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Transcript
Thyroid gland By Dr.Mohamed Abd AlMoneim Attia Thyroid hormone synthesis • Uptake of iodide by thyroid gland • Oxidation of iodide to produce molecular iodine • Organification – Iodination of tyrosine residues on thyroglobulin – Monoiodotyrosine (MIT) and diiodotyrosine (DIT). • Coupling – formation of T4 and T3 • Proteolysis of thyroglubulin and secretion of thyroid hormones • Conversion of T4 to T3 in peripheral tissues 2 Thyroid hormone synthesis T 4 TBP T3 & Free T4 & T3 (Iodide Organification) 4. Coupling 3 Metabolism of thyroid hormones Outer ring Inner ring (T4) 5’-deiodinase (4X potent than T4) 4 General principles • T4 secretion is stimulated by thyroid-stimulating hormone (TSH). In turn, TSH secretion is inhibited by T4, forming a negative feedback loop. • The gland synthesizes T4 > T3 (20:1) but T3 is 4-times more potent than T4 • Most of the circulating T3 is derived from peripheral deiodination of T4. • B-blockers and corticosteroids inhibit peripheral conversion of T4 into T3. Thyroid hormones • Mechanism of action • T4 and T3 must dissociate from thyroxine binding globulin (TBG) in plasma before entering into the cells. • In the cells, T4 is deiodinated to T3 that enters nucleus and attaches to specific receptors which promotes mRNA and protein synthesis. 6 Preparations of thyroid hormones • L-thyroxine: a synthetic sodium salt of T4 (t ½ is 7 days). • Liothyronine: a synthetic sodium salt of T3 (t ½ is 1 day). Hypothyroidism (myxodema) • Hypothyroidism in infants leads to cretinism . • It is treated by replacement with L-thyroxin (T4). • Children require more T4 than adults due to rapid growth. • During pregnancy, hypothyroid woman require higher doses • T3 has a shorter t ½ than T4 and is therefore used for emergency treatment of myxoedema coma. Management of myxedema coma Management: • Hospitalization in intensive care unit (ICU). • All medications must be given intravenously . • Intravenous fluids should be given with caution (can aggravate hyponatremia commonly associated with hypothyroidism and avoid excessive water intake. • L-thyroxine (T4): 400 μg IV initially, followed by 50 μg daily I͘ ntravenous .T3 can be used. • Hydrocortisone: 200 mg I.V. because the patient usually has associated adrenal insufficiency. • Treatment of associated diseases e.g. infection or heart failure. Hyperthyroidism (thyrotoxicosis) • It is a clinical syndrome results from high levels of thyroid hormones. • Clinical picture:.It resemble sympathetic over-activity because thyroxin increases sensitivity of B-receptors to circulating catecholamines. • There are tachycardia, arrhythmia, sweating, exophthalmos, etc. Investigations: • Measuring serum T3, T4, and TSH: T4 is ↑ and TSH is decreased • Assay for positive thyroid antibodies: 90% +ve in Grave's disease. • Thyroid scan for tumors. Management: • Medical treatment: mainly for Grave’s disease • Surgical thyroidectomy: mainly for multiple nodular goiter Antithyroid Drugs 1. Thiouracil drugs (thioamides): • (Carbimazole - Methimazole - Propylthiouracil) Pharmacokinetics: • Methimazole is the active metabolite of Carbimazole. • The t1/2 of propylthiouracil is 1.5 hr while the t1/2 of methimazole is 6 hrs. • The short t½ of these drugs has little effect on their effect because they are selectively accumulated in the thyroid. • Propylthiouracil is preferable during pregnancy because it does not cross placental barrier (because it is strongly bound to plasma protein). Mechanism of action: • They inhibit oxidation of iodides by inhibiting peroxidase enzyme. • Propylthiouracil also inhibits the peripheral conversion of T4 into T3. • They have slow onset of action (3-4 weeks) but propylthiouracil has faster effect (so it is used in thyrotoxic crisis). Doses and duration: • Carbimazole (Neomercazole): start with 30 mg/d till reach euthyroid state (after 4-8 weeks) then maintain on 15 mg /d for 1-2 years (until the gland undergo spontaneous remission). • Propylthiouracil: start with 300 mg/d for 4-8 weeks then 150 mg/d for 1-2 years. Adverse effects: • Agranulocytosis & bone marrow depression. • Hypothyroidism with increased size and vascularity of the gland due to ↑ TSH ͘ • Hypothyroidism of the infant (fetal goiter) if given during pregnancy. • Cholestatic jaundice. • Hypersensitivity reactions: may require stopping of the drugs. • There is 50-68% incidence of relapse. Precautions during thiouracil treatment: • Therapy with thiouracil drugs should continue for 1-2 years and should be stopped gradually (to prevent relapse). • Follow up with WBC count. • If used during pregnancy, propylthiouracil is the drug of choice. 2. β-blockers • Propranolol • It controls sympathetic over activity e.g. tachycardia and arrhythmia. • It ↓ insomnia, and tremors • It inhibits peripheral conversion of T4 to T3. • If propranolol is contraindicated give diltiazem (calcium channel blocker). 3. Radioactive iodine • It is an effective oral treatment for thyrotoxicosis caused by Graves’ disease or by toxic nodular goiter. • Delayed hypothyroidism is the main adverse effect so; replacement therapy with T4 is required after functional ablation. Contraindication: • Pregnancy and lactation: I131 crosses placental barrier and excreted in milk. • Age < 16 years for fear of delayed malignant changes. 4. Iodides • Potassium iodides or Lugol’s iodine: (10% KI + 5% iodine) is given 1-2 weeks before surgery in order to: • Inhibit synthesis and release of T4 & T3. • Inhibit release of TSH leading to ↓↓ size and vascularity of the gland. • Improvement in thyrotoxic symptoms occurs within 2-7 days, but if therapy with iodides is continued (>2-4 weeks), the beneficial effects disappear and manifestations of hyperthyroidism reappear (iodine escape). Therapeutic uses: • Preparation of the patient before operation to decrease size and vascularity of the gland. • Treatment of thyroid storm . Adverse effects: • Metallic taste. • Swollen salivary glands, mucous membrane ulceration and gastric irritation. • Increased lacrimal and nasal secretions (rhinorrhea). • Allergic reactions: skin rash, drug fever, etc. • Iodine escape if used > 2-4 weeks. Preparation of patient before operation: • Carbimazole: 10 mg t.d.s. 7-10 weeks before operation to reach euthyroid state. • Potassium iodide: 1-2 weeks before operation to ↓ size and vascularity of the gland (see below). • Propranolol: to control HR and cardiac arrhythmia. • Sedatives (phenobarbitone or diazepam): to ↓ anxiety ͘ Thyrotoxic crisis (thyroid storm) • It is a sudden severe exacerbation of the manifestations of thyrotoxicosis due to sudden release of T3&T4 (medical emergency). • It is a common postoperative complication if the patient was not well-prepared. Manifestations: • High fever with vomiting and sweating • Tachycardia and arrhythmia, occasionally heart failure and shock. • Convulsions, coma, and even death from heart failure. Management: • Intravenous fluids and antipyretics to control dehydration and fever. Aspirin must be avoided because it displaces thyroid hormones binding from thyroid binding globulin (TBG) • Propranolol: 1-2 mg slowly I.V. or 40 mg oral /6 hrs. It controls excessive adrenergic response (tachycardia, arrhythmia, tremors, etc.). • Esmolol is short-acting β-blocker can be also given. • If β-blockers are contraindicated give diltiazem orally or by I.V. infusion. • Potassium iodides: 10 drops orally/day to block hormone release and peripheral conversion of T4 to T3. • Propylthiouracil: 250 mg/6 hrs orally to block hormone synthesis. It acts more rapidly than other thiouracil drugs. • Hydrocortisone: 50 mg I.V./6h to elevates BP and reduces toxemia. It also blocks peripheral conversion of T4 to T3. GOOD LUCK