Mechanism of Thyroid hormone Action Schematic diagram of thyroid hormone activation and inactivation in a cell expressing D2 and D3. The T3 that enters the cell can either be deiodinated to 3,3?-T2 or enter the nucleus and bind to the thyroid hormone receptor. An additional source of T3 is that generated by outer ring deiodination of T4 within the cell. The interaction of T3 with the thyroid hormone receptor (TR) bound as a heterodimer with retinoid X receptor (RXR) to the thyroid hormone?response element (TRE), usually in the 5? flanking region of a T3-responsive gene, causes either an increase or a decrease in the transcription of that gene. Differential Expression by TRs There are several alternatively spliced gene products from each of these genes forming both active and inactive gene products. The active proteins are TR?1, and TRs ?1, ?2, and ?3. There are tissue-specific preferences in expression of the various TRs suggesting that they subserve different functions in different tissues. In general, TR?, particularly TR?2, is thought to be important in the hypothalamus and pituitary where regulation of thyroid function occurs. In addition to differences in the amino-terminus between TR?1 and TR?2, the two proteins are under the regulation of different promoters, which can function in tissue-specific patterns. TR?2 is down-regulated by T3, whereas TR?1 mRNA expression is not affected.TR?2 is also expressed in the cochlea (auditory portion of the inner ear). TR?1 is expressed in all tissues, although its mRNA is especially highly expressed in the kidney, liver, brain and heart. TR?1 mRNA is expressed in the brain and at lower levels in skeletal muscle, lungs, and heart. TR?3 mRNA is expressed at very low levels but is more abundant in the liver or kidneys and lungs in comparison with other tissues. Physiological Effects of Thyroid Hormones Fetal Development: Functional at 11 weeks of gestation (humans); prior to that, placenta deiodinases keep fetal T4/T3 low. Important for brain; muscle and bone development (differentiation) . Oxygen consumption: Regulates Na+, K+ ATPase activity; # mitochondria. Heart: Regulates contractility (pulse) and cardiac output. Via Ca2+ ATPase; myosin heavy chain, others (stroke volume and heart rate), changes different isoforms of NaK-ATPase. Skeletal muscle: Regulates protein catabolism and loss of muscle tissue. Gastrointestinal tract: Regulates increased gut motility that may lead to hyperdefecation or Pseudodiarrhea (more than three times daily). Liver: increases hepatic gluconeogenesis and glycogenolysis ? can worsen glycemic control in diabetes. Bone: increased bone turnover (more resorption) leading to hypercalciuria. Other endocrine effects: decreased GH, impaired puberty (GnRH), but also may cause precocious puberty (TSH on gonadotropin receptors). In adults, hypothyroidism causes hyperprolactinemia in women and anovulation is also common. CHANGES IN THYROID HORMONE DURING ILLNESS Hormone Severity of Illness Free T3 Free T4 Reverse T3 TSH Probable Cause Mild ? N ? N ? D2, D1 Moderate ?? N, ? ? ?? N, ? ?? D2, D1, ? ?D3 Severe ??? ? ? ?? ?? D2, D1, ?D3 Recovery ? ? ? ? ? N = no change Regulation of the hypothalamic-pituitary-thyroid axis. AGRP, Agouti-related protein; CART, cocaine- and amphetamine-regulated transcript; CRH, corticotropin-releasing hormone; NPY, neuropeptide Y; POMC, proopiomelanocortin; T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thyrotropin. Assessment of Thyroid Status Tests that evaluate- State of the hypothalamic-pituitary-thyroid axis (TSH) Estimates of T4 or T3 in serum (total; free; free vs bound ratio Impact of thyroid hormone on tissues (BMR; change in enzymes or LDL cholesterol) Presence of autoimmune disease (detection of antibodies directed against the thyroid follicle cell) TgAb and TPOAb (Hashimotos? disease) TgAb,TSH-R, TPO (Graves? disease); Major Ab binds to TSH-R and stimulates c-AMP. Thyroid is site of autoantibody protection. Thyroidal iodine metabolism 123I radioiodine uptake (T˝=0.5day) Infant Goiter Goiter: a swelling in the neck (just below Adam's apple or larynx) due to an enlarged thyroid gland. Iodine deficiency/excess Excess: The quantity of iodine organified in thyroglobulin which includes T4 and T3 displays a biphasic response to increasing doses of iodide, at first increasing and then decreasing as a result of a relative blockade of organic binding. This decreasing yield of organic iodine from increasing doses of iodide, termed the Wolff-Chaikoff effect, results from a high concentration of inorganic iodide within the thyroid cell. Deficiency: The response of vertebrates to iodine deficiency is designed to conserve this limited resource and improve the efficiency of its utilization. These adjustments occur at the hypothalamic, pituitary, thyroid, and peripheral tissue levels. Removal of iodine from the diet causes a rapid decrease in serum T4 concentrations and a simultaneous increase in serum TSH The log/linear relationship between TSH (on the vertical axis) and the free T4 concentrations (FT4). Typical free T4 concentrations in hypothyroid, euthyroid, and hyperthyroid patients are shown. Effects of acute depletion of dietary iodine on serum T3, T4, and TSH in rats. Animals received a low iodine diet (LID) without or with supplementation of potassium iodide (KI) in drinking water. Iodine Excess Saturated solution of potassium iodide 38 mg/drop Lugol's solution 6 mg/drop Iodized salt (1 part KI/10,000 NaCl) 760 ?g/10 g Amiodarone 75?200 mg tablet Iopanoate, ipodate 350 mg/tablet Angiographic and CT dyes 400?4000 mg/dose Povidone-iodine 10 mg/mL Kelp tablets 150 ?g/tablet Prenatal vitamins 150 ?g/tablet Iodinated glycerol 25 mg/mL Quantity of iodine required to suppress radioactive iodine to <2% >30 mg/day The thyroid is also protected against an excess of iodide that might otherwise lead to hyperthyroidism. As with the response to iodine deficiency, there are multiple levels of defense against this eventuality. The usual source of excess iodine is pharmaceutical, with radiographic dyes, amiodarone, and povidone-iodine being the most common sources . IODINE CONTENT OF VARIOUS IODINATED PHARMACEUTICALS[*] Protection against Excess I The quantity of iodine organified in thyroglobulin which includes T4 and T3 displays a biphasic response to increasing doses of iodide, at first increasing and then decreasing as a result of a relative blockade of organic binding. This decreasing yield of organic iodine from increasing doses of iodide, termed the Wolff-Chaikoff effect, results from a high concentration of inorganic iodide within the thyroid cell. In normal subjects given iodide, the inhibition of iodothyronine formation is reduced over time. This ?escape? or ?adaptation? phenomenon occurs because iodide transport activity decreases probably through a decrease in NIS expression. Consequently, thyroidal iodide falls to levels insufficient to maintain the full Wolff-Chaikoff effect. Importantly, it does not occur in the third trimester fetus, so chronic high iodine intake during pregnancy must be avoided because it will cause fetal hypothyroidism and compensatory potentially obstructive goiter Clinical Aspects Hyperthyroidism Hypothyroidism Others Goiter: Enlargement of the thyroid gland. Hypothyroidism: Iodine deficiency (endemic goiter). Hashimotos?s disease (Antibody induced) Infections Drug induced (block synthesis/secretion T4) Hyperthyroidism: Tumor growth of the thyroid Excessive TSH activity Graves? disease (Antibody induced) Chorionic gonadotropin excess (B subunit impact) Pregnancy Hypothyroidism Reduced production of thyroid hormone is the central feature of the clinical state termed hypothyroidism. Permanent loss or destruction of the thyroid, through processes such as autoimmune destruction or irradiation injury, is described as primary hypothyroidism . Hypothyroidism due to transient or progressive impairment of hormone biosynthesis is typically associated with compensatory thyroid enlargement. Central or secondary hypothyroidism, due to insufficient stimulation of a normal gland, is the result of hypothalamic or pituitary disease or defects in the thyroid-stimulating hormone (TSH) molecule. Hypothyroidism Symptoms Fatigue Sluggishness Increased sensitivity to cold Constipation Pale, dry skin A puffy face Hoarse voice An elevated blood cholesterol level Unexplained weight gain Muscle aches, tenderness and stiffness Pain, stiffness or swelling in your joints Muscle weakness Heavier than normal menstrual periods Brittle fingernails and hair Depression Hypothyroidism: Causes 1. Iodine deficiency: Hypothyroidism: Causes 1. Iodine deficiency: Regions that have low iodine soil levels (shaded areas). Iodine supplementation prevents this disorder. Iodinized salt Iodate (bread) iodine deficiency gives rise to goiter (so-called endemic goiter), as well as cretinism, which results in developmental delays and other health problems. According to WHO, in 2007, nearly 2 billion individuals had insufficient iodine intake, a third being of school age. ... Thus iodine deficiency, as the single greatest preventable cause of mental retardation, is an important public-health problem. 2. Hashimoto's disease Hashimoto's disease is the most common cause of hypothyroidism in areas of the world in which dietary iodine is sufficient. The terminology used to classify autoimmune thyroid diseases does not reflect our current understanding of the pathophysiology of these disorders and suggests that Hashimoto's disease and Graves' disease are distinct entities. Autoantibodies to the TSH receptor that act as TSH antagonists may be the cause of some cases of the atrophic form of Hashimoto's disease (in the past referred to as primary myxedema). Both Graves' disease and Hashimoto's disease may occur within the same families and may share human leukocyte antigen (HLA) and other genetic susceptibility haplotypes. Furthermore, thyroid failure occurs in some patients with Graves' disease, and hyperthyroidism and even orbitopathy develop in some patients with Hashimoto's disease. Both types of patients may have autoantibodies to thyroglobulin, TPO, and the TSH receptor. Hence, the diseases must be closely related, and autoimmune thyroid disease can be viewed as a spectrum from hyperthyroidism to hypothyroidism Hashimoto's Thyroiditis: Risk Factors Genetic Susceptibility Nongenetic Factors Pregnancy Iodine & Drugs Cytokines Irradiation Age Infection Hypothyroidism: Clinical Symptoms Lethargy Sensitivity to cold Slowed intellect Slowed motor activity Myxedema: Swelling Husky voice Numbness Life-threatening condition: Myxedema coma Cardiorespiratory failure Incidence: 1 in 4000 newborns 2% adult women 0.2% adult men Hypothyroidism Myxedema: Accumulation of mucinous edema in the face and other parts of the body. Hypothyroidism: Causes 3. Endemic Cretinism: Endemic to iodine-poor regions and individuals not exposed to iodine supplements. Iodine deficiency in gestating fetuses and infants (first 3 years of life). Severe mental and growth retardation. Treatment: Dietary iodine (fetal development); Thyroxine. Hypothyroidism: Causes 4. Inherited defects: Reduced function gene mutation in: TSH TSH receptor TRH TRH-receptor Iodide transport defect (NIS/Pendrin). Reduced TPO activity. Reduced peripheral deiodinase activity. Pendred?s Syndrome The normal gene makes a protein the researchers have named pendrin. The gene is located on human chromosome 7, which contains approximately 5 percent of the genes in the human genome. When altered, the gene produces defective pendrin and causes Pendred syndrome, a disorder that typically produces deafness at birth due to an improper development of the inner ear. In addition to deafness, later in life, Pendred syndrome patients develop goiters-abnormal swellings in the neck caused by an enlarged thyroid gland. Worldwide, the most common cause of goiter is lack of iodine in the diet. The researchers suspect the underlying defect in Pendred syndrome is not lack of iodine, but interference of iodine's ability to bind to thyroglobulin, a protein produced by the gland that is necessary for the synthesis of thyroid hormones. Because goiter is not always found in Pendred syndrome patients, it is likely that alterations in the pendrin gene will turn out to be responsible for some cases of deafness that had not previously been attributed to this disorder. Hypothyroidism in Animals More common in dogs than cats. Hyperthyroidism/Thyrotoxicosis: Clinical Symptoms Sudden weight loss, even when your appetite and food intake remain normal or even increase Rapid heartbeat (tachycardia) ? commonly more than 100 beats a minute ? irregular heartbeat (arrhythmia) or pounding of your heart (palpitations) Increased appetite Nervousness, anxiety or anxiety attacks, irritability Tremor ? usually a fine trembling in your hands and fingers Sweating Changes in menstrual patterns Increased sensitivity to heat Changes in bowel patterns, especially more frequent bowel movements An enlarged thyroid gland (goiter), which may appear as a swelling at the base of your neck Fatigue, muscle weakness Difficulty sleeping Hyperthyroidism: Causes 2. Toxic Adenoma: Gain of function mutations of TSH-receptor (Plummer?s disease). Constitutive activation of TSH-receptor. Occurs in men and women in their 30s and 40s. Treatment: Thyroidectomy; radiochemical thyroidectomy ?Thionamides? 1. Graves? disease Graves? Disease Graves' disease is most common in the third and fourth decades of life, is rare before age 10 years, and occurs in the elderly, sometimes in an apathetic form. The features include diffuse goiter, thyrotoxicosis, infiltrative orbitopathy, and occasionally infiltrative dermopathy. In other respects, the symptoms and signs of thyrotoxicosis are the same in Graves' disease as in patients with other causes of hyperthyroidism. The major antigen of Graves? Disease is the thyrotropin receptor Risk Factors for Graves? Disease Genetic susceptibility: large number of genetic loci implicates a polygeneic or complex disorder. Infection: assocation, but no know causative factor Stress: severe emotional stress Gender: Women (7-10:1) and more prevalent after puberty. (sex hormones?); but also occurs after metapause Pregnancy: rebound from immunosuppression after delivery (postpartum Graves? disease). Iodine and Drugs: Hyperthyroidism: Causes 3. Thyrotrope disorders: Tumorigenic Anterior Pituitary cells. 4. Thyroid hormone resistance: TR Loss of function Hyperthyroidism: Causes 5. Pregnancy: Doubling of serum T4 and T3 levels during pregnancy. Increase blood volume. Increase in TBG in serum. Increased usage of T4/T3 by peripheral tissues and by the placenta. Result: Increased iodine requirement (200 micrograms/day). Changes in various critical components of the thyroid-pituitary axis during pregnancy. Note the early increase in free T4, probably due to thyroidal stimulation by hCG, which causes a reciprocal modest suppression of serum TSH during the late first trimester. Fetal Thyroid Function Rates of production and degradation of T4 per body mass are 10x that of the adult. D1 is reduced and D3 is enhanced, favoring rT3 formation ? leading to D2 being the main pathway for T3 production. Fetal thyroid function starts at the end of the first trimester Maternal TSH does not pass into the fetal circulation, but maternal T4 does pass via specific membrane transporters Upon birth, newborn TSH and T4 rapidly increase likely due to temperature changes. Schematic diagram of thyroid cell stimulation and blockade by antibodies to the thyrotropin-stimulating hormone receptor. Such autoantibodies may act as agonists or antagonists, or may be neutral, depending on how they interact with the receptor binding site The TSHR is G protein?linked with seven transmembrane domains and employs cAMP and the phosphoinositol pathways for signal transduction. The human TSHR (hTSHR) is the primary autoantigen of Graves' disease. An overview of the most likely mechanisms involved in the cause and/or precipitation of Graves' disease. MHC, Major histocompatibility complex. Insult may be direct (thyroid) or by a viral inffection leading o T cell activation. However, initiation may be elsewhere in the body. Treatments for Hyperthyroidism Antithyroid agents. Iodide Transport Inhibitors Thionamides: Produce an iodide deficiency within the thyroid. Immunosuppressive actions. Thyroidectomy Immunosuppression (Graves? Disease) Hyperthyroidism in Animals More common in cats (older cats) than dogs. ?Primary Hyperthyroidism?: tumorigenic thyroid. Medical Uses of Radioactive Iodine Radioactive iodine uptake test: Orally administer 123I - t˝ = 13.4 hr Measure thyroid uptake Radioimaging: Orally administer 123I Scan thyroid for: Hot nodules: Cold nodules: Radiothyroidectomy: Exterior exposure to 131I - t˝ = 8 d Thyroxine replacement therapy Research 125I - t˝ = 60 d Goiter Carcinoma Levothyroxine: Synthetic T4 ? Recommended that it be taken ˝ hr before meals to maximize absorption Thyroxine, or 3,5,3',5'-tetraiodothyronine The natural hormone is chemically in the L-form, as is the pharmaceutical agent. Dextrothyroxine (D-thyroxine) Manufacture of Levothyroxine The key brands of levothyroxine in the U.S. include: Unithroid, manufactured by Jerome Stevens Pharmaceuticals and distributed by Watson. Approved by the FDA in August of 2000. Levoxyl, manufactured by King Pharmaceuticals. Approved by the FDA in May 2001. Levo-T, manufactured by Mova. Approved by the FDA in 2002. Synthroid, manufactured by Abbott Labs (used to be manufactured by Knoll Pharmaceuticals, and prior to that, Boots Pharmaceuticals) (FDA-approved as of July 2002) Levothroid, manufactured by Forest Laboratories. FDA-approved as of July 2002). All the levothyroxine products, Synthroid, Unithroid, Levoxyl and Levothroid, have different fillers and binders, so people may have different allergic responses to the different brands. (Levoxyl is also fast-dissolving, and should be taken with sufficient water, and swallowed quickly to maximize absorption.) If you react to one levothyroxine, your doctor might want to try other brands to see if you react to those brands as well.
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