Thyrotoxicosis

21-10-2014

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 (T4)

Triiodothyronine (T3)

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

T4

Primary secretory product of the thyroid gland, which is the only source of T4

The thyroid secretes approximately 70-90 g of T4 per day

T4 concentrations are 50 times greater than T3

T3

Biologically active hormone responsible for majority of thyroid hormone effects

Circulating T3 is derived from 2 processes

– About 80% comes from deiodination of T4 in liver, kidney & other peripheral

tissues– About 20% comes from direct thyroid secretion

Physiology and Biochemistry

Thyroid Hormones: T4 and T3

Synthesized by attaching iodine to the amino acid tyrosine

Thyroxine (T4) contains 4 iodine atoms, while triiodothyronine (T3) contains 3 iodine atoms

Thyroxine (T4) and triiodothyronine (T3) are secreted by follicular epithelial cells of the thyroid

Chemistry of T3 and T4 Formation

Tyrosine

Monoiodotyrosine

Diiodotyrosine

3,5,3'-Triiodothyronine

Thyroxine

Iodinase

HO

I

I I

I

CH2CH

NH2

COOH5’

3’

5

3O

Thyroxine (T4)3,5,3’,5’-Tetraiodothyronine

HO

I I

I

CH2CH

NH2

COOHO

Triiodothyronine (T3)3,5,3’-Triiodothyronine

Synthesis and Secretion of Thyroid Hormones

Capillary

Thyroid follicle cellThyroglobulin is synthesizedand discharged into the follicle lumen

1

Rough ER

Golgi apparatus

Colloid

Iodine enters folliclelumen where it is attachedto tyrosine in colloid.forming DIT and MIT

3

Trapping(active uptake)of iodide (I-)

Oxidation Active form of iodine

Iodide (I-)

2a

2b

DIT (T2) MIT (T1)

Thyroglobulincolloid

Iodinated tyrosines are linked together to form T3 and T4

4

Lysosomal enzymes cleave T4 and T3 from thyroglobulin colloid and hormones diffuse from follicle cell into bloodstream

T3

T4 T3

T4

To peripheral tissues

T3

T4

6

Thyroglobulin colloid is endocytosed and combined with a lysosome

5

T3 T4

Lysosome

Uptake

Organificatio

n

Coupling

Storage

Release

Production of T4 and T3

T4 – Iodide = rT3 ( Reverse T3 ) … Inactive form

T4 – Iodide = T3 ( 80% of T3 )

MIT + DIT = T3

DIT + DIT = T4

Activation occurs with 5' deiodination of the outer ring of T4

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-asparaginaseNicotinic 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

HypertrophyIncreasedsecretion

(Thyrotropin-releasing hormone)

Anterior pituitary

Hypothalamus(? Increased temperature)

Thyroidstimulatinghormone

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

High Normal Low

Free T4

Low Normal

HypothyroidismSubclinical

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

GROUP TSHRAb (%)

TgAb (%)

TPOAb (%)

General population

~0 5-20 8-27

Graves’ disease

80-95 50-70 50-80

Autoimmune thyroiditis

10-20 80-90 90-100

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 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 (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 adenoma – 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 Mania Pheochromocytoma Weight loss due to cancer

Thyroid Scan

Radioisotopes of Iodine Tc99m 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 RAIU Toxic 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

1st trimester of pregnancy

Secondary hypothyroidism

↑T4 & T3

Normal T4 & T3

Normal FT4

↓ T4/FT4

↓ TSH, Normal FT4

Subclinical Thyrotoxicosis

T3 toxicosis

Summary

TSH

LowHigh

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

Thank You