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Overview o Thyroid
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growth development maintaining normal body temperature energy metabolism regulation Receptors:
Thyrotropin (TSH, a pituitary hormone) modulates thyroid function by binding to TSH receptors (TSH-R) TSH-R: localization and properties:
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Iodide:
Metabolism: Iodide intake: gastrointestinal tract absorption from food, water, or medication.
Iodide:
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rapid absorption enters extracellular pool thyroid removes amount required for hormone secretion
Graves' disease:
Greenspan, F.S., and Dong, B. J.. Histamine, Thyroid and Antithyroid Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 619-633.
Wartofsky, L., Diseases of the Thyroid, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 20122034
Thyroid Hormones
Chemistry of thyroid hormones: o Active isomer -- levo (L-form) -- thyroxine, triiodothyronine, reverse iodothyronine (reverse T4) Pharmacokinetics:
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T4 -- well absorbed from the ileum and duodenum following oral administration-- about 80% absorbed on average Modification of absorption:
o o
T3 -- almost completely absorbed (95%) following oral administration T4 and T3 absorption may be impaired by myxedema (may require parenteral administration {IV}, as a result) Factors that alter T4 and T3 clearance:
hyperthyroidism: increases hypothyroidism: decreases Drugs (hepatic microsomal enzymes inducers): Clearance is enhanced; Euthyroid state may be maintained because of thyroid hyperfunction.
Increases in the number of TBG binding sites (due to pregnancy, estrogen use, oral contraceptive use)
more thyroid hormone is bound; elimination rate declines (only free hormone can be eliminated); normal hormone concentration would be eventually restored
1. 2.
Mechanism of Hormone Action: Unbound T4 and T3 diffuse into the cell (passive diffusion, possibly active transport) Inside cell: 3. T4 converted to T3 4. T3 is transported to the cell nucleus where T3 binds to a specific T3 nuclear receptor
Thyroid hormones: metabolic actions o nuclear receptor activation results in increased RNA and protein synthesis: examples -
increased Na/K ATPase causes increased ATP turnover, increased oxygen consumption --calorigenic effect
Physiological system
Hyperthyroidism (thyrotoxicosis)
Hypothyroidism
skin --appendages
warm, moist skin; sweating; fine, thin hair; Plumber's pale, cool, puffy skin; brittle nails; pretibial hair and nails dermopathy (Graves' disease) Upper lid retraction (wide stare); Eyelid drooping; periorbital periorbital edema; edema; puffy, nonpitting exophthalmos, facies; large tongue diplopia (Graves' disease) decreased peripheral increased peripheral resistance, increased resistance, decreased cardiac output, cardiac output, stroke
Eyes, face
Cardiovascular
stroke volume, heart volume, heart rate, pulse rate, pulse pressure; pressure; congestive heart congestive heart failure (low output); failure (highbradycardia (low voltage output); increased ECG with prolonged PR contractility,. interval, flat T wave); arrhythmogenic; pericardial effusion angina Respiratory dyspnea; reduced vital capacity increased appetite; increased bowel movement frequency; hypoproteinemia Nervousness, hyperkinesia, variable emotional states Weakness; fatigue; hypercalcemia, osteoporosis, increased deep tendon reflex hypoventilation (CO2 retention) pleural effusions decreased appetite, decreased bowel movement frequency; ascites
Gastrointestinal
CNS
lethargy, neuropathy
Musculoskeletal
muscle fatigue, reduced deep tendon reflex, increased alkaline phosphatase, LDH, AST
Renal
Increased renal blood Decreased renal blood flow; flow; increased GFR; decreased GFR; reduced mild polyuria water excretion anemia (increased RBC turnover); increased erythropoiesis decreased fertility; menstrual irregularity; enhanced gonadal steroid metabolism increased basal rate; negative nitrogen balance, hyperglycemia; increased free fatty acids, decreased cholesterol and triglycerides; anemia (decrease production rate, decreased iron absorption, decreased folate acid absorption, autoimmune pernicious anemia),decreased erythropoiesis infertility;hypermenorrhea, decreased libido; impotence, decreased gonadal steroid metabolism decreased basal rate; delayed insulin degradation, with increased sensitivity; enhanced cholesterol and triglyceride levels; decreased hormone degradation; decreased requirements for fat-and
Hematopoietic
Reproductive
Metabolic
increased hormone degradation; increased water-soluble vitamins; requirement for fat- decreased drug and water-soluble detoxification. vitamins; enhanced drug detoxification * * Adapted from Table 38-4, Greenspan, F.S., and Dong, B. J.. Histamine, Thyroid and Antithyroid Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) AppletonLange, 1998, p 625. Greenspan, F.S., and Dong, B. J.. Histamine, Thyroid and Antithyroid Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 619-633. Wartofsky, L., Diseases of the Thyroid, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 20122034
Animal origin:
dessicated thyroid-- never justifiable; many disadvantages {protein antigenicity; product instability and variable hormone concentration; difficulty and lab assessment}
Applications:
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Rationale:
low-cost stability non-allergenic (no foreign protein) serum levels readily obtained long half-life (seven days) -- supports once-daily dosing since T4 is converted to T3 inside the cell, T4 administration produces both hormones
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Liothyronine -- more active than levothyroxine but not recommended because of:
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higher hormonal activity enhances cardiotoxicity (T3 -- contraindicated in patients with cardiac disease)
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Antithyroid Drugs:
Overview o Purpose:
Approach:
use drugs that change tissue response to thyroid hormones destroy the the thyroid with surgical or radiation interventions
Definition:
"goitrogens" -1. compounds that suppress T3 and T4 secretion 2. thereby increasing TSH 3. increased TSH levels produces thyroid gland enlargement (goiter)
Thioamides:
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Propylthiouracil
rapidly absorbed bioavailability: 50 -- 80% (incomplete absorption/large firstpass effect) metabolism: glucuronidation by the liver; excreted by the kidney short half-life (1.5 hours) but accumulated by the thyroid crosses placental barrier (increased protein binding compared to methimazole makes propylthiouracil preferable for use in pregnancy since less free drug is available to cross into the fetus)
Methimazole
(about 10 times more active than propylthiouracil) well absorbed accumulated by the thyroid
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Major action: inhibits thyroidal peroxidase-catalyzed reactions, blocking iodine organification: -- thus preventing hormone synthesis. Propylthiouracil and methimazole (too a much reduced degree) inhibit peripheral deiodination of T4 and T3
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Toxicity:
Frequency of adverse effects: 3-12%. Most common: maculopapular pruritic rash Most serious potential reaction: agranulocytosis -- risk 0.3% 0.6 % of patients; reversible upon discontinuation; cross sensitivity between propylthiouracil and methimazole possibly increased risk in:
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Anion Inhibitors
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Competitive inhibition:
Major clinical use -- potassium perchlorate ( not often used because of the possibility of causing aplastic anemia)
Iodides
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decreased thyroidal size and vascularity may induce hyperthyroidism (jodbasedow) may precipitate hypothyroidism
Clinical Considerations:
may be useful in short-term management of thyroid storm maybe helpful in preoperative preparation for surgery (due to reduction in gland vascularity, size, and fragility) Major disadvantages:
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may delay initiation of thioamides treatment may delay use of radioactive iodine treatment
chronic iodide used in pregnancy: avoid -- iodide crosses the placenta and may cause fetal goiter
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iodide as monotherapy: not appropriate; iodide block lasts only 2-8 weeks; withdrawal at this time may exacerbate thyrotoxicosis
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Iodide use, if at all, should be initiated only after thioamide treatment and not used if radioactive iodine therapy is planned
Useful in management of hyperthyroidism (off label use) Ipodate and iopanoic acid inhibit T4 to T3 conversion in:
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adjunctive treatment of thyroid storm alternatives if thioamides and iodides are contraindicated
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Radioactive Iodine:
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131
Mechanism of Action:
rapidly absorbed, concentrated in the thyroid incorporated into thyroid follicles beta emission is the basis for therapeutic efficacy Thyroid parenchymal destruction occurs within a few weeks.
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Contraindication:
131
I-- not administered to pregnant women or nursing mother;131I crosses placental barrier and excreted in breast milk.
Applicable drugs:
Hypothyroidism
Overview: hypothyroidism 1. cause: inadequate thyroid hormone synthesis 2. Cretinism -- when hypothyroidism is present from birth and accompanied by developmental abnormalities 3. Myxedema: severe hypothyroidism associated with:
deposition of hydrophilic mucopolysaccharides in the dermis (ground substance) and other tissues-- causing:
Pretibia myxedema
Adult hypothyroidism: Pretibial myxedema in the foot and lower extremity skin 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.
Goitrous Biosynthesis defect (genetic) Transmitted by the mother (antithyroid drugs) Iodine deficiency Drug-induced {e.g. salicylates,
lithium,iodides, phenylbutazone,iodoantipyrine}
Suprathyroid (Trophoprivic) Pituitary Panhypopituitarism Isolated low TSH levels Hypothalamic Congenital defect Infection (e.g. encephalitis) Neoplasm; Infiltrative (sarcoidosis)
Hypothyroidism: pathogenesis 1. inadequate thyroid hormone synthesis causes TSH hypersecretion which results in goiter 2. if this compensatory physiological response is insufficient, goitrous hypothyroidism occurs o Causes of goitrous hypothyroidism (North America)
Iodide-induced goiter with or without hypothyroidism: intrinsic defect inorganic binding mechanism
Euthyroid patients with Graves' disease {particularly following surgery or radioiodine therapy}, patients with Hashimoto's disease, and normal fetuses are particularly susceptible to iodide-induced goiter.
(Right) Struma lymphomatosa in Hashimoto thyroiditis, gross. Note: diffuse, pale yellow infiltrate affecting the entire thyroid. The yellow infiltrate is caused by an influx of lymphocytes, which may form follicles. Normal thyroid (Left) 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.
Hypothyroidism: Clinical presentation o Neonates (note that cretinism may be present at birth, but usually is apparent within the first few months after birth as a function of the extent of thyroid failure)
manifestations:
Since early clinical diagnosis may be difficult and early treatment is necessary to ensure normal intellectual development,all neonates should be screened for hypothyroidism by measuring serum T4 or TSH
Young Children:
coarse features, protruding tongue, broad, flat nose, widely set eyes, dry skin, coarse hair. impaired mental development, retarded bone age, epiphyseal dysgenesis, delayed dentition.
Older Child:
Adult:
fatigue, lethargy, constipation, cold intolerance, slowing of intellectual and motor activity lessened appetite; increased weight dry skin; dry hair (may fall out) deeper, hoarser voice With Advanced Disease: (florid myxedema)
dull, expressionless facies, sparse hair, periorbital puffiness , large tongue, rough and doughy skin (cool, pale) enlarged heart (dilation, pericardial effusion) adynamic ileus Without treatment: myxedema coma possible with respiratory depression and increased PCO2
Laboratory Tests:
increased levels in thyroprivic and goitrous normal or undetectable in pituitary or hypothalamic hypothyroidism
in hypothalamic hypothyroidism: TSH hypersecretion is associated with hypersecretion of other pituitary hormones
All hypothyroidism:
decreased serum T4 and free T4I serum T3 may be decreased less than serum serum T4
Pharmacological treatment:
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Synthetic hormones:
Neonatal, infantile, and juvenile hypothyroidism: early full replacement therapy vital to improve likelihood of:
If neonatal, infantile, and juvenile presentations result from pituitary and hypothalamic hypothyroidism, treatment with hydrocortisone should precede thyroid replacement therapy:
Rationale:acute adrenocortical insufficiency may because by the increase in metabolic rate with increase glucocorticoid clearance following thyroid hormonal treatment
Adults:
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myxedema coma
hypothyroid patients needing to undergo emergency surgery (these patients have extreme sensitivity to CNS depressants);
to patients with myxedema coma and systemic illness may have reduced ability to convert T4 to T3. In these cases supplemental liothyronine may be added to levothyroxine.
*- Thyroprivic: refering to lack of thyroidhormone (e.g. removal of the gland or suppression of glandular function)
Thyrotoxicosis:
Definition:clinical, physiological, biochemical consequences when tissues respond to excess thyroid hormone Most important causes: those associated with prolonged hormone overproduction by the thyroid. Causes:
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Extra-pituitary unregulated thyroid stimulation: 1. Graves' disease 2. Hashimoto's disease 3. trophoblastic tumor
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Chronic thyroiditis Excessive TSH secretion by pituitary tumor (rare) Autonomous thyroid gland hyperfunction Ingestion of meat contaminated with animal thyroids ("hamburger toxicosis")
Hyperthyroidism is only associated with conditions in which thyroidal hyperfunction leads to thyrotoxicosis.
Graves' disease
dermopathy ophthalmopathy
Thyroid Pathology :
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soft, enlarged, vascular Parenchymal hypertrophy/hyperplasia Lymphocytic infiltration (suggesting the immunological nature of the disease)
"Diffuse toxic goiter of Graves disease, gross, showing symmetric, non-nodular hypervascular enlargement of the thyroid" 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.
skeletal muscle fiber degeneration cardiac enlargement diffuse liver fibrosis with fatty infiltration skeletal decalcification body tissue loss
1. 2.
Ophthalmopathy:characterized by -inflammatory orbital content infiltrate (lymphocytes, mast cells, plasma cells)
nervousness, insomnia, tremors, frequent bowel movements, heat intolerance, sweating, emotional instability weight loss despite adequate or increased appetite muscle weakness oligomenorrhea/amenorrhea in premenstrual women dyspnea palpitations exacerbation of angina/cardiac failure (older patients)
Ocular Presentations: -- distinct from ophthalmopathy associated with Graves' disease; ocular signs mainly due to excessive sympathetic stimulation
characteristics stare (widening palprebral fissures) lid lag infrequent blinking failure to wrinkle brow upon upward gaze
Cardiovascular effects:
wide pulse pressure sinus tachycardia atrial arrhythmias (particularly atrial fibrillation) systolic murmurs occasionally heart failure
Common manifestations:
hyperfunctioning goiter
asymmetric, lobular
ophthalmopathy
proptosis (sensitive to antiadrenergic agents) including: 1. ophthalmoplegia 2. periorbital swelling 3. conjunctivitis 4. corneal ulceration, optic neuritis, optic atrophy
Diagnosis:
Thyroid Storm:
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Fulminating increase in symptoms of thyrotoxicosis "Medical storm" is now likely to be seen in undertreated patients. Precipitated by surgery or complicating illness, often sepsis. Presenting syndrome:
extreme irritability coma or delirium high fever, 41oC tachycardia hypotension vomiting diarrhea
Treatment:
manage dehydration: IV glucose/Saline, vitamin B complex glucocorticoids (possible reduction in adrenal reserve; increase glucocorticoid requirement and thyrotoxicosis digitalis may be required to control elevated ventricular rates in the presence of atrial fibrillation Block hormone synthesis by large dose propylthiouracil; followed by large doses of iodine, oral or parenteral; sodium ipodate may be used instead of iodine
Propranolol (adrenergic antagonist) important in the absence of CHF Combination treatment with propylthiouracil, iodine, dexamethasone is likely to result in serum T3 levels returning to normal within one to two days.
Greenspan, F.S., and Dong, B. J.. Histamine, Thyroid and Antithyroid Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 619-633. Wartofsky, L., Diseases of the Thyroid, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 20122034