Thyrotoxicosis Dr Madhukar Mittal Medical Endocrinology

Thyroid Gland : Overview Location  In the anterior neck, affixed to anterior and lateral aspects of trachea by loose connective tissue, upper margin of isthmus just below the cricoid cartilage Structure  Butterfly-shaped with two lateral lobes connected by isthmus Blood supply  Superior and inferior thyroid arteries Epiglottis Thyroid cartilage Trachea Isthmus Thyroid gland

Functions of the Thyroid Gland Secretes two hormones  Thyroxine (T 4 )  Triiodothyronine (T 3 )  Play a central role in cell differentiation during development  Help maintain thermogenic and metabolic homeostasis in adult  Regulate oxygen use and basal metabolic rate

Thyroid Hormones: T4 and T3 T 4  Primary secretory product of the thyroid gland, which is the only source of T 4  The thyroid secretes approximately  g of T 4 per day  T 4 concentrations are 50 times greater than T 3 T 3  Biologically active hormone responsible for majority of thyroid hormone effects  Circulating T3 is derived from 2 processes –About 80% comes from deiodination of T 4 in liver, kidney & other peripheral tissues –About 20% comes from direct thyroid secretion

Physiology and Biochemistry

Thyroid Hormones: T 4 and T 3 Synthesized by attaching iodine to the amino acid tyrosine Thyroxine (T 4 ) contains 4 iodine atoms, while triiodothyronine (T 3 ) contains 3 iodine atoms Thyroxine (T 4 ) and triiodothyronine (T 3 ) are secreted by follicular epithelial cells of the thyroid Chemistry of T 3 and T 4 Formation TyrosineMonoiodotyrosineDiiodotyrosine 3,5,3'- Triiodothyronine Thyroxine Iodinase HO I II I CH 2 CH NH 2 COOH 5’ 3’ 5 3 O Thyroxine (T 4 ) 3,5,3’,5’-Tetraiodothyronine HO II I CH 2 CH NH 2 COOH O Triiodothyronine (T 3 ) 3,5,3’-Triiodothyronine

Synthesis and Secretion of Thyroid Hormones Capillary Thyroid follicle cell Thyroglobulin is synthesized and discharged into the follicle lumen 1 Rough ER Golgi apparatus Colloid Iodine enters follicle lumen where it is attached to tyrosine in colloid. forming DIT and MIT 3 Trapping (active uptake) of iodide (I - ) Oxidation Active form of iodine Iodide (I - ) 2a 2b DIT (T 2 ) MIT (T 1 ) Thyroglobulin colloid Iodinated tyrosines are linked together to form T 3 and T 4 4 Lysosomal enzymes cleave T 4 and T 3 from thyroglobulin colloid and hormones diffuse from follicle cell into bloodstream T3T3 T4T4 T3T3 T4T4 To peripheral tissues T3T3 T4T4 6 Thyroglobulin colloid is endocytosed and combined with a lysosome 5 T3T3 T4T4 Lysosome  Uptake  Organification  Coupling  Storage  Release

Production of T 4 and T 3 T 4 – Iodide=rT 3 ( Reverse T 3 ) … Inactive form T 4 – Iodide=T 3 ( 80% of T 3 ) MIT + DIT=T 3 DIT + DIT=T 4 Activation occurs with 5' deiodination of the outer ring of T 4

Variation of levels in Binding Proteins Free T3 and free T4 remain stable, but Total T3 and T4 may vary  Binding Proteins  Bound T3 and T4  Binding Proteins  Bound T3 and T4 Clinical conditions that effect the concentrations of the Thyroid Binding Proteins also effect the Total T3 and Total T4 hormones  But the Total T3 and T4 are not the physiologically active forms

Factors That Influence Thyroxine- Binding Globulin (Androgens) L-asparaginase Nicotinic acid Anabolic steroids

Effects of Thyroid Hormones on Specific Bodily Mechanisms Basal metabolic rate Body weight Cardiovascular system  Blood flow  Cardiac output  Heart rate  Strength of heart muscle Respiration Gastrointestinal motility Central nervous system Function of the muscles Sleep Endocrine glands Sexual function

Regulation of Thyroid Hormone Secretion

Regulation of Thyroid Hormones: Hypothalamic-Pituitary- Thyroid Axis Negative Feedback Mechanism IodineThyroid Hypertrophy Increased secretion (Thyrotropin- releasing hormone) Anterior pituitary Hypothalamus (? Increased temperature) Thyroid stimulating hormone

TSH ( Thyroid Stimulating Hormone ) Glycoprotein hormone Composed of Alpha and Beta subunits Same subunits as LH, FSH and HCG 2 fold increase or decrease in T4 results in a 100 fold increase or decrease in TSH

Biological pitfalls in thyroid test interpretation Anomalous binding of T4 or T3 to serum proteins  Genetic  Drug induced  Disease induced  Pregnancy Disrupted set point of the hypothalamic-pituitary-thyroid axis  Nonthyroid illness  Drugs  Thyroid hormone resistance  Acute psychiatric illness

Thyroid Dysfunction TSH HighNormal Low Free T4 LowNormal Hypothyroidism Subclinical Hypothyroidism Normal Free T4 High Subclinical Hyperthyroidism Hyperthyroidism Joshi S. Journal of The Association of Physicians of India; 2011:14-20.

Diseases of the Thyroid

Definitions Goiter  Enlargement of the thyroid gland Hypothyroid  Inadequate thyroid hormone production Thyroiditis  Inflammation of the thyroid gland Thyrotoxicosis  State resulting from excess production/exposure to thyroid hormone Hyperthyroidism  Thyrotoxicosis caused by a hyperfunctioning thyroid gland  Excludes thyroiditis or excessive exogenous thyroid hormone

Thyroid hypo- and hyperfunction Hypothyroidism Results from decreased production of thyroid hormones Increased TSH Decreased T4/T3 + Goitre Hyperthyroidism Excessive secretion of T3 & T4 Increased T3, T4 Decreased TSH Thyroid Scan (Increased RAI Uptake) + Goitre

Autoimmune Thyroid Disease TSH-R Ab stim (TSI) Graves’ Disease (Hyperthyroid) Thyroid peroxidase Ab Thyroglobulin Ab TSH-R Ab block Hashimoto’s (Hypothyroid) Thyroid Autoantibodies

Prevalence Of Thyroid Autoantibodies GROUPTSHRAb (%) TgAb (%) TPOAb (%) General population ~ Graves ’ disease Autoimmune thyroiditis

Thyrotoxicosis Increased production and/or secretion of thyroid hormones Decreased TSH, Increased T4/T3

Causes Graves’ disease  MC (60-90%)  Autoimmune  Stimulation of thyroid by IgG antireceptor antibody –Activates the TSH receptor –Results in autonomous thyroid hormone secretion Toxic Adenoma Toxic Multinodular Goiter Iodine-induced (Jod basedow) Subacute Thyroiditis (Inflammation of thyroid gland) Ectopic thyroid tissue (struma ovarii, functioning metastatic thyroid tissue) Trophoblastic tumor Factitious Hyperthyroidism Increased TSH secretion

 Primary hyperthyroidism –Graves’ disease –Toxic multinodular goitermultinodular goiter –Toxic adenoma –Activating mutation of the TSH receptor –Somatic: Toxic adenoma –Germ line: Familial or sporadic non-autoimmune hyperthyroidism (rare) –Activating mutation of Gs α (McCune–Albright syndrome) –Rare –Functioning follicular thyroid carcinoma metastases –Struma ovarii –Drugs: iodine excess (Jod–Basedow phenomenon)

 Thyrotoxicosis without hyperthyroidism –Subacute thyroiditis, early stage –Silent thyroiditis –Other causes of thyroid destruction: amiodarone, radiation, infarction of adenomaamiodarone –Surreptitious ingestion of excess thyroid hormone (thyrotoxicosis factitia) or thyroid tissue

Nervousness/Tremor Mental Disturbances/ Irritability Difficulty Sleeping Bulging Eyes/Unblinking Stare/ Vision Changes Enlarged Thyroid (Goiter) Menstrual Irregularities/ Light Period Frequent Bowel Movements Warm, Moist Palms First-Trimester Miscarriage/ Excessive Vomiting in Pregnancy Neck Pain Persistent Dry or Sore Throat Difficulty Swallowing Palpitations/ Tachycardia Impaired Fertility Weight Loss Heat Intolerance Increased Sweating Signs and Symptoms of Hyperthyroidism Sudden Paralysis

Disorders that can mimic features of thyrotoxicosis  Panic attacks Panic attacks  Mania  Pheochromocytoma Pheochromocytoma  Weight loss due to cancer

Thyroid Scan Radioisotopes of Iodine Tc 99m pertechnetate Uses  Differential diagnosis of thyrotoxicosis  Evaluation of solitary thyroid nodules  Follow-up of thyroid cancer  Evaluation of substernal mass  To rule out Ectopic thyroid tissue

Thyroid Scan Increased radioactive iodine uptake Graves’ Toxic Multinodular Goitre Toxic adenoma TSH producing Pituitary tumour Reduced radioactive iodine uptake Subacute Thyroiditis  de Quervain’s  Silent/Postpartum  Radiation Struma ovarii Metastatic follicular Thyroid carcinoma Factitious

RAIU Images: Graves’ Disease and Toxic Autonomous Nodule Graves disease : Diffuse increase of RAIUToxic autonomous nodule : Increases RAIU corresponding to right thyroid nodule

RAIU Images: Toxic Goiter and Subacute Thyroiditis Toxic multinodular goiter : Multiple patchy areas of increased RAIU Subacute thyroiditis : Suppressed RAIU in the neck. Salivary gland uptake seen

Treatment Antithyroid drugs  Carbimazole  Methimazole  Propylthioracil (PTU) Beta Adrenergic Blockers  Inderal (Propranolol) Radioactive Iodine Therapy Surgery Other drugs  Stable Iodine - Lugol’s Solution, SSKI  Lithium  Dexamethasone

Ultrasonography of the Thyroid Ultrasonography provides accurate information on the size, shape, and texture of the thyroid gland It is the most valuable technique to evaluate the anatomy of the thyroid gland Mostly used for detecting nodular thyroid disease The thyroid gland is slightly more echo-dense than the adjacent structures because of its iodine content

Thyroid USG Uses  Detection of nodules and cysts  Monitor nodule size  Can be used for guided FNAC  Evaluation of malignancy, cervical lymph nodes  Thyroid agenesis Ultrasonography of the thyroid where radionuclide scanning is contraindicated  Pregnancy  Breast-feeding  Following recent iodine exposure

Interpretation of Thyroid function tests

↓ TSH Thyrotoxicosis Subclinical thyrotoxicosis 1 st trimester of pregnancy Secondary hypothyroidism ↑T4 & T3 Normal T4 & T3 Normal FT4 ↓ T4/FT4

↓ TSH, Normal FT4 Subclinical Thyrotoxicosis T 3 toxicosis

Summary

TSH Low High FT4 FT4 & FT3 Low 1° Hypothyroid Low Central Hypothyroidism MRI, etc. High Thyrotoxicosis High 2° thyrotoxicosis Resistance FT3, SHBG MRI RAIU

Intricacies in thyroid Management Thyroid in pregnancy Congenital hypothyroidism Thyroid disease in children Thyroid disease in cardiac patients Thyroid emergencies Goitre Malignancy

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