Thyroid and Parathyroid Function
                                          PHTY 615
–Must be a sufficient amount of iodine in the diet to provide iodide needed for thyroid
   hormone function
•Thyroid cells...
•Cardiovascular effects
   –Thyroid hormones increase heart rate and myocardial contractility
       •Increase cardiac out...
–Heat intolerance

  –Lethargy/slow cerebration
  –Weight gain
–High doses may cause symptoms associated with hypothyroidism
•Large dose...
•Natural or synthetic analogs necessary in most forms of hypothyroidism
•Administration of thyroid hormones especially imp...
•PTH works with Calcitonin and Vitamin D in regulating CA2+ homeostasis

              Regulation of Bone Mineral Homeosta...
•Secreted by cells located in the thyroid gland (C cells)
   –Calcitonin is physiologic antagonist of PTH
Pharmacological Control of Bone Mineral
•Chronic disturbances in CA2+ homeostasis can also ...
•Inorganic compounds that appear to adsorb directly to CA2+ crystals in
the bone and decrease bone resorption
  –Inhibits ...
•Thyroid disorders
  –Excessive doses can cause opposite disorder
•Bone disorders
  –Hypercalcemia can be detected by ECG
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Thyroid and Parathyroid Function.doc

  1. 1. Thyroid and Parathyroid Function PHTY 615 Introduction •Hormones secreted from the thyroid gland involved in controlling metabolism –Also work synergistically with other hormones to promote normal growth and development •Parathyroid glands essential in regulating calcium homeostasis and are important in maintaining proper bone mineralization •Problems with thyroid and parathyroid glands often treated by pharmacologic methods Function of the Thyroid Gland •Gland on either side of the trachea in the anterior neck –Bilateral lobes connected by a central isthmus –Rich vascular supply and extensive nerve supply from the sympathetic NS •Thyroid gland synthesizes thyroxine and triiodothyroxine Normal Thyroid Gland Synthesis of Thyroid Hormones •First step is adding iodine to the residues of AA tyrosine •2 iodinated tyrosines combine to create thyroid hormones –Monoiodotyronsine + Diiodotyrsine = Triiodotyronsine (T3) –Diiodotyronsine + Diiodotyrsine = Thyroxine (T4) •Plasma levels of T4 much higher than T3 but: –T3 may exert most of physiologic effects –T4 may be precursor to T3 •T3 converted to T4 in peripheral tissue –Both T4 and T3 required for normal physiologic function Iodine uptake •Na+/I- symport protein controls serum I- uptake •Based on Na+/K+ antiport potential •Stimulated by TSH •Inhibited by Perchlorate Synthesis of Thyroid Hormones •Thyroid follicle cells take up and concentrate iodide in the bloodstream
  2. 2. –Must be a sufficient amount of iodine in the diet to provide iodide needed for thyroid hormone function •Thyroid cells also make protein called thyroglobulin (TGB) –2 iodinated tyrosine residues combine with TGB to make T4 and smaller amounts of T3 –TGB lysed from the iodinated tyrosines before released into the bloodstream Regulation of Thyroid Hormone Release •Controlled by hypothalamic-pituitary system •Thyrotropin-releasing hormone (TRS) from hypothalamus stimulates release of thyroid-stimulating hormone (TSH) from the anterior pituitary •TSH stimulates release of T3 and T4 •Negative feedback system controls TSH release from the anterior pituitary gland Thyroid Hormone Control Control of T3 and T4 Release Under normal conditions, decreases in T3/T4 cause TRH release from the hypothalamus (HPT) which then causes TSH release from the pituitary (PIT). TSH then stimulates: 1) T3/T4 synthesis and secretion 2) thyroid gland growth. When T3/T4 levels increase, negative feedback shuts off TRH and TSH secretion. Physiologic Effects of Thyroid Hormone •Affect wide variety of peripheral tissue •T4 and T3 may act directly on cell or facilitate function of other hormones •Thermogenesis –T4 and T3 increase basal metabolic rate and subsequent heat production –Important in maintaining adequate body temperature during exposure to the cold –Increase in thermogenesis achieved by thyroid hormone stimulating various tissues •Skeletal mm, cardiac mm, liver, kidneys Physiologic Effects of Thyroid Hormone •Growth and development –Thyroid hormones facilitate normal growth and development •Stimulate release of growth hormone and enhances its effect on peripheral tissue –Thyroid hormones directly enhance development of many physiologic systems •Especially skeletal mm and CNS –When thyroid hormones not present: •Severe growth restriction and mental retardation ensues Physiologic Effects of Thyroid Hormone
  3. 3. •Cardiovascular effects –Thyroid hormones increase heart rate and myocardial contractility •Increase cardiac output –Unclear how thyroid hormones increase myocardial sensitivity to other hormones •Norepinephrine and Epinephrine •Metabolic effects –Increase intestinal glucose absorption –Increase activity of several enzymes involved in carbohydrate metabolism –Enhances lypolysis by increasing response of fat cells to other lypolytic hormones Mechanism of Action of Thyroid Hormones •Thyroid hormones enter the cell and bind to specific receptors in the cell nucleus –Thyroid hormone receptors act as DNA transcription factors that bind to specific DNA sequences that regulate gene expression –Alter protein synthesis in the cell •Most if not all of thyroid hormone effects are secondary to altered protein production –Proteins may increase transport of specific substances across cell membrane or new protein may be directly involved in metabolic pathway Treatment of Thyroid Disorders •Two primary categories –Hyper and Hypothyroidism •Several subtypes –Hyperthyroidism •Primary: Graves disease, thyroid adenoma •Secondary: Induced by excessive hypothalamic or pituitary stimulation –Hypothyroidism •Primary: Genetic deficiency of enzymes that synthesize thyroid hormones •Secondary: Hypothalamic or pituitary deficiencies, Cretinism (childhood hypothyroidism), Myxedema (Adult hypothyroidism) Hypothyroidism and its Treatment: Hypothyroidism and its Treatment: When the pituitary can't make TSH there is no signal to the thyroid gland to make T3/T4. Thus secondary hypothyroidism is (i.e. pituitary- mediated) associated with decreased T3/T3 AND TSH and thyroid atrophy. Clinical Manifestations •Hyperthyroidism –Nervousness –Weight loss –Diarrhea –Tachycardia –Insomnia –Increased appetite
  4. 4. –Heat intolerance –Wasting –Goiter –Anorexia •Hypothyroidism –Lethargy/slow cerebration –Weight gain –Constipation –Bradycardia –Sleepiness –Cold Intolerance –Weakness –Dry, course skin –Facial edema Hyper- thyroidism Features: Hypo- thyroidism Myxedema Features: Hyperthyroidism •Thyrotoxicosis: –Increased secretion of thyroid hormones –Usually enlarged thyroid gland •Toxic goiter = Graves disease •Thought to be immune system problem •Treatment –Ablation of the thyroid gland •Surgical removal or administration of radioactive iodine Antithyroid Agents •Directly inhibit thyroid hormone synthesis •Propylthiouracil (Propyl-Thyracil), Methimazole (Tapazole) •Drugs inhibit thyroid peroxidase enzyme needed to prepare iodide for addition to tyrosine •Also prevent coupling of tyrosine residues to thyroglobulin molecule –Propylthiouracel also blocks conversion of T4 to T3 in peripheral tissue •Adverse effects –Skin rash and itching (mild)
  5. 5. –High doses may cause symptoms associated with hypothyroidism Iodide •Large doses of iodide (>6mg/day) causes a rapid decrease in thyroid function •In sufficient amounts, iodide inhibits virtually all steps involved in thyroid hormone biosynthesis –High iodide levels limit uptake of iodide into thyroid follicle cells, inhibits formation of T4 and T3, and decreases secretion of completed hormones •Effect of Iodide lasts ~2 weeks –Iodide used temporarily for individuals awaiting thyroidectomy Radioactive Iodine •Selectively destroys thyroid tissue in Graves disease •Radioactive iodine administered orally and rapidly sequestered in thyroid gland •Begins to emit beta radiation destroying thyroid follicle cells •Patients must subsequently take thyroid hormone supplements Beta-Adrenergic Blockers •Adjunctive treatment to thyrotoxicosis •BB do not lower thyroid hormone levels •BB help suppress symptoms such as tachycardia, palpitations, fever, restlessness •BB may be helpful in severe, acute, exacerbations of thyrotoxicosis •BB also administered preoperatively to control symptoms •Acebutolol, atenolol, metoprolol, nadolol, propanolol, timolol Hypothyroidism •Many causes –Idiopathic, autonomic, lymphocytic destruction, congenital impairment, low dietary iodine intake, genetic –Goiter may also occur but for different reasons •Decrease dietary iodine –TSH stimulates production of thyroglobulin –Thyroid hormone incomplete –No negative feedback and thyroglobulin production continues –Primary treatment •Thyroid hormone replacement therapy Thyroid Hormones
  6. 6. •Natural or synthetic analogs necessary in most forms of hypothyroidism •Administration of thyroid hormones especially important in infants and children –Adequate amounts needed for normal physical and mental development •Thyroid hormone replacement is likewise necessary following thyroidectomy or pharmacological ablation •Thyroid hormone maintenance may be beneficial for patients in preliminary or subclinical phase of hypothyroidism –May prevent full blown hypothyroidism •Main side effect is symptoms of hyperthyroidism Hypothyroidism: Treatments -Sodium levothyroxine (Synthroid®-T4) -Sodium liothyronine (Cytomel®-T3) -4-times as potent as T4, more rapid onset of action, same efficacy Parathyroid Gland Anatomy •Four Parathyroid glands are usually found posterior to the thyroid gland •Total weight of parathyroid tissue is about 150mg •Parathyroid hormone (PTH) is made by these glands Function of the Parathyroid Glands •Parathyroid hormone (PTH) –Polypeptide synthesized within cells of parathyroid glands •Calcium concentration in bloodstream controls PTH release •Decrease in CA2+ concentration increases PTH release and increased CA2+ concentration decreases PTH release •PTH increases blood CA2+ level by altering CA2+ metabolism in bone, kidneys, and GI tract Function of the Parathyroid Glands •PTH increases bone resorption, liberating CA2+ –Enhances development and action of osteoclasts •PTH increases renal resorption of CA2+ •PTH lastly increases absorption of CA2+ in the GI tract –Caused by interaction between PTH and Vitamin D metabolism –PTH increases conversion of Vitamin D to calcitriol –Calcitriol stimulates CA2+ absorption from the GI tract •PTH crucial in maintaining adequate levels of calcium in the body
  7. 7. •PTH works with Calcitonin and Vitamin D in regulating CA2+ homeostasis Regulation of Bone Mineral Homeostasis •Bone –Provides rigid framework for body and readily available and easily interchangeable CA2+ pool –Balance between bone formation and resorption important –CA2+ and phosphate needed for bone to maintain rigidity –Excessive resorption of these minerals result in bone demineralization •Bone at increased risk for failure (fracture) –Balance between bone resorption and formation controlled by complex interaction between local and systemic factors –Several hormones regulate bone formation and help maintain adequate calcium levels Parathyroid Hormone •Discussed previously –Increase in PTH = Increase in blood CA2+ levels –High PTH levels accelerates bone breakdown –Low-Normal PTH levels may enhance bone formation •May have implications for treatment of osteoporosis Vitamin D •Steroid like hormone from dietary sources or synthesized in skin from cholesterol derivatives in the presence of ultraviolet light •Vitamin D produces several metabolites important in bone mineral homeostasis •Vitamin D derivatives such as 1,25 Dihydroxyvitamin D3 increases serum CA2+ and phosphate levels by increasing CA2+ and phosphate absorption in GI tract and decreases renal CA2+ and phosphate excretion •Overall effect of Vitamin D is to enhance bone formation by increasing levels of primary minerals (CA2+ and phosphate) •Also suppresses synthesis and release of PTH Synthesis, Release & Activity of Active Vitamin D •Vitamin D3 is may be obtained from the diet or made in the skin •It is converted to the active form (1,25-OH-D3 by sequential enzymatic reactions in the liver and kidney (stimulated by PTH) •Vitamin D3 stimulates intestinal calcium uptake, increased bone calcium resorption & increased kidney phosphate uptake
  8. 8. Calcitonin •Secreted by cells located in the thyroid gland (C cells) –Calcitonin is physiologic antagonist of PTH •Calcitonin lowers blood calcium and stimulates bone formation –Increases incorporation of CA2+ into skeletal storage •Renal excretion of CA2+ also increased by Calcitonin effect on the kidney •Effect of Calcitonin on bone mineral metabolism relatively minor •Calcitonin does have important therapeutic function –Pharmacological doses may be helpful in preventing bone less Calcium Metabolism: Hormonal Regulation of Calcium and Phosphate Balance •Decreased Plasma Calcium Causes: •Increased PTH •Resulting in mobilization of bone Ca & phosphate, increased renal phosphate excretion & Ca retention and increased Vitamin D3 synthesis •The outcome is a rise in plasma Ca levels & maintenance of normal phosphate levels Summary •PTH & calcitonin release are regulated by plasma Ca levels •Bone Ca & phosphate serve as a ready reserve for maintenance of plasma levels •Bone, kidney & intestine participate in the regulation of plasma calcium •PTH, Vitamin D, & calcitonin balance plasma [Ca++] for bone synthesis, muscle contraction, & cell signaling •Endocrine diseases result from pathway or glandular hypo or hyper secretion Pharmacological Control of Bone Mineral Homeostasis •Blood CA2+ levels must be maintained within fairly limited range to ensure adequate supply of calcium for various physiologic functions –Normal range = 8.6-10.6 mg/100 ml •Plasma levels <6 mg/100 ml causes tetanic mm contractions •Plasma levels >12 mg/100 ml depresses nervous system function –Sluggish, lethargy, possible coma
  9. 9. Pharmacological Control of Bone Mineral Homeostasis •Chronic disturbances in CA2+ homeostasis can also produce problems with bone calcification •Various metabolic diseases can alter blood CA2+ levels leading to hypo or hypercalcemia •Pharmacological methods used to help control bone mineral levels in the bloodstream and maintain adequate bone mineralization Calcium Supplements •Administered to ensure adequate calcium levels in the bloodstream •Calcium supplements used to help prevent bone loss in conditions such as osteoporosis –Can’t prevent osteoporosis alone but helpful when combined with other treatments such as estrogen replacement •Dose of calcium supplement should make up the difference between dietary calcium intake and established guidelines –Amount depends on amount to dietary calcium, age, gender, hormonal and reproductive status •Excessive doses must be avoided to prevent hypercalcemia –Constipation, drowsiness, fatigue, headache –More pronounced: Confusion, irritability, cardiac arrhythmias, hypertension, nausea, vomiting, muscle and bone pain Vitamin D •Precursor for other compounds that increase intestinal absorption and decrease renal excretion of CA2+ and phosphate •Used to increase blood CA2+ and phosphate levels and enhance bone mineralization •Vitamin D analogs such as calcitriol combined with CA2+ supplement to help treat: –Postmenopausal osteoporosis –Bone loss with antiinflammatory steroids Vitamin D •Vitamin D is fat soluble –Excessive doses can accumulate in body and lead to toxicity •Early signs = headache, increased thirst, decreased appetite, metallic taste, fatigue, GI disturbance •Increased toxicity = Hypercalcemia, HTN, cardiac arrhythmias, renal failure, mood changes, seizures Bisphosphonates
  10. 10. •Inorganic compounds that appear to adsorb directly to CA2+ crystals in the bone and decrease bone resorption –Inhibits osteoclast activity •Bisphosphonates often used in Pagets disease –Help prevent excessive bone turnover and promote adequate mineralization •Used to inhibit abnormal bone formation –Heterotopic ossification Bisphosphonates •Treatment of choice for prevention and treatment of bone loss during prolonged administration of antiinflammatory steroids •Used in postmenopausal women •Adverse effects –Tenderness and pain over site of bony lesions in Pagets disease –Fracture risk with excessive doses –GI disturbances Calcitonin •Derived from synthetic sources to mimic effects of endogenous hormone •Promotes bone mineralization •Used to treat hypercalcemia and decrease bone resorption in Pagets disease •Used in postmenopausal and glucocorticoid-induced osteoporosis •Aerosolized versions of Calcitonin now available –Oral delivery difficult because absorbed poorly from the GI tract Estrogen Therapy •Critical in maintaining adequate bone mineralization in women •Used with other adjunct treatments –Calcium supplement, Calcitonin, Calcitriol, Bisphosphonates •May increase risk of breast and uterine cancer •Selective Estrogen Receptor Modulators (SERMS) –Activates receptors in certain tissues and blocks effect in others –Primary SERM used to prevent osteoporosis is Reloxifene (Evista) •Binds to and activates estrogen receptors in bone –Prevents bone loss and demineralization •Reloxifene blocks estrogen receptors on breast and uterine tissue Special Concerns for Rehabilitation Patients •PTs need to be concerned with side effects of different drugs
  11. 11. •Thyroid disorders –Excessive doses can cause opposite disorder •Bone disorders –Hypercalcemia can be detected by ECG •Can prevent life threatening disorder •Exercise –Helps to stimulate bone formation