Thyroid physiology & Hypothyroidism

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A CASE PROFILE OF THYROID DISEASE 1 Dr.Mohammed Siraj Dr.Parvez Khan Dr.Mohammed Sadiq Azam Dr.Praneetha Gayathri

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THYROID GLAND HORMONOGENESIS 2

Thyroid Regulation: 

Thyroid Regulation 3 PLASMA T4 + FT4 HYPOTHALAMUS - TRH ANT. PITUITARY - TSH THYROID T4 and T3 PLASMA T3 + FT3 TISSUES FT4 to FT3, rT3 TSH -R

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www.drsarma.in 4

In the Thyroid Gland: 

In the Thyroid Gland There the following 5 steps in the hormonogenesis Trapping of inorganic Iodine from dietary Iodides Activation of Iodine to high valance I 2 Incorporation of I 2 into Tyrosine of Thyroid Globulin Coupling of formed MIT and DIT to form T 4 & T 3 Proteolysis of Thyroglobulin to release T 4 & T 3 5

The Thyronines: 

The Thyronines Mono Iodo Tyrosine – MIT Di Iodo Tyrosine – DIT Tri Iodo Thyronine – T 3 – half life 6 hours Tetra Iodo Thyronine – T 4 half life 7 days Reverse T 3 - metabolically inactive T 4 is 99.9% protein bound to TBG, TPA, TA T 3 is 99.5% protein bound to TBG, TPA, TA Bound hormones are inactive – should not be measured Only Free T4 and Free T3 are metabolically active 6

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7 The Thyroxines Tri Iodo Thyronine – T 3 - 10% is from thyroid gland - 90% derived from conversion of T 4 to T 3 Tetra Iodo Thyronine – T 4 - Is exclusively from thyroid gland From the thyroid gland - 80% of hormone secreted is T 4 - 20% of hormone secreted is T 3

Throid hormones in peripheral tissues: 

Throid hormones in peripheral tissues Plasma transport by thyroxine binding globulin TBG -75 -80%bound Transthyretin 10-15% Albumin 5-10% 8

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9 Thyroid Function Tests

Thyroid Function Tests: 

Thyroid Function Tests TSH Free T4 Free T3 Anti-Thyroid Antibodies Nuclear Scintigraphy FNAC of nodule 10

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11 LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH LOW NORMAL HIGH FREE THYROXINE or FT4 BASIC THYROID EVALUATION

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12 LOW NORMAL HIGH FREE THYROXINE or FT4 EUTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH BASIC THYROID EVALUATION

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13 LOW NORMAL HIGH FREE THYROXINE or FT4 PRIMARY HYPOTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH BASIC THYROID EVALUATION

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14 LOW NORMAL HIGH FREE THYROXINE or FT4 PRIMARY HYPERTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH BASIC THYROID EVALUATION

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15 LOW NORMAL HIGH FREE THYROXINE or FT4 SECONDARY HYPOTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH BASIC THYROID EVALUATION

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16 LOW NORMAL HIGH FREE THYROXINE or FT4 SECONDARY HYPERTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH BASIC THYROID EVALUATION

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17 LOW NORMAL HIGH FREE THYROXINE or FT4 SUB-CLINICAL HYPERTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH BASIC THYROID EVALUATION

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18 LOW NORMAL HIGH FREE THYROXINE or FT4 SUB-CLINICAL HYPOTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH BASIC THYROID EVALUATION

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19 LOW NORMAL HIGH FREE THYROXINE or FT4 NON THYROID ILLNESS or NTI LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH BASIC THYROID EVALUATION

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20 LOW NORMAL HIGH FREE THYROXINE or FT4 NTI or Pt. on ELTROXIN LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH BASIC THYROID EVALUATION

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21 LOW NORMAL HIGH FREE THYROXINE or FT4 EUTHYROID SUB-CLINICAL HYPERTHYROID NON THYROID ILLNESS - NTI NTI or Pt. on ELTROXIN SUB-CLINICAL HYPOTHYROID SECONDARY HYPERTHYROID SECONDARY HYPOTHYROID PRIMARY HYPERTHYROID PRIMARY HYPOTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH BASIC THYROID EVALUATION

THYROID HORMONES: 

THYROID HORMONES TEST REFERENCE RANGE TSH Normal Range 0.3 - 4.0 mU/L Free T 4 Normal Range 0.7-2.1 ng / dL 22 TSH upper limit will soon be revised to 2.5 mU/L

Thyroid Antibodies: 

Thyroid Antibodies Anti Microsomal (TM ) Antibodies Anti Thyroglobulin (TG) Antibodies Anti Thyroxine Per Oxidase (TPO) Ab. Anti Thyroxine antibodies Thyroid Stimulating (TSA) Antibodies 23 High titres TPO Ab in Hashimotos & Reidle’s thyroiditis Anti thyroxine Ab in peripheral resistance to Thyroxine TSA (TSI) in Graves’ Hyperthyroidism

hypothyroidism: 

24 hypothyroidism

Hypothyroidism: 

Hypothyroidism Epidemiology Most common endocrine disease Females > Males – 8 : 1 Presentation Often unsuspected and grossly under diagnosed 90 % of the cases are Primary Hypothyroidism Menstrual irregularities, miscarriages, growth retard. Vague pains, anaemia, lethargy, gain in weight 25

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26 Disease Burden 5% of the general population are Sub-clinically Hypothyroid 15 % of all women > 65 yrs. are hypothyroid Detecting sub-clinical hypothyroidism in pregnancy is highly essential – order for TSH and FT 4 routinely in all pregnant women at the beginning of each trimester All persons aged above 60 years – Order for TSH

Causes of Hypothyroidism: 

Causes of Hypothyroidism Primary hypothyroidism with Goitre Aquired Hashimotos thyroiditis Iodine deficiency Drugs blocking synthesis or release of T4 Goitrogens Cytokines Thyroid infiltration Congenital Iodide transport or utilization defect Iodotyrosine dehalogenase deficiency TPO deficiencyn \ nd dysfunction Defects in thyroglobulin synthesis 27

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ATROPHIC HYPOTHYROIDISM Acquired HASHIMOTOS DISEASE Postablative due to 131 Iodine surgery Congenital Thyroid agenesis or dysplasia TSH receptor defects Thyroidal Gs protein abnormalities Idiopathic TSH unresponsiveness TRANSIENT HYPOTHYROIDISM following subacute painless or postpartum thyroiditis 28

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CONSUMPTIVE HYPOTHYROIDISM hemangiomas ,hemangioendoheliomas CENTRAL HYPOTHYROIDISM Acquired pituatary origin hypothalamic disorders dopamine & or severe stress Congenital TSH deficiency/structural abnormality TSH receptor defect RESISTANCE TO THYROID HARMONE generalised or pituatary dominant 29

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30 Multi system effects - Hypothyroidism General Lethargy, Somnalence Weight gain, Goitre Cold Intolerence Cardiovascular Bradycardia, Angina CHF, Pericardial Effusion HyperlipIdemia, Xanthelsma Haematological Iron def. Anaemia, Normo cytic /chromic Anaemia Reproductive system Infertility, Menorrhagia Impotence, Inc. Prolactin Neuromuscular Aches and pains Muscle stiffness Carpel tunnel syndrome Deafness, Hoarseness Cerebellar ataxia Delayed DTR, Myotonia Depression, Psychosis Gastro-intestinal Constipation, Ileus, Ascites Dermatological Dry flaky skin and hair Myxoedema, Malar flushes Vitiligo, Carotenimia, Alopecia

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31 Clinical Signs of Hypothyroidism Coarse Hair; Dry cool and pale skin Goitre (not in all cases), Hoarseness of voice Non-pitting oedema (myxoedema) Puffiness of eyes and face Delayed relaxation of DTR Slow hoarse speech and slow movements Thinning of lateral 1/3 of eye brows Bradycardia, pericardial effusion

Thyroid Failure - Organ Systems: 

Thyroid Failure - Organ Systems Cardiovascular Decreased ventricular contractility Increased diastolic blood pressure Decreased heart rate Central Nervous Decreased concentration General lack of interest Depression Gastro-instestinal Decreased GI motility Constipation 32

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33 Thyroid Failure - Organ Systems Musculoskeletal Muscle stiffness, cramps, pain, weakness, myalgia Slow muscle-stretch reflexes, muscle enlargement, atrophy Renal Fluid retention and oedema Decreased glomerular filtration

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Reproductive Arrest of pubertal development Reduced growth velocity Menorrhagia, Amenorrhea Anovulation, Infertility Hepatic Increased LDL / TC Elevated LDL + triglycerides 34 Thyroid Failure - Organ Systems

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35 Thyroid Failure - Organ Systems Skin and Hair Thickening and dryness of skin Dry, coarse hair, Alopecia Loss of scalp hair and / or lateral eyebrow hair

HORMONAL EFFECTS ON THYROID FUNCTION: 

HORMONAL EFFECTS ON THYROID FUNCTION Glucocorticoid Excess- decreased TSH,TBG,TTR Decreased serum T3/T4 and increase Rt3 production Decreased T4 and increased T3 in graves disease Deficiency-Increased TSH Estrogen -Increased TBG sialylation and half life in serum Increased TSH in post menopausal women Increased T4 requirement in hypothyroid patients Androgen -Decreased TBG Decreased T4 requirment in hypothyroid patient Growthhormone -Decreased D3 activity 36

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www.drsarma.in 37

Cassava Plant: 

Cassava Plant 38 Topiaco - Sago (Javva Arisi)

Tapioca Root - Sago: 

Tapioca Root - Sago 39 Tapioca (tubers) Dried Tapioca - Sago

Myxedema: 

Myxedema 40

Myxedema: 

Myxedema 41

Co-morbidity: 

Co-morbidity Hypercholosterolemia Depression Infertility – Menstrual Irregularities Diabetes mellitus 42

Hypothyroidism and Hypercholesterolemia: 

Hypothyroidism and Hypercholesterolemia 14% of patients with elevated cholesterol have hypothyroidism Approximately 90% of patients with overt hypothyroidism have increased cholesterol and / or triglycerides 43

Lipids in Patient with Hypothyroidism: 

Lipids in Patient with Hypothyroidism Hypercholesterolemia (>200 mg/dL) Hypertriglyceridemia (>150 mg/dL) Hypercholesterolemia and mild Hyper TG Normal Lipids 44 N= 268

Effect of Thyroxine therapy on Hypercholesterolemia in Patients with mild Thyroid failure: 

Effect of Thyroxine therapy on Hypercholesterolemia in Patients with mild Thyroid failure “The decrease in total cholesterol achieved with [Thyroxine replacement] substitution therapy in patients with subclinical hypothyroidism [mild thyroid failure] may be considered as an important decrease in cardiovascular risk favouring treatment.” 45

Suspect Hypothyroidism: 

Suspect Hypothyroidism Amenorrhea Oligomenorrhea Menorrhogia Galactorrhea Premature ovarian failure Infertility Decreased libido Precocious / delayed puberty Chronic urticaria 46

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47 Algorithm for Hypothyroidism

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48 Algorithm for Hypothyroidism Measure TSH Elevated TSH Normal TSH Measure FT4 Considering Pituitary Normal Low No Yes Sub-clinical hypo TPO + TPO - T4 repl Annual FU Primary hypothyroid TPO + TPO - No tests Measure FT4 Low Normal No tests Evaluate Pituitary Sick Euthyroid Drugs effect Hashimoto Others

Hormone replacement: 

Hormone replacement 49

Treatment: 

Treatment Goal : Normalize TSH level regardless of cause of hypothyroidism Treatment : Once daily dosing with Levothyroxine sodium (1.6µg/kg/day-1.8ug/kg/day) Monitor TSH levels at 6 to 8 weeks, after initiation of therapy or dosage change 50

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Treatment of choice is levothyroxin Not recommended for use : Desiccated thyroid extract Combination of thyroid hormones T 3 replacement except in Myxedema coma 51 Treatment

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Age (in elderly start with half dose) Severity and duration of hypothyroidism (↑ dose) Weight (0.5µg /kg/day ↑ upto 3.0 µg/kg/day) Malabsorption (requires ↑ dose) Concomitant drug therapy (only on empty stomach) Pregnancy ( 25% -50%↑ in dose), safe in lactating mother Presence of cardiac disease (start alt. day Rx) 52 Dosage Adjustments

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Goal : normalize TSH level – 25, 50 and 100 mcg tablets avail. Starting dose for healthy patients < 50 years at 1.0 µg/kg/day Starting dose for healthy patients > 50 years should be < 50 µg/day. Dose ↑ by 25 µg, if needed, at 6 to 8 weeks intervals. Starting dose for patients with heart disease should be 12.5 to 25 µg/day and increase by 12.5 to 25 µg/day, if needed, at 6 to 8 weeks intervals 53 Start Low and Go Slow

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54 How the patient improves Feels better in 2 – 3 weeks Reduction in weight is the first improvement Facial puffiness then starts coming down Skin changes, hair changes take long time to regress TSH starts showing decrements from the high values TSH returns to normal eventually

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Malabsorption Syndromes Reduced Absorption Cholestyramine resin Sucralfate Ferrous sulfate Soybean formula Aluminum hydroxide Colestipol hydrochloride 55 Drugs that affect metabolism Rifampin Carbamazepine Phenytoin Phenobarbitol Amiodarone Drug Interactions

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Over-replacement risks Reduced bone density / osteoporosis Tachycardia, arrhythmia. atrial fibrillation In elderly or patients with heart disease, angina, arrhythmia, or myocardial infarction 2 Under-replacement risks Continued hypothyroid state Long-term end-organ effects of hypothyroidism Increased risk of hyperlipidemia 56 Inappropriate Dosage

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57 Massive Pericardial Effusion in Hypo 20.2.98

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58 Clearing of Pericardial Effusion with Rx. 26.7.98

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59 Reappearance of Pericardial Effusion after treatment is discontinued 14.9.99

FT4 evaluation: 

FT4 evaluation CENTRAL HYPOTHROIDISM AFTER SURGERY 60

Diet in Iodine deficiency: 

Diet in Iodine deficiency Iodized salt Selenium supplementation Avoid Cassava Avoid cabbage (goitrogens) Avoid formula milk Fish, meat, milk & eggs 61

Special situations: 

Special situations 62

Myxedema Coma: 

Myxedema Coma Precipitating factors : Infection, trauma, stroke, cardiovascular, hemorrhage drug overdose, diuretics Signs and Symptoms : Mental confusion, hypothermia, bradycardia , older age, ↓ Na, ↓ glucose, ↑ CO2, ↓ WBC, ↓ Hct , ↑ CPK ↓ EKG voltage, myxedema, b- carotnenemia Treatment Initial IV THYROXINE 500-800 mcg/day ,followed by daily dose of I.V thyroxine 100 mcg thereafter ,alt I.V leothyronine 25mcg b.d 63

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64 Sick Euthyroid Syndrome Total T 3 reduced FT 3 reduced Total T 4 reduced FT 4 Normal TSH Normal Clinically Euthyroid

Case-1: 

Case-1 T3 -0.04nmo/l 0.93-2.33nmol/lit T4-59.70nmol/l 60-120 nmol /lit TSH-2.52IU/ml >7.0-hypothyroid <0.2 hyperthyroid 65

Case 2: 

Case 2 T3 -1.42nmol/l T4-106.96nmol/l TSH-<0.05IU/ml 66

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67 The Commandments Highly suspect hypothyroidism Growth and pubertal delay Unexplained depression TSH is the test in Hypothy. TSH, FT 4 to confirm Dx. Nine square magic Test cord blood for TSH All obese patients TSH a must For all pregnant -test TSH, FT 4 Postmenopausal 15% Hypothy Start low and go slow Use Levothyroxine only Always on empty stomach Thyroxine - avoid empirical use

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Thank you 68