Thyrotoxicosis Dr Madhukar Mittal Medical Endocrinology 21 10

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Thyrotoxicosis Dr Madhukar Mittal Medical Endocrinology 21 -10 -2014

Thyrotoxicosis Dr Madhukar Mittal Medical Endocrinology 21 -10 -2014

Thyroid Gland : Overview Epiglottis Location Thyroid cartilage Structure Thyroid gland Isthmus Trachea In

Thyroid Gland : Overview Epiglottis Location Thyroid cartilage Structure Thyroid gland Isthmus Trachea 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 Butterfly-shaped with two lateral lobes connected by isthmus Blood supply Superior and inferior thyroid arteries

Functions of the Thyroid Gland Secretes two hormones Thyroxine (T 4) Triiodothyronine (T 3)

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: T 4 and T 3 T 4 Primary secretory product of the

Thyroid Hormones: T 4 and T 3 T 4 Primary secretory product of the thyroid gland, which is the only source of T 4 The thyroid secretes approximately 70 -90 g of T 4 per day T 4 concentrations are 50 times greater than T 3 Biologically active hormone responsible for majority of thyroid hormone effects Circulating T 3 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

Physiology and Biochemistry

Thyroid Hormones: T 4 and T 3 I I 3’ HO 5’ 3 O

Thyroid Hormones: T 4 and T 3 I I 3’ HO 5’ 3 O 5 CH 2 CH COOH I Thyroxine (T 4) 3, 5, 3’, 5’-Tetraiodothyronine I I HO Chemistry of T 3 and T 4 Formation NH 2 I Iodinase NH 2 CH 2 O Tyrosine CH COOH Monoiodotyrosine I Triiodothyronine (T 3) 3, 5, 3’-Triiodothyronine 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 Diiodotyrosine 3, 5, 3'Triiodothyronine Thyroxine

Synthesis and Secretion of Thyroid Hormones Thyroid follicle cell 1 Thyroglobulin is synthesized and

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

Production of T 4 and T 3 T 4 – Iodide= MIT + DIT

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

Variation of levels in Binding Proteins Free T 3 and free T 4 remain

Variation of levels in Binding Proteins Free T 3 and free T 4 remain stable, but Total T 3 and T 4 may vary Binding Proteins Bound T 3 and T 4 Clinical conditions that effect the concentrations of the Thyroid Binding Proteins also effect the Total T 3 and Total T 4 hormones But the Total T 3 and T 4 are not the physiologically active forms

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

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

Effects of Thyroid Hormones on Specific Bodily Mechanisms Basal metabolic rate Body weight Cardiovascular

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 Hormone Secretion

Regulation of Thyroid Hormones: Hypothalamic-Pituitary. Thyroid Axis Negative Feedback Mechanism Hypothalamus (? Increased temperature)

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

TSH ( Thyroid Stimulating Hormone ) Glycoprotein hormone Composed of Alpha and Beta subunits

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 T 4 results in a 100 fold increase or decrease in TSH

Biological pitfalls in thyroid test interpretation Anomalous binding of T 4 or T 3

Biological pitfalls in thyroid test interpretation Anomalous binding of T 4 or T 3 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 High Normal Low Free T 4 Low Normal High Hypothyroidism Subclinical

Thyroid Dysfunction TSH High Normal Low Free T 4 Low Normal High Hypothyroidism Subclinical Hyperthyroidism Joshi S. Journal of The Association of Physicians of India; 2011: 14 -20.

Diseases of the Thyroid

Diseases of the Thyroid

Definitions Goiter Hypothyroid Inflammation of the thyroid gland Thyrotoxicosis Inadequate thyroid hormone production Thyroiditis

Definitions Goiter Hypothyroid Inflammation of the thyroid gland Thyrotoxicosis Inadequate thyroid hormone production Thyroiditis Enlargement of the thyroid gland 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 Hyperthyroidism Results from decreased production of thyroid hormones Increased

Thyroid hypo- and hyperfunction Hypothyroidism Hyperthyroidism Results from decreased production of thyroid hormones Increased TSH Decreased T 4/T 3 + Goitre Excessive secretion of T 3 & T 4 Increased T 3, T 4 Decreased TSH Thyroid Scan (Increased RAI Uptake) + Goitre

Thyroid Autoantibodies Thyroid peroxidase Ab Thyroglobulin Ab TSH-R Ab block TSH-R Ab stim (TSI)

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

Prevalence Of Thyroid Autoantibodies GROUP TSHRAb (%) Tg. Ab (%) TPOAb (%) ~0 5

Prevalence Of Thyroid Autoantibodies GROUP TSHRAb (%) Tg. Ab (%) TPOAb (%) ~0 5 -20 8 -27 Graves’ disease 80 -95 50 -70 50 -80 Autoimmune thyroiditis 10 -20 80 -90 90 -100 General population

Thyrotoxicosis Increased production and/or secretion of thyroid hormones Decreased TSH, Increased T 4/T 3

Thyrotoxicosis Increased production and/or secretion of thyroid hormones Decreased TSH, Increased T 4/T 3

Causes Graves’ disease MC (60 -90%) Autoimmune Stimulation of thyroid by Ig. G antireceptor

Causes Graves’ disease MC (60 -90%) Autoimmune Stimulation of thyroid by Ig. G 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 goiter Toxic adenoma Activating mutation

Primary hyperthyroidism – – Graves’ disease Toxic multinodular goiter Toxic adenoma Activating mutation of the TSH receptor – Somatic: Toxic adenoma – Germ line: Familial or sporadic non-autoimmune hyperthyroidism (rare) – Activating mutation of Gsα (Mc. Cune–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

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

Signs and Symptoms of Hyperthyroidism Nervousness/Tremor Mental Disturbances/ Irritability Difficulty Sleeping Bulging Eyes/Unblinking Stare/

Signs and Symptoms of Hyperthyroidism 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 Sudden Paralysis

 Disorders that can mimic features of thyrotoxicosis Panic attacks Mania Pheochromocytoma Weight loss

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

Thyroid Scan Radioisotopes of Iodine Tc 99 m pertechnetate Uses Differential diagnosis of thyrotoxicosis

Thyroid Scan Radioisotopes of Iodine Tc 99 m 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 Reduced radioactive iodine uptake Graves’ Toxic Multinodular Goitre

Thyroid Scan Increased radioactive iodine uptake Reduced radioactive iodine uptake Graves’ Toxic Multinodular Goitre Toxic adenoma TSH producing Pituitary tumour 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

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

RAIU Images: Toxic Goiter and Subacute Thyroiditis Toxic multinodular goiter : Multiple patchy areas

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

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

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

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

Interpretation of Thyroid function tests

↓ TSH Thyrotoxicosis ↑T 4 & T 3 Subclinical thyrotoxicosis Normal T 4 &

↓ TSH Thyrotoxicosis ↑T 4 & T 3 Subclinical thyrotoxicosis Normal T 4 & T 3 1 st trimester of pregnancy Normal FT 4 Secondary hypothyroidism ↓ T 4/FT 4

↓ TSH, Normal FT 4 Subclinical Thyrotoxicosis T 3 toxicosis

↓ TSH, Normal FT 4 Subclinical Thyrotoxicosis T 3 toxicosis

Summary

Summary

TSH Low High FT 4 & FT 3 FT 4 High Low 1° Hypothyroid

TSH Low High FT 4 & FT 3 FT 4 High Low 1° Hypothyroid Low Central Hypothyroidism 2° thyrotoxicosis MRI, etc. • Resistance • FT 3, SHBG • MRI High Thyrotoxicosis RAIU

Intricacies in thyroid Management Thyroid in pregnancy Congenital hypothyroidism Thyroid disease in children Thyroid

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

Thank You

Thank You