and multifactorial, indicating that both environment and multiple genes provide susceptibility to these very common disorders.

Nonendocrine and endocrine autoimmune disorders can occur with increased frequency in people with AITD. Chronic lymphocytic gastritis causing pernicious anemia may accompany AITD, particularly in older patients. AITD also occurs commonly in association with type 1 diabetes and pernicious anemia.61,91,104 Another, less common, association is AITD and Addison disease.82

AITD can occur as part of autoimmune polyglandular syndrome type 2 (APS 2) and, more rarely, APS 1.161,175 APS 2 affects women more often than men with onset in childhood or early adulthood and is diagnosed when Addison disease (or adrenal autoantibodies) occurs together with AITD and/or type 1 diabetes. In contrast to the polygenic nature of APS 2, mutations in AIRE (the autoimmune regulator gene that is a transcription factor; gene location: chromosome 21q22.3) produce autoimmune polyglandular syndrome type 1 (APS 1), which is inherited in an autosomal recessive pattern, thus affecting males and females equally.18,93

Another variant of AITD is postpartum thyroiditis (PPT).192 PPT develops presumably as a consequence of a decline in the natural immunosuppression of pregnancy following delivery. PPT follows ≈5% of all pregnancies and ≈10% of pregnancies in women with type 1 diabetes. The clinical phenotype of PPT is transient hypothyroidism, hyperthyroidism, or both (one following the other) with a return to the euthyroid state by approximately 1 year postpartum. Women with thyroid autoantibodies are at highest risk for PPT. Later in life, permanent clinical evidence of AITD can develop in women afflicted with PPT. Thyroid autoimmunity, even in the absence of hypothyroidism, may impair fertility in women and increase the risk of spontaneous abortion in those women who do become pregnant.154 Therefore an indication for thyroid autoantibody testing in the absence of hypothyroidism would be female infertility or recurrent miscarriage. Convincing data suggest that T4 treatment of pregnant women who are positive for thyroid autoantibodies (especially TPOA) leads to a higher frequency of miscarriage (13.8%) than is seen in pregnant women who lack TPOA (2.4% rate of miscarriage), and that T4 treatment of the TPOA-positive group reduces the rate of miscarriage to approximately 3.5%.136

Inborn Errors in Thyroid Hormone Biosynthesis

Inborn errors in thyroid hormone biosynthesis (dyshormonogenesis) are rare causes of primary hypothyroidism. These defects usually present early in life and can appear in newborns as a goiter. In very rare cases, asphyxia from tracheal compression has been reported.213 Biochemical defects include iodine transport defects from loss-of-function mutations in the NIS (no increase in the perchlorate discharge); defects in thyroperoxidase, DUOX2,130 and pendrin (with increased perchlorate discharge); thyroglobulin deficiency; and iodotyrosine dehalogenase mutations (potentially causing iodine deficiency through loss of MIT, DIT, and iodine in the urine).129

Developmental Hypothyroidism Disorders

Developmental causes of primary hypothyroidism involve aplasia or hypoplasia of the thyroid gland and ectopic and lingual thyroid glands.202 These disorders account for ≈75% of cases of congenital hypothyroidism. Other causes of congenital hypothyroidism include thyroid dyshormonogenesis (10% of cases; see earlier), hypothalamic or pituitary abnormalities (5% of cases). Ten percent of cases of congenital hypothyroidism are transient.

Rare causes of congenital hypothyroidism involve loss-of-function mutations in the pituitary TRH receptor,23 the TSH beta chain,128 and the TSH receptor.19,58 Mutations in anterior pituitary transcription factors (HESX1, LHX3, LHX4, PROP1, PIT1) can lead to TSH deficiency. Causes of transient congenital hypothyroidism include (1) severe maternal iodine deficiency, (2) acute iodine exposure, (3) transplacental passage of thionamides taken for treatment of maternal hyperthyroidism, (4) transplacental transfer of TSH receptor blocking antibodies, (5) hypothyroxinemia of prematurity, and (6) heterozygosity for a DUOX2 mutation.

Dried blood spot (DBS) screening for congenital hypothyroidism in North America reveals a general population frequency of congenital hypothyroidism of ≈1 in 4000. Congenital hypothyroidism is more common in Hispanic infants, less common in Caucasian infants, and least common in African American infants. The male-to-female ratio is 1 : 2. A higher frequency of congenital hypothyroidism is seen in infants with Down syndrome (≈1 in 140).

Clinically, fewer than 1 in 20 hypothyroid babies are recognized in the newborn nursery by physicians. This emphasizes the critical need for newborn biochemical screening. Early intervention improves clinical outcomes in these cases. However, some studies report that even with rapid treatment after birth, the IQ of affected children may be ≈10 points below that of their unaffected siblings. An increased frequency of neuropsychologic deficits has been reported in children with appropriately treated congenital hypothyroidism.

In North America, screening for congenital hypothyroidism is carried out predominantly by measuring total T4 on DBSs. A common practice is to measure TSH in babies who have the lowest 10% of T4’s measured on the day of testing. Usually if the TSH is 60 mcIU/mL or greater (after the first 24 to 48 hours of life), a presumptive diagnosis of primary hypothyroidism is made, and the infant is transferred to a referral center emergently to be evaluated and started on thyroxine replacement therapy (e.g., 10 to 15 µg/kg/d). If the TSH is between 20 and 59 mIU/L, the infant is clinically evaluated and repeat thyroid function testing is performed before thyroid hormone replacement is started. If the TSH is less than 20 mIU/L, primary hypothyroidism is excluded. Screening with “T4 only testing” will lead to missed rare cases of central hypothyroidism (1/100,000) and cases of hypothyroidism wherein TSH is elevated but T4 is not yet depressed. In Europe, many screening programs use a TSH-first strategy. Although TSH screening will detect subclinical hypothyroidism (see later), cases of central hypothyroidism will be missed. Transcription factor mutations involving TTF-1 and Pax8 have been recognized in some children with congenital hypothyroidism. It is not clear whether molecular testing will prove useful in future screening programs for congenital hypothyroidism.

Hypothyroidism Caused by Iodine Deficiency or Excess

Worldwide, the most common cause of goiter is iodine deficiency. In iodine-deficient areas, especially mountainous areas, iodine deficiency produces “endemic” goiter. Frank hypothyroidism, however, is far less common because with iodine deficiency, more T3 is synthesized than T4, and within the thyroid gland, more T4 is converted to T3 to maintain the euthyroid state overall. Endemic goiters can develop nodularity (with or without hemorrhage into the nodule); in such cases, neoplasia must be excluded. Large goiters can produce dysphagia, obstruction of the trachea, or compression of the recurrent laryngeal nerves. A rare cause of iodine deficiency is nephrotic syndrome, with increased urinary loss of iodine often in the form of thyroid hormone.53,114

A significant danger of iodine deficiency is maternal hypothyroidism leading to an insufficient supply of thyroid hormone to the fetus in the first half of gestation, when the fetus is entirely dependent on maternal thyroid hormone. Thus maternal hypothyroidism can produce a reduction in the IQ of the affected child. Maternal iodine deficiency will produce fetal iodine deficiency.

Although it is logical that iodine deficiency would produce hypothyroidism because iodine is a necessary component in the synthesis of thyroid hormone, it is ironic that excess iodine can interfere with normal thyroid gland function.106 However, excessive iodine does suppress thyroid gland function. High doses of iodine [super-saturated potassium iodide (SSKI) or Lugol’s solution] are routinely used before planned surgical thyroidectomy for Graves’ disease, to inhibit further thyroid hormone release and decrease the vascularity of the gland to reduce surgical blood loss.

Excess iodine reduces thyroid hormone release and inhibits organification of iodine and iodination of Tg (the Wolff-Chaikoff effect). The Wolff-Chaikoff effect can speculatively be interpreted as an autoregulatory response of the thyroid gland to avoid excessive production of thyroid hormone when exposed to high doses of exogenous iodine. Nondietary sources of excess iodine include amiodarone (an antiarrhythmic drug), povidone-iodine (used to disinfect the skin before surgery), and radiologic contrast agents that contain iodine. Excess iodine does not usually cause permanent thyroid dysfunction because the gland normally recovers (“escapes”) from suppression after approximately 10 days of high-dose iodine administration. However, if the patient has underlying disease that may involve the thyroid (e.g., Hashimoto thyroiditis, Graves’ disease), escape from the Wolff-Chaikoff effect is less likely and permanent hypothyroidism can develop.

Drug-Induced Hypothyroidism

Various drugs affect thyroid gland function (Table 55-4).63 Collectively known as thionamides or thioureas, propylthiouracil (PTU), methimazole, and carbimazole inhibit the oxidation of iodide and the subsequent binding of iodine to tyrosine residues in Tg. Other drugs with thionamide-like activity include ethionamide, aminoglutethimide, phenylbutazone, and para-aminosalicylic acid. Evidence suggests an immunosuppressive effect of thionamides on thyroid autoimmunity.

TABLE 55-4

Effects of Some Drugs on Tests of Thyroid Function


↓, Reduced serum concentration; ↑, increased serum concentration; image, no change.

Data from Smallridge RD. Chapter 33. Thyroid function tests. In: Becker KL, ed. Principles and practice of endocrinology and metabolism, 7th edition. Philadelphia, Pa: JB Lippincott, 1995:299-306; Stockigt JR. Thyroid hormone changes in critical illness: the sick euthyroid “syndrome.” Diagn Endo Metab 1997;15:39-46.

PTU, methimazole, and carbimazole are commonly used to treat hyperthyroidism. (Note: Carbimazole is not available in the United States.) When large doses of PTU are used, the drug decreases peripheral conversion of T4 to T3 through inhibition of the D1 deiodinase. Because of this effect (in addition to the direct suppressive effect of PTU on the thyroid gland), some endocrinologists argue that PTU should be chosen over methimazole for the treatment of hyperthyroidism. However, recognition of serious or even fatal liver disease in a small (but significant) number of children treated with PTU is increasing.100 Therefore, many pediatric endocrinologists discourage the routine use of PTU for the treatment of hyperthyroidism in children. Reduced granulocyte counts and subsequent infections are serious but uncommon side effects of thionamides. Therefore the white blood cell count and the differential count should be monitored during such therapy.

A potential advantage of methimazole over PTU is its longer half-life (PTU t1/2 = 1.5 hours and methimazole t1/2 = 6 hours). Both PTU and methimazole cross the placenta, can interfere with fetal thyroid function, and can cause goiter. Additionally, methimazole has been associated with aplasia cutis and choanal atresia. Therefore during pregnancy, PTU is the preferred drug in the treatment of maternal hyperthyroidism.

A variety of other drugs have been known to cause hypothyroidism. For example, lithium, which is used in the treatment of bipolar disorder (manic-depressive illness), can induce hypothyroidism.85 The action of lithium appears similar to that of high-dose iodine, inhibiting thyroid hormone release and organification of iodine. Prolonged use of nitroprusside, a drug used to treat acute-onset, severe hypertension or severe heart failure by inducing preload and afterload reduction, may lead to hypothyroidism. Cyanide (CN) released from nitroprusside is metabolically converted to thiocyanate (SCN), which inhibits iodide uptake by the thyroid gland. Fortunately, nitroprusside only rarely causes hypothyroidism. Amiodarone is an antiarrhythmic drug that contains two iodine atoms per molecule and can induce hypothyroidism or hyperthyroidism.22,204 Various recombinant DNA-derived biologicals (e.g., interferon-alpha, interleukin-2) used to treat chronic viral hepatitis or cancer have been found to cause thyroid dysfunction (hypothyroidism or hyperthyroidism).124

Central Hypothyroidism

In a patient with clinical evidence of hypothyroidism, supported by laboratory findings of a low FT4, if TSH is not elevated to the extent predicted (by FT4), or if TSH is within or below the reference interval, central hypothyroidism should be considered.92,229 Isolated pituitary TSH deficiency is rare, as most patients with secondary hypothyroidism also have other anterior pituitary hormone deficiencies (panhypopituitarism). Causes of central hypothyroidism (hypothalamic or pituitary disease) include (1) tumor, (2) hemorrhage, (3) trauma, (4) malformation, (5) postinfectious damage, and (6) postsurgical damage. Also, several rare autosomal recessive or dominant hereditary disorders involving transcription factor mutations can cause hypopituitarism and TSH deficiency: examples include paired-like homeodomain transcription factor-1 (Pit-1) and PROphet of Pit-1 (PROP1) mutations.131

Subclinical Hypothyroidism

Subclinical hypothyroidism is defined by a persistent elevation in TSH (6 to 12 weeks or longer) in the setting of FT4 concentrations that are repeatedly found within the reference interval.49 Other conditions wherein TSH is elevated but FT4 is normal encompass recent reinstitution of thyroid hormone replacement therapy (FT4 returns to normal before TSH declines), poor compliance with treatment in primary hypothyroidism, recovery from nonthyroidal illness, positively interfering heterophilic antibodies [e.g., human antimouse antibodies (HAMA)] in double-antibody immunoassays, and thyroid hormone resistance.

Subclinical hypothyroidism is very common, affecting 3 to 8% of the general population. By the sixth decade of life, 10% of the population exhibits laboratory findings consistent with subclinical hypothyroidism. Consequences of subclinical hypothyroidism include a high risk of progression to clinical hypothyroidism, dyslipidemia, vascular endothelial dysfunction, increased risk of cardiovascular disease and death, and possible neurocognitive deficits. The general consensus is that if TSH is repeatedly 10 mIU/L or greater, thyroid hormone replacement therapy is warranted. It is controversial whether thyroid hormone therapy is beneficial when TSH is less than 10 mIU/L, except during pregnancy, wherein any persistent TSH elevation requires treatment.

Controversy is ongoing over the appropriate upper limit of the reference interval for TSH. Basing the TSH reference interval on the central 95% of the general, healthy population results in an upper limit of normal between 4.0 and 5.0 mIU/L for many TSH assays. If patients with thyroid autoantibodies such as TPOA, a family history of thyroid disease, or an abnormal thyroid gland ultrasound are excluded from the reference population, the upper limit of the reference interval declines to approximately 2.5 to 3.0 mIU/L. Therefore, an upper limit of 2.5 to 3.0 mIU/L for TSH may be a truer definition of normal, because the reference population mostly excludes individuals with endogenous thyroid disease or propensity to develop thyroid disease. However, it is unclear how patients with TSH concentrations between 2.5/3.0 mIU/L and 4.0/5.0 mIU/L should be managed. It has been argued that lowering the upper limit of the reference interval will provide no clear patient benefit and inevitably will lead to confusion and possible overtreatment of subclinical hypothyroidism. Overtreatment carries the risk of predisposing the patient to osteoporosis and atrial fibrillation. As noted previously, the value of treatment when TSH is between 4.0/5.0 and 9.9 mIU/L is currently debated. Another component of the TSH reference interval debate is that according to National Health and Nutrition Examination Survey (NHANES) data,9,134A,209 TSH rises as populations age. For example, in healthy adults age 80 and older, the upper limit of the reference interval for TSH is 7.5 mIU/L.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on The Thyroid: Pathophysiology and Thyroid Function Testing

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