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בלוטת התריס פיזיולוגיה ומחלות ד"ר סמיר קאסם השרות לאנדוקרינולוגיה ומטבוליזם Thyroid gland- anatomy Thyroid anatomy Thyroid histology Thyroid Hormones Thyroglobuline Calcitonine THYROID HORMONES T4 T3 rT3 -The thyroid production rate of T4 is 80 to 100 µg (100 to 130 nmoles) / day. -T4 is degraded at a rate of about 10 % / day. – •80 % is deiodinated, 40 % to form T3 and 40 % to form rT3. The remaining 20 % is conjugated with glucuronide and sulfate. Thyroid hormone biosynthesis TPO (1)iodide (I-)trapping by the thyroid follicular cells; (2) diffusion of iodide to the apex of the cells; (3) transport of iodide into the colloid; (4) oxidation of inorganic iodide to iodine and incorporation of iodine into tyrosine residues within thyroglobulin molecules in the colloid; (5) combination of two diiodotyrosine (DIT) molecules to form tetraiodothyronine (thyroxine, T4) or of monoiodotyrosine (MIT) with DIT to form triiodothyronine (T3); (6) uptake of thyroglobulin from the colloid into the Regulation of Thyroid hormone secretion Thyrotropin-releasing hormone (TRH) increases the secretion of thyrotropin (TSH), which stimulates the synthesis and secretion of trioiodothyronine (T3) and thyroxine (T4) by the thyroid gland. T3 and T4 inhibit the secretion of TSH, both directly and indirectly by suppressing the release of TRH. T4 is converted to T3 in the liver and many other tissues by the action of T4 monodeiodinases. Some T4 and T3 is conjugated with glucuronide and sulfate in the liver, excreted in the bile, and partially hydrolyzed in the intestine. Some T4 and T3 formed in the intestine may be reabsorbed. Drug interactions may occur at any of these sites. Regulation of transcription by thyroid hormones Thyroid investigations Blood – Imaging : – Scan U/S CT PET • • • • Assessment of bioactive thyroid hormones Check free hormone levels: Free T4 (Free T3) Check thyroid hormone “biosensor’: TSH TT3 Thyroid function tests FT4 TT3 TSH (“sensitive”, mIU/L) nmol/L nmol/L pmol/L 21 3.0 10 1.2 4 0.15 Hypo Hyper Hypo Hyper Hypo Hyper Serum factors in thyroid disease 1-Anti-thyroid antibodies: Anti- microsomal or thyroid peroxidase (TPO) Anti- thyroglobulin 2-Thyroid stimulating antibodies: Thyroid Stimulating Immunoglobulin (TSI) = TSH receptor Stimulating antibody TSI- growth promoting TSI- hormone secretion stimulation TSI- block 3-Thyroglobulin 4-Sex hormone binding globulin (SHBG) 5-Cholesterol 6- Calcitonine (Medullary Thyroid carcinoma) Thyroid ultrasound Fine Needle Aspiration Nl thyroid scan - Hot nodule – Cold Nodule Thyroid diseases – Part II (clinical) Hyperthyroidism Hypothyroidism Thyroiditis Nodules and Goiter • • • • Thyroid abnormalities Function Structure Thyroiditis Hyperthyroidism Hypothyroidism Etiolog y RX Goiter Nodular Benign Diffuse Malignant Function ? () סימטומים של תירוטוקסיקוזים Hyperactivity / nervousness Heat Intolerance / increased sweating Fatigue / weakness Weight loss WITH increased appetite Palpitations Dyspnea Diarrhea Oligomenorhea-amenorrhea- loss of libido Eye complaints EXCLUSIVELY in Grave’s disease – – – – – – – – – סימנים בבדיקה גופנית Sinus tachycardia, Atrial Fibrillation (10%) Eye-lid retraction and staring Goiter (multinodular / diffuse) Fine tremor / hyperreflexia Warm – moist skin Hair loss Muscle weakness and wasting Palmar erythema – Onycholysis Psychosis Congestive (high output) heart failure / IHD Thrill over thyroid Grave’s disease exclusively Exophtalmy • • • • • • • • • • • • Thyrotoxicosis- Causes Primary hyperthyroidism Graves' disease Toxic multinodular goiter Toxic adenoma Functioning thyroid carcinoma metastases Activating mutation of the TSH receptor Activating mutation of Gsα (McCune-Albright syndrome) Struma ovarii Drugs: iodine excess (Jod-Basedow phenomenon) Thyrotoxicosis without hyperthyroidism Subacute thyroiditis Silent thyroiditis Other causes of thyroid destruction: amiodarone, radiation, infarction of adenoma Ingestion of excess thyroid hormone (thyrotoxicosis factitia) or thyroid tissue Secondary hyperthyroidism TSH-secreting pituitary adenoma Thyroid hormone resistance syndrome: occasional patients may have features of thyrotoxicosis Chorionic gonadotropin-secreting tumors a Gestational thyrotoxicosisa a Circulating TSH levels are low in these forms of secondary hyperthyroidism. Note: TSH, thyroid-stimulating hormone. Graves’ disease • Diffuse toxic goiter • Opthalmopathy • Dermopathy Etiology: Autoimmune Anti-TSH receptor antibodies Anti-thyroid antibodies expression of HLA-DR3 association with: -diabetes mellitus -Addison’s disease -pernicious anemia Graves disease- goiter Graves diseaseopthalmopathy - Exophtalmus Graves’ disease dermopathy The effect of high- dose PTU Pulse rate: TT3 FT4 140 50 45 120 40 Normal range 100 35 30 80 25 Upper limit of normal 20 0 1 2 3 4 5 Days PTU dose mg/day: 1200 600 6 10 9 8 7 6 5 4 3 2 1 0 Causes of Hypothyroidism Primary Autoimmune hypothyroidism: Hashimoto's thyroiditis, atrophic thyroiditis – Iatrogenic: 131I treatment, subtotal or total thyroidectomy, external – irradiation of neck for lymphoma or cancer Drugs: iodine excess (including iodine-containing contrast media and – amiodarone), lithium, antithyroid drugs, p-aminosalicyclic acid, interferon-α and other cytokines Congenital hypothyroidism: absent or ectopic thyroid gland, – dyshormonogenesis, TSH-R mutation Iodine deficiency – Infiltrative disorders: amyloidosis, sarcoidosis, hemochromatosis, – scleroderma, cystinosis, Riedel's thyroiditis Transient Silent thyroiditis, including postpartum thyroiditis – Subacute thyroiditis – Withdrawal of thyroxine treatment in individuals with an intact thyroid – • Secondary Hypopituitarism: tumors, pituitary surgery or irradiation, infiltrative disorders, Sheehan's – syndrome, trauma, genetic forms of combined pituitary hormone deficiencies Isolated TSH deficiency or inactivity – Hypothalamic disease: tumors, trauma, infiltrative disorders, idiopathic – • TSH, thyroid-stimulating hormone; TSH-R, TSH receptor. Signs and Symptoms of Hypothyroidism (Descending Order of Frequency) Symptoms • •Signs Dry coarse skin; Tiredness, weakness Dry skin cool peripheral extremities Feeling cold Puffy face, hands, and feet Hair loss (myxedema) Difficulty concentrating and poor memory Diffuse alopecia Constipation Bradycardia Weight gain with poor appetite Peripheral edema Dyspnea Delayed tendon reflex relaxation Hoarse voice Carpal tunnel syndrome Menorrhagia (later oligomenorrhea or Serous cavity effusions amenorrhea) Paresthesia Impaired hearing Laboratory: serum thyroid hormones, cholesterol anemia (iron def., megaloblastic) Hypothyroidism- therapy • Levothyroxine (1.7 mcg/kg/d) 0.05-0.3 mg/day • Combined L-T4 and L-T3 may be beneficial with respect to well-being • In elderly patients (at high risk for CVD), “go low, go slow” Myxedema Coma Extreme hypothyroidism: • Coma • Hypothermia • Hypoventilation • Hypoglycemia • Hyponatremia • Bradycardia Laboratory: FT4 , TT3, TSH Lactascent serum Co2 retention Myxedema Coma- therapy Ventilation Treat: Hypoglycemia Precipitating factors Give: T4 or T3 I.V. Corticosteroids Causes of thyroiditis Acute • -Bacterial infection: especially Staphylcoccus Streptococcus and Enterobacter -Fungal infection: Aspergillus Candida Coccidioides Histoplasma and Pneumocystis -Radiation thyroiditis after 131I treatment -Amiodarone (may also be subacute or chronic) Subacute Viral (or granulomatous) thyroiditis – Silent thyroiditis (including postpartum thyroiditis) – Mycobacterial infection – Chronic - Autoimmunity: focal thyroiditis, Hashimoto's thyroiditis, atrophic thyroiditis Riedel's thyroiditis - Parasitic thyroiditis: echinococcosis, strongyloidiasis, cysticercosis - Traumatic: after palpation • • Clinical course of subacute thyroiditis. The release of thyroid hormones is initially associated with a thyrotoxic phase and suppressed thyroid-stimulating hormone (TSH). A hypothyroid phase then ensues, with low T4 and TSH levels that are initially low but gradually increase. During the recovery phase, increased TSH levels combined with resolution of thyroid follicular injury leads to normalization of thyroid function, often several months after the beginning of the illness. ESR, erythrocyte sedimentation rate; UT4, unbound T4 Subacute thyroiditis Etiology: (Post) viral inflammation of thyroid Symptoms & signs: Hyperthyroidism Painful swelling of thyroid Pain irradiation to ear Fever Sometimes “silent” Laboratory: ESR acute phase reactants (CRP, fibrinogen) Subacute thyroiditis- therapy Non-steroid anti-inflammatory agents (NSAIDS) β-blockers Corticosteroids Goiter and nodules