Lecture #4: THE THYROID GLAND: ANATOMY & PHYSIOLOGY

  

Structure

1.      Made up of two large lobes and narrow connecting isthmus.

2.      A thin worm–like projection of thyroid tissue often extends upward from the isthmus.

3.      Weight of the thyroid in an adult is approximately 30 grams.

4.      Located in the neck, on the anterior and lateral surfaces of the trachea, just below the larynx.

5.      Composed of follicles:

a.      Small hollow spheres

b.      Filled with thyroid colloid that contains thyroglobulins

Functions of thyroid gland

1.      Raise BMR (Basal Metabolic Rate).

2.      Exert anabolic action on protein metabolism during growth and a permissive action on the effects of growth hormone on tissue growth. Catabolic effect on protein metabolism predominantly in hyperthyroid adults.

3.      Required for normal development of Central Nervous System.

4.      Accelerates all phases of glucose metabolism, including absorption from the small intestine, uptake by tissue cells and oxidation.

5.      Increase mobilization and oxidation of fatty acids and the catabolism of cholesterol.

Hormones secreted by thyroid gland

1.      Thyroxine and triiodothyronine

2.      Calcitonin

Development and maturation

The thyroid has both adrenergic (epinephrine and norepinephrine releasing), postganglionic sympathetic nerve fibers and cholinergic (acetylcholine releasing), postganglionic parasympathetic nerve fibers. The adrenergic nerves originate from the cervical ganglia and the cholinergic nerves from the vagus nerve. Adrenergic nerves can directly affect metabolic process of the thyroid parenchymal cell by activating adenylate cyclase and mimicking the effect of thyroid–stimulating hormone (TSH). Both nerve types control arterial and venous blood flow through vasoactive neuropeptides.

Embryonic development of the thyroid gland starts as an ingrowing pocket of epithelial cells (invagination) of the primitive pharynx at 16–17 days of gestation. Invagination continues downward, assuming a flask–like shape with a narrowed neck called thyroglossal duct. Positioning of the thyroid gland is completed at 45 to 50 days of gestation. The thyroglossal duct is mostly resorbed, leaving a pit at the base of the tongue at its proximal end. Approximately one third of individuals have a distal end that persists as the pyramidal lobe of the thyroid. Cells originating the fourth pharyngeal pouch develop into parafollicular cells during the seventh week of gestation. Parafollicular cells ultimately produce calcitonin. The parathyroid tissue from the third and fourth pharyngeal pouches is also well developed and positioned behind the lobes of the thyroid by the end of the seventh week of gestation. By the tenth week, there is evidence of thyroglobulin synthesis, accumulation of iodide, and incorporation of iodide into organic molecules. During the second trimester, there is detection of thyroxine (T₄) and TSH, suggesting that the thyroid gland is under control of the pituitary gland.

The follicle is the fundamental structural unit of the thyroid gland. It consists of a single layer of follicular cells circumventing a lumen filled with a proteinaceous fluid, colloid. The adult thyroid gland has approximately 3 million follicles varying in size from 50–500 mu in diameter. The follicular cell may vary from a flat formation to columnar, with the basal side of the cell projecting outward from the lumen and surrounded by an extensive capillary plexus. The apex (apical side) of the follicular cell is directed inward toward the lumen where proteinaceous thyroglobulin glycoprotein is stored. Interfollicular spaces are filled with capillary blood supply, lymphatic network, adrenergic sympathetic fibers and cholinergic parasympathetic fibers.

The ultrastructure of the follicular cell relates to the specific functions of hormone synthesis and secretion. Thyroglobulin synthesis begins at the rough endoplasmic reticulum (RER) near the outer perimeter of the cell and continues to the Golgi apparatus for addition of monosaccharides and sialic acid. The thyroglobulin prohormone is then transported in exocytic vesicles to the inner apical surface containing peroxidase activity responsible for coupling and iodination of thyroglobulin. To release thyroid hormones from the lumen, pseudopods extend from the apical membrane into the colloid, forming phagocytic vesicles and sequestering colloid droplets. These phagosomes fuse with vacuoles containing proteolytic enzymes, lysosomes, forming phagolysosomes. Thyroglobulin is digested, releasing iodothyronines. Egression of thyroglobulin from the lumen, through the follicular cell, and ultimately into peripheral circulations as iodothyronines, monoiodothyronines (MIT), diiodothyronines (DIT), triiodothyronines (T₃), T₄, and reverse T₃ (rT₃) is regulated by TSH.

The Thyroid Hormone

1.      Tetraiodothyronine (T₄) or thyroxine – contains four iodine atoms; approximately 20 times more abundant than T₃; major importance is as precursor to T₃.

2.      Triiodothyronine (T₃) – contains those iodine atoms; considered to be the principal thyroid hormone; T₃ binds efficiently to nuclear receptors in target cells.

Hormones influencing T₃ and T₄ production

1.      Thyrotropin–releasing hormone

A tripeptide originating from the hypothalamus, directly regulates pituitary TSH release and has been implicated in extra pituitary roles of neurotransmitter and neuromodulator in CNS. TRH is derived from a large precursor prepro–TRH genome, which has encoded other peptides, structurally different from TRH, that are present throughout the CNS. A DNA fragment of 3.3–kilobase pairs has been identified as human prepro–TRH transcriptional unit. In the genomic DNA fragment there are three exons (a portion of the gene that translates into a protein coding sequence) and two intervening introns (a non–coating portion of the gene that does not translate into protein eventhough it is transcribed into RNA). A portion of the complementary DNA (cDNA) arising from the exon has the identical base pair sequence as a glucocorticoid receptor DNA binding unit, giving support to the concept that TRH gene expression maybe under the regulation of glucocorticoid.

2.      Thyroidal peroxidase

A membrane–bound glycoprotein with a molecular weight of about 102,000 and a heme compound as the prosthetic group of the enzyme. This enzyme mediates both the oxidation of iodide ions and the incorporation of iodine into tyrosine residues of thyroglobulin. It is synthesized in the rough endoplasmic reticulum. After insertion into the membrane of its cisternae, it is transferred to the apical cell surface by Golgi elements and exocytic vesicles. Here, at the cell colloid interface, it is available for iodination and hormogenesis in thyroglobulin. Thyroidal peroxidase biosynthesis is stimulated by TSH.

3.      Thyroxine–binding globulin (TBG)

Synthesized primarily in the liver, it contains four carbohydrate chains, representing 23% of the molecule by weight and has homology with alpha–1– antitrypsin and alpha–2–antichymotrypsin. Normally, there are about ten sialic acid residues per molecule. Pregnancy or estrogen therapy increases the sialic acid content of the molecule, resulting in decreased metabolic clearance and elevated serum levels of the TBG. Each molecule of TBG has a single site for T₃ and T₄. The serum concentration of TBG is 15 – 30 ug/ml or 280 – 560 nmol/L.

Androgenic steroids and glucocorticoids lower the levels, as does major systemic illness. Drugs such as salicylates, phenytoin, phenylbutazone and diazepam may bind to TBC, displacing T₄ and T₃, in effect producing a low TBG state. Heparin stimulates lipoprotein lipase, releasing free fatty acid, which displace T₃ and T₄ from TBG. This can occur in vivo and also in vitro, where even minute quantities of heparin will increase the measured levels of free T₄ and T₃.

4.      Thyroxine–binding prealbumin

Transerythrin or thyroxine–binding prealbumin (TBPA) contains 127 amino acids. It binds about 10% of circulating T₄. Its affinity for T₃ is about tenfold lower than for T₄, so that it mostly carries T₄. The dissociation of T₄ and T₃ from TBPA is very rapid, so that TBPA is a source of rapidly available T₄. There are binding sites of TBPA for retinol–binding protein, but the transport of T₄ is independent of the retinol–binding protein. The concentration of TBPA in serum is 120–140 mg/L or 2250–4300 nmol/L.

Increased levels of TBPA may be familial and may occur in patients with glucagonoma or pancreatic islet cell carcinoma. These patients have an elevated total T₄ but a normal free T₄. Abnormal TBPA has been described in familial amyloidotic polyneuropathy, associated with a low total T₄ but normal free hormone level.

5.      Albumin

Albumin has one strong binding site for T₄ and T₃ and several weaker ones. Because of its high concentration in serum, albumin carries about 15% of circulating T₄ and T₃. The rapid dissociation rates of T₄ and T₃ from albumin make this carrier a major source of free hormone to tissues. Hypoalbuminemia, as occurs in nephrosis or in cirrhosis of the liver, is associated with a low total T₄ and T₃, but the free hormone levels are normal.

Familial dysalbuminemic hyperthyroxinemia is an autosomal dominant inherited disorder in which 25% of the albumin exhibit high affinity T₄ binding, resulting in an elevated total T₄ level, but, normal free T₄ and euthyroidism. Affinity for T₃ may be elevated but is usually normal.

6.      Thyroid stimulating hormone (see discussion on Anterior Pituitary)

The Thyroglobulin

Thyroglobulin is a glycoprotein containing about 140 tyrosyl residues and about 10% carbohydrate in the form of mannose, N–acetyl–glucosamine, galactose, fucose, sialic acid and chondroitin sulfate. The iodine content of the molecule can vary from 0.1% to 1% by weight.

In thyroglobulin containing 0.5% iodine, there would be 5 molecules of monoiodotyrosine (MIT), 4.5 molecules of diiodotyrosines (DIT), 2.5 molecules of thyroxine (T₄), and 0.7 molecules of triiodothyronine (T₃). About 75% of the thyroglobulin monomer consists of repetitive domains with no hormogenic sites.

There are four tyrosyl sites for hormogenesis on the thyroglobulin molecule: One site is located at the amino–terminal end of the molecule and the other three are located in a sequence of 600 amino acids at the carboxyl terminal end. There is a surprising homology between this area of the thyroglobulin molecule and the structure of acetylcholinesterase, suggesting conservation in the evolution of these proteins.

Regulation of secretion of thyroid hormone

Secretion of thyroid hormone is controlled by negative feedback or feedback inhibition and follows the pathway of the hypothalamus–pituitary–thyroid axis. The primary control mechanism begins with the hypothalamus located in the brain, which secretes thyrotropin releasing hormone (TRH), also known as thyroid stimulating hormone–releasing factor (TSH–RF). TRH, in turn, stimulates the pituitary to secrete TSH. TSH directly acts on the follicular cells of the thyroid, to secrete TSH. TSH directly acts on the follicular cells of the thyroid increasing the release and production of thyroid hormone. The increasing greatest production in thyroid hormone is T₄, which is significantly more abundant than T₃. Most of the hormone secreted is bound to protein, particularly thyroxine–binding globulin (TBG), but only the free forms of T₃ and T₄ are biologically active and have regulatory feedback. In situations of elevated TBG, the total thyroid hormone concentration is elevated, but euthyroid status is maintained as a result of reestablished equilibrium between free and bound thyroid hormone. Increased amounts of free T₃ retard TSH secretion and secondarily alter the synthesis of TSH. Free T₃ also decreases the number of receptor sites on the pituitary for TRH. Consequently, it is free T₃ that is primarily involved in the feedback to the pituitary (and the hypothalamus), decreasing secretion of TSH and subsequent thyroid hormone release. Free T₄ is involved in the control mechanism indirectly because of the peripheral conversion of T₄ to T₃.

TRH secreted by the hypothalamic neurons is transported to the pituitary via the hypophyseal portal system. Eventhough the hypothalamus secretes TRH. The stimulus for TSH, it is not considered the primary target for feedback control. Even the mildest elevation of free T₃ greatly impairs the responsiveness of the pituitary to TRH, suggesting that the control is directed to the pituitary level.

In addition to free T₃ and T₄, other compounds have been shown to influence the feedback inhibition mechanism. Increased levels of somatostatin, growth hormone, dopamine, glucocorticoids and opiates inhibit either TRH or TSH response to TRH. In contrast, patients with adrenocortical insufficiency have elevated TSH levels. Even in conditions of normal hormone TSH and cortisol have an inverse circadian (24 hours cyclic) relationship. TSH has a small increase in concentration between 11 PM and 1 AM with the rise beginning before sleep induction. The lowest TSH concentration occurs about 11 AM. Additional factors, decreasing TSH production and thyroid secretion include starvation or severe malnutrition, physical injury and infection. The effect is advantageously adaptive, resulting in conservation of body resources to combat illness.

It is postulated that the TRH–secreting neurons of the hypothalamus are noradrenergic nerve fibers because their activity can be blocked by noradrenergic antagonists. Consequently, norepinephrine is thought to be a stimulus to the hypothalamus, resulting in increased TRH secretion. Elevated amounts of TRH prevent sleep–induced increases in growth hormone in normal subjects. This may have a predominantly inhibitory effect on release of growth hormone.

Cold exposure, particularly in the newborn immediately after birth and to a lesser extent in adults in severe prolonged hypothermia, stimulates TRH release, releasing in a TSH surge and corresponding rise in thyroid hormone production. Other factors ultimately increasing thyroid hormone production include estrogens, psychic stress, norepinephrine and sleep.

Biosynthesis of thyroid hormone

The synthesis of T₄ and T₃ by the thyroid gland involves six major steps:

1.      Active transport of iodine across the basement membrane into the thyroid cell (iodide trapping)

Iodine is transported across the basement membrane of the thyroid cell by an active energy–requiring process that is dependent upon Na⁺–K⁺ ATPase. This active transport system allows the human thyroid gland to maintain a concentration of free iodide 30 to 40 times than in plasma. The thyroiodide trap is markedly stimulated by TSH and by TSH receptor stimulating antibody found in Grave’s disease. It is saturable with large amount of iodine and inhibited by ions such as ClO₄^–, SCN, NO₃^– and TcO₄^–. Some of these ions have clinical utility.

2.      Oxidation of iodide and iodination of tyrosyl residues in thyroglobulin

Within the thyroid cell, at the cell–colloid interface, iodine is rapidly oxidized by H₂O₂, catalyzed by thyroperoxidase and converted to an active intermediate which is incorporated into tyrosyl residues in the thyroglobulin. H₂O₂ is probably generated by a dihydronicotinamide adenine dinucletide phosphate (NADPH) oxidase in the presence of calcium; this process is stimulated by TSH. The iodinating intermediate may be iodinium ion (I⁺), hypoiodate or an iodine–free radical. The site of iodination at the apical (colloid) border of the cell can be demonstrated by autoradiography.

Thyroidal peroxidase will catalyze iodination of tyrosyl molecules in proteins other than thyroglobulin, such as albumin or thyroglobulin fragments. However, no thyroactive hormones are formed in these proteins. The metabolically inactive protein may be released into the circulation, draining thyroidal iodide reserves.

3.      Coupling of iodotyrosine molecules within thyroglobulin to form T₃ and T₄

a.      Oxidation of iodotyrosyl residues within the same thyroglobulin molecule to form a quinol ether intermediate.

b.      Coupling of activated iodotyrosyl residues within the same thyroglobulin molecule to form a quinol ether intermediate.

c.       Splitting of the quinol ether to form iodothyronine, with conversion of the alamine side chain of the donor iodotyrosine to dehydroalanine.

For this process to occur, the dimeric structure of thyroglobulin is essential, within the thyroglobulin molecule, two molecules of DIT may couple to form T₄ and an MIT and a DIT molecule may couple to form T₃. Thiocarbazide drugs – particularly propylthiouracil, methimazole and carbimazole – are potent inhibitors of thyroidal peroxidase and will block thyroid hormone synthesis. These drugs are clinically useful in the management of hyperthyroidism.

4.      Proteolysis of thyroglobulin, with release of free iodothyronines and iodotyrosines

At the cell–colloid interface, colloid is engulfed into a colloid vesicle by a process of micropinocytosis and is absorbed into the thyroid cell. The lysosomes then fuse with the colloid vesicle and hydrolysis of thyroglobulin occurs, releasing T₄, T₃, MIT, DIT, peptide fragments and amino acids. T₃ and T₄ are released into the circulation, while DIT and MIT are deiodinated and the iodine is conserved. Thyroglobulin with low iodine content is hydrolyzed more rapidly than thyroglobulin with high iodine content, which may be beneficial in geographic areas where natural iodine intake is low. The mechanism of transport of T₃ and T₄ through the thyroid cell is not known, but it may involve a specific hormone carrier.  Thyroid hormone secretion is stimulated by TSH, which activates adenyl cyclase, and by the cAMP analogue (Bu)₂cAMP, suggesting that it is cAMP–dependent.

Thyroglobulin proteolysis is inhibited by excess iodide and by lithium, which, as lithium carbonate, is used for the treatment of manic–depressive states. A small amount of unhydrolyzed thyroglobulin is also released from the thyroid cell; this is markedly increased in certain situations such as subacute thyroiditis, hyperthyroidism or TSH induced goiter.

5.      Deiodination of iodotyrosines within the thyroid cell, with conservation and reuse of the liberated iodide.

6.      Intrathyroidal deiodination

MIT and DIT formed during the synthesis of thyroid hormone are deiodinated by intrathyroidal deiodinase. This enzyme is NADPH– dependent flavoprotein found in mitochondria and microsomes. It acts on MIT and DIT but not on T₃ and T₄. The iodide released is mostly reutilized for hormone synthesis; a small amount leaks out of the thyroid into the body pool. The 5’–deiodinase that converts T₄ to T₃ in peripheral tissues is also found in the thyroid gland. In situations of iodide deficiency, the activity of this enzyme may increase the amount of T₃ secreted by the thyroid gland, increasing the metabolic efficiency of hormone synthesis.

Clinical significance of T₃ and T₄

1.      Hyperthyroidism or Thyrotoxicosis

Hyperthyroidism occurs when excessive amounts of thyroid hormones in circulation affect peripheral tissues.

Thyroid storm is the term used for the thyroid crisis a patient with thyrotoxicosis may experience that requires emergency treatment. Thyroid storm may occur after an injection, childbirth, diabetic ketoacidosis, the withdrawal of antithyroid drugs, the therapeutic use of Iodine–123 or surgical treatment in the thyrotoxic patient.

The effects of a sudden increase in circulating thyroid hormone result in a spectrum of metabolic responses. The characteristic increase in metabolic rate appears to be due to the induction of key enzymes regulating metabolism such as Na–K–ATPase, which potentiates the calorigenic effects of hormones such as catecholamines. Another pathway involves a rise in the level of adenosine diphosphate (ADP), which stimulates mitochondria and increases the rate of oxidative phosphorylation. This uncontrolled heat generation results in fever that can exceed 104^oF, which may be lethal.

Signs and symptoms of thyrotoxicosis

1.      Nervousness, weight loss despite good appetite, heat intolerance and increase perspiration. The skin becomes warm and moist as the body attempts to dissipate the increased heat production.

2.      Cardiovascular manifestations include systolic hypertension and trachycardia, which may contribute greatly to congestive heart failure.

3.      The patient may experience dyspnea related to intercostal muscle weakness. This symptom is due to catabolism of muscle protein and to increased oxygen used.

4.      Because the thyroid hormone affects the nervous system, emotional lability and hyperkinesia may be observed.

Laboratory findings in thyrotoxicosis

1.      Propylthiouracil is the drug of choice in thyroid storm because it inhibits the monodeiodination of T₄ to T₃ in peripheral tissue.

2.      Propranolol is given to counteract some of the peripheral effects of thyroid hormones and corticosteroids are administered because patients in thyroid storm are often steroid deficient.

3.      Supportive therapy to cool the patient and restore fluid and electrolyte balance is given.

Categories of Thyrotoxicosis

1.      Disease cause by excess thyroid stimulators

a.      Grave’s disease

Grave’s disease can affect any age as well as either gender, however, most patients are women between 30 and 50 years old. The typical patient presents with diffuse goiter, thyrotoxicosis and opthalmopathy. The enlarged thyroid gland contains hyperplastic follicular cells and varying degree of lymphocytic infiltration. This infiltrates causes thickening of the skin. Because of the increased conversion of androgen to estrogen, male patients may complain of decreased libido and gynecomastia and female patients may have menstrual disorders.

Grave’s opthalmopathy

(1)   Sensation of a foreign body in the eye, tearing, blurred or double vision and deep orbital pressure.

(2)   Enlargement of the extraocular muscle is the predominant orbital abnormality. A chronic inflammatory pattern is present with edema, excess mucopolysaccharide, fatty infiltration and fibroblast proliferation.

(3)   Abnormal immunoglobulins stimulate collagen production. The patient characteristically demonstrates bilateral exophthalmos (protrusion of the eyeball from the eye socket) and eyelid retraction.

Two types of Grave’s disease in the newborn

(1)   The infant with the first form typically is born with small, weak muscles, enlarged thyroid and prominent puffy eyes. Tachycardia and respiratory distress may be observed. TRAb are present in both mother and baby. In contrast to infants with normally elevated levels of TSH at birth, infants with Grave’s disease have suppressed levels. This disease is caused by the transplacental transfer of TRAb from the mother to the fetus with subsequent development of thyrotoxicosis. This disease is self–limited as the TRAb disappear.

(2)   The second form is characterized by slower onset of symptoms and persistent brain dysfunction. This form, requiring prolonged therapy, may be caused by genetic inheritance of defective lymphocyte immunoregulation. Because thyrotoxic fetuses are at high risk for preterm labor, intrauterine growth retardation and death, it has been recommended that serial sonography and careful monitoring of fetal thyroid response to maternally administered propylthiouracil. Also, fetal blood sampling and subsequent thyroid function testing may give additional information regarding fetal thyroid status in order to approximately adjust pharmacologic therapy in the mother.

2.      Iatrogenic and factitious causes

Exogenous hyperparathyroidism is usually caused by iatrogenic administration of replacement hormones that are in doses exceeding the amount needed for normalization. It may also be due to factitial or surreptitious ingestion of thyroid hormones.

3.      Primary thyroid disease

a.      Marine–Lenhart Syndrome or Toxic multinodular goiter

Seen in older patients with long standing multinodular goiter. Symptoms include arrhythmia, tachycardia, heart failure, weight loss, tremors and sweating; opthalmopathy is rare in this condition. Laboratory findings include elevated T₃ and somewhat elevated T₄.

b.     Plummer’s disease or toxic adenoma

Most patients are more than 40 years of age and present with symptoms of weight loss, weakness, shortness of breath, tachycardia and heat intolerance. However, opthalmopathy is not present. Serum T₃ is markedly elevated with a borderline increase in the T₄ value.

4.      Rare forms of thyrotoxicosis

Struma ovarii

Hydatidiform mole

2.      Hypothyroidism

Hypothyroidism is a condition characterized by a deficiency of thyroid hormones that causes a generalized slowing of metabolic processes.

Signs and symptoms of hypothyroidism

a.      Fatigue, cold intolerance, impaired memory, change in personality, dyspnea with exertion, hoarsness from thickened vocal cords, constipation secondary to slowed intestinal peristalsis, muscle cramps, paresthesias and dry skin that has a yellow tinge possible due to carotene accumulation caused by decreased conversion of carotene to Vitamin A.

b.      The skin is infiltrated by mucopolysaccharide that cause sodium and water retention, giving the face a puffy appearance, especially around the eyes.

c.       Speech slows because of tongue enlargement and latency of tendon reflexes increases.

d.     Patients often have mild weight gains because the rate of metabolism decreases.

e.      Serum cholesterol and triglycerides increase because the rate of degradation of lipids is below the rate of synthesis.

f.        Myocardial contractility is reduced and the heart may show enlargement or radiography as a result of pericardial effusion.

g.      In children (cretinism), hypothyroidism is characterized by growth retardation and delayed bone and teeth development.

Laboratory findings in hypothyroidism

a.      Decreased T₄ causes impaired hemoglobin synthesis and red blood cell production

b.      Iron deficiency anemia may result both from loss in the presence of menorrhagia and from impaired iron absorption.

c.       Folate deficiency anemia may result from intestinal absorption of folic acid.

d.     Pernicious anemia is present because of autoantibodies.

Untreated hypothyroidism

Myxedema coma is the end stage of untreated hypothyroidism. It is characterized by progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, water intoxication, shock and death. There may be signs of other illnesses such as myocardial infarction, pneumonia, cerebral thrombosis and GI bleeding.

In pituitary myxedema, adrenal insufficiency may be present, and glucocorticoid replacement is essential.

Laboratory findings in myxedema coma

1.      Lactescent serum, high serum carotene, elevated serum cholesterol and increase cerebrospinal fluid protein.

2.      Pleural, pericardial or abdominal effusion with high protein content maybe present

3.      Serum test will reveal a low FT₄ and a markedly elevated TSH

4.      ECG shows sinus bradycardia and low voltage.

Two types of hypothyroidism

a.      Congenital hypothyroidism (cretinism)

Primary neonatal hypothyroidism may be a result of placental transfer of thyroid antibodies from a mother with Hashimoto’s thyroiditis, which results in antibody–related immune destruction of the fetal thyroid. An “ectopic thyroid” that functions poorly may be the result of a fetal thyroid gland that fails to descend during embryonic development.

Symptoms that are observed, in neonates include respiratory distress in the presence of increased birth weight, delayed skeletal maturation, hypothermia, persistence of physiologic jaundice beyond 3 days, hoarse cry and edema.

After delivery, TSH increases rapidly to a peak at 30 minutes, returning to its initial value within 48 hours. This neonatal surge of TSH is thought to be the result of exposure to coolness that follows emergence in the extrauterine environment. T₄ and T₃ increase rapidly and are in the hyperthyroid range by 24 hours of life. In addition to the usual extrathyroidal mechanisms, conversion of T₄ to T₃ during the perinatal period is stimulated by glucocorticoids. Higher concentration of TBG in neonatal plasma also contributes to the elevated T₄ values. By the 10^th day of life, serum T₄ and T₃ are lower but still exceed normal adult values. A serum T₄ less than 6 ng/dl with a TSH value greater than 30 uU/ml indicate neonatal hypothyroidism.

Efforts are currently being made to diagnose this condition even earlier, using ultrasonography to detect fetal goiter, fetal blood and amniotic fluid testing and monitoring of sTSH levels. Treatment with intraamniotic fluid injections of levothyroxine sodium can then suppress TSH levels and decrease the size of fetal goiter.

b.     Acquired hypothyroidism is caused by:

(1)   Radioactive iodine therapy

(2)   Subtotal thyroidectomy

(3)   Lithium carbonate, a medication prescribed for bipolar disorder, can cause hypothyroidism by inhibiting the release of thyroid hormones, decreasing TSH–induced adenosine monophosphate (AMP) and inhibiting coupling of mono and diiodotyrosines.

(4)   Secondary hypopituitarism may be due to a pituitary adenoma, although most pituitary lesions are diagnosed from the loss of growth hormone and gonadotropins that occurs before loss of TSH and ACTH.

3.      Thyroiditis – is a collective term used to describe inflammation of the thyroid gland.

a.      Acute Suppurative Thyroiditis – is an inflammatory disease cause by bacterial invasion such as Streptococcus pyogenes, Staphylococcus aureus and Streptococcus pneumoniae. (Click here for Gram (+) cocci)

Laboratory findings: neutrophilic leukocytosis, elevated ESR

Confirmatory diagnosis is made by fine needle aspiration biopsy and culture revealing a pathogenic organism.

b.     Subacute granulomatous thyroiditis or De Quervain’s thyroiditis – is an acute inflammatory disorder of the thyroid gland most likely due to virus such as mumps virus, coxsackievirus and adenovirus.

On physical examination, the gland is tender so the patient may object to pressure upon it. There are no signs of local redness or heat suggestive of abscess formation, clinical signs of toxicity, including tachycardia, tremor and hyperflexia may be present.

Laboratory findings:

Elevated T₃ and T₄ level

Depressed TSH and RAIU

Elevated ESR

c.       Chronic lymphocytic thyroiditis or Hashimoto’s thyroiditis – is an autoimmune disease by infiltration of thyroid tissue by lymphocytes and plasma cells. Some follicular cells are enlarged with vacuolized cytoplasm containing eosinophilic granules.

Riedel’s struma – a variant of Hashimoto’s thyroiditis with extensive fibrosis extending outside the gland and involving overlying muscle and surrounding tissue.

Schmidt’s syndrome – represents destruction of multiple endocrine glands on an autoimmune basis. It occurs when Addison’s disease is associated with Hashimoto’s thyroiditis.

4.      Neoplasms (Click here for discussion on Neoplasm)

a.      Papillary carcinoma – characterized by a firm, solitary, “cold” nodule, which is clearly different from rest of the gland using an isotope scan.

b.     Follicular carcinoma – characterized by the presence of small follicles, though colloid formation is poor. It is more invasive than papillary cancer and can spread to the lymph nodes or blood vessels with metastases to bone, lung and other tissues.

“Hurthle cell” carcinoma – a variant of follicular carcinoma characterized by large individual cells with pink–staining cytoplasm filled with mitochondria. They behave like follicular cancer except that they rarely take up radioiodine.

c.       Medullary carcinoma – arises from the C or parafollicular cells of the thyroid gland, which have an endocrine function. The parafollicular cells all produce excess calcitonin and some may produce excess ACTH, prostaglandin, serotonin and other amines, which indicate this condition to be a multiple endocrine neoplasia.

After total thyroidectomy, calcitonin levels should be determined by provocative testing with pentagastrin or calcium to ensure that all malignant tissue has been removed.

d.     Undifferentiated (anaplastic) anemia – includes small cell, giant cell, and spindle cell carcinoma. They usually occur in older patients with a long history of goiter in whom the gland suddenly – over weeks or months – begins to enlarge and produce pressure symptoms, dysphagia or vocal cord paralysis. Death from massive local extension usually occurs within 6 – 36 months. These tumors are very resistant to therapy.