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Knowledge is essential Applied, it is Wisdom Wisdom is Happiness www.drsarma.in 1 2 Clinical Exam. of Thyroid • Have patient seated on a stool / chair • Inspect neck – also while drinking water • Examine with neck in relaxed position • Palpate from behind the patient • Remember the rule of finger tips • Use the tips of fingers for palpation • Palpate firmly down to trachea • Pemberton’s sign for RSG 3 Where to look for Thyroid ? 4 Clinical Anatomy of Thyroid 5 Clinical Exam of Thyroid 6 Clinical Exam of Thyroid 7 Thyromegaly 8 9 Thyroid Regulation HYPOTHALAMUS - TRH ANT. PITUITARY - TSH TSH -R THYROID T4 and T3 PLASMA T4 + FT4 PLASMA T3 + FT3 TISSUES FT4 to FT3, rT3 10 In the Thyroid Gland There the following 5 steps in the hormonogenesis 1. Trapping of inorganic Iodine from dietary Iodides 2. Activation of Iodine to high valance I2 3. Incorporation of I2 into Tyrosine of Thyroid Globulin 4. Coupling of formed MIT and DIT to form T4 & T3 5. Proteolysis of Thyroglobulin to release T4 & T3 11 Metabolism of Thyroid Hormones Thyroid Gland 100 nm Thyroxine FT4 < 5 nm Reverse T3 (rT3) 45 nm 35 nm 5 nm Triiodothyronine (FT3) 20 nm Tertrac etc., 12 What happens in Fluorosis Normal catabolism -Thyroxine FT4 FT3 rT3 rT3 will be LOW rT3 ÷ T3 ratio will be LOW Normal deiodination of T4 Abnormal catabolism -Thyroxine FT4 FT3 rT3 rT3 will be HIGH rT3 ÷ T3 ratio will be HIGH Fluoride affects the normal deiodination of T4 13 The Thyronines Mono Iodo Tyrosine – MIT Di Iodo Tyrosine – DIT Tri Iodo Thyronine – T3 – half life 6 hours Tetra Iodo Thyronine – T4 half life 7 days Reverse T3 - metabolically inactive T4 is 99.9% protein bound to TBG, TPA, TA T3 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 14 The Thyroxines Tri Iodo Thyronine – T3 - 10% is from thyroid gland - 90% derived from conversion of T4 to T3 Tetra Iodo Thyronine – T4 - Is exclusively from thyroid gland From the thyroid gland - 80% of hormone secreted is T4 - 20% of hormone secreted is T3 15 16 Thyroid Function Tests 1. TSH 2. Free T4 3. Free T3 4. Anti-Thyroid Antibodies 5. Nuclear Scintigraphy 6. FNAC of nodule 17 What tests should I order ? As per the Guidelines of the AACE and ATA, ITS 1. TSH alone if Hypothyroidism is suspected 2. TSH and Free T4 only if Hyperthyroidism is suspected or for routine evaluation 3. Free T3 if T3 toxicosis is suspected 4. For follow-up of treatment only TSH 5. Don’t order for Total T4 or Total T3 6. Never order RIU in pregnancy or lactation 18 Which Lab to choose ? 1. Depends on the method of estimation of hormones 2. Equilibrium Dialysis is the gold Standard for TSH 3. Radio-immuno assay - 3rd or 4th gen. RIA is the best 4. Reliability of ELISA is not adequate 5. Chemiluminescence immuno assay - CIA is the gold standard for FT4 but expensive and less widely available Choose a lab which offers 3rd or 4th generation RIA method 19 How to interpret results ? 20 The Nine Square Game To evaluate our Thyroid patient As per the AACE and ITS Guidelines 21 FREE THYROXINE or FT4 BASIC THYROID EVALUATION LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 22 FREE THYROXINE or FT4 BASIC THYROID EVALUATION EUTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 23 FREE THYROXINE or FT4 BASIC THYROID EVALUATION PRIMARY HYPOTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 24 FREE THYROXINE or FT4 BASIC THYROID EVALUATION PRIMARY HYPERTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 25 FREE THYROXINE or FT4 BASIC THYROID EVALUATION SECONDARY HYPOTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 26 FREE THYROXINE or FT4 BASIC THYROID EVALUATION SECONDARY HYPERTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 27 FREE THYROXINE or FT4 BASIC THYROID EVALUATION SUB-CLINICAL HYPERTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 28 FREE THYROXINE or FT4 BASIC THYROID EVALUATION SUB-CLINICAL HYPOTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 29 FREE THYROXINE or FT4 BASIC THYROID EVALUATION NON THYROID ILLNESS or NTI LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 30 FREE THYROXINE or FT4 BASIC THYROID EVALUATION NTI or Pt. on ELTROXIN LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 31 FREE THYROXINE or FT4 BASIC THYROID EVALUATION PRIMARY NTI or Pt. SECONDARY HYPERTHYROID on ELTROXIN HYPERTHYROID SUB-CLINICAL EUTHYROID HYPERTHYROID SUB-CLINICAL HYPOTHYROID SECONDARY NON THYROID PRIMARY HYPOTHYROID ILLNESS - NTI HYPOTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 32 FREE THYROXINE or FT4 BASIC THYROID EVALUATION EUTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 33 FREE THYROXINE or FT4 BASIC THYROID EVALUATION PRIMARY HYPOTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 34 FREE THYROXINE or FT4 BASIC THYROID EVALUATION PRIMARY HYPERTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 35 FREE THYROXINE or FT4 BASIC THYROID EVALUATION SECONDARY HYPOTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 36 FREE THYROXINE or FT4 BASIC THYROID EVALUATION SECONDARY HYPERTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 37 FREE THYROXINE or FT4 BASIC THYROID EVALUATION SUB-CLINICAL HYPERTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 38 FREE THYROXINE or FT4 BASIC THYROID EVALUATION SUB-CLINICAL HYPOTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 39 FREE THYROXINE or FT4 BASIC THYROID EVALUATION NON THYROID ILLNESS or NTI LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 40 FREE THYROXINE or FT4 BASIC THYROID EVALUATION NTI or Pt. on ELTROXIN LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 41 FREE THYROXINE or FT4 BASIC THYROID EVALUATION PRIMARY NTI or Pt. SECONDARY HYPERTHYROID on ELTROXIN HYPERTHYROID SUB-CLINICAL EUTHYROID HYPERTHYROID SUB-CLINICAL HYPOTHYROID SECONDARY NON THYROID PRIMARY HYPOTHYROID ILLNESS - NTI HYPOTHYROID LOW NORMAL HIGH THYROID STIMULATING HORMONE - TSH 42 THYROID HORMONES TEST REFERENCE RANGE TSH Normal Range 0.3 - 4.0 mU/L Free T4 Normal Range 0.7-2.1 ng/dL TSH upper limit will soon be revised to 2.5 mU/L 43 T.F.T. in Progressive Hypothyroidism TSH Mild Moderate Severe Normal Range Free T4 Free T3 44 Nucleotide Scintigraphy • I 123 and TC 99m Radio Nucleotide Scintigraphy • This test is not at all required in hypothyroidism • This is only to confirm a hyper functioning thyroid or • To assess whether a nodule is ‘hot’ or ‘cold’ • Never order for this test for hypothyroidism • Similar is the case with FNAC – in hypothyroid goiter • If TSH is high and FT4 is low there is no role for FNAC 45 Thyroid Antibodies • • • • • Anti Microsomal (TM ) Antibodies Anti Thyroglobulin (TG) Antibodies Anti Thyroxine Per Oxidase (TPO) Ab. Anti Thyroxine antibodies Thyroid Stimulating (TSA) Antibodies High titres TPO Ab in Hashimotos & Reidle’s thyroiditis Anti thyroxine Ab in peripheral resistance to Thyroxine TSA (TSI) in Graves’ Hyperthyroidism 46 HYPOTHYROIDISM Current Trends in Dx. and Rx. 47 General Considerations 48 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 In clear cut cases - typical signs and symptoms Low free T4 and High TSH Easily treatable with oral Levo-thyroxine 49 Classification 50 Classification of Hypothyroidism A. Primary 1. Enlarged Thyroid Primary contd.. 3. Post Ablative - Permanent - Hashimoto’s (65%) - Transient - Iodine Deficiency (25%) - Sub-clinical - Drug-induced (Lithium) - Dysharmonogenesis 4. Congenital 2. Normal Thyroid - Spontaneous Atrophic B. Secondary / Central Pituitary/ hypothalamic 51 IDD 52 Clinical considerations 53 Disease Burden 1. 2. 3. 4. 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 FT4 routinely in all pregnant women at the beginning of each trimester All persons aged above 60 years – Order for TSH 54 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 55 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 56 What the mind knows the eyes see !! Order for TSH alone as a screen • Psychiatric patients Other Autoimmune • Elderly women / men Rx. Grave’s Ophthalmopathy • Hypercholesterolemia Family H/o thyroid disease • Lithium, Amiodarone Neck irradiation therapy • Postpartum women Previous Rx for thyrotoxicosis disease Autoimmune Thyroiditis 57 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 58 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 59 Thyroid Failure - Organ Systems Reproductive • • • • Arrest of pubertal development Reduced growth velocity Menorrhagia, Amenorrhea Anovulation, Infertility Hepatic • Increased LDL / TC • Elevated LDL + triglycerides 60 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 61 Clinical Photographs 62 Congenital Hypothyroidism 63 www.drsarma.in 64 Endemic Goiter 65 Urine Iodine Conc. < 50 µg/L www.drsarma.in 66 www.drsarma.in 67 Myxedema 68 Macroglossia 69 Xanthomata Tuberous Xanthoma Xanthelasma 70 Solid Oedema Xanthomata 71 Myxoedema with Carotineamia 72 Recovery after L-Thyroxine 73 Normal Pituitary Fossa Pituitary Tumor – Secondary Hypo 74 26.7.98 Clearing of Pericardial Effusion with Rx. 75 14.9.99 Reappearance of Pericardial Effusion after treatment is discontinued 76 Co-morbidity • Hypercholosterolemia • Depression • Infertility – Menstrual Irregularities • Diabetes mellitus 77 Hypothyroidism and Hypercholesterolemia • 14% of patients with elevated cholesterol have hypothyroidism • Approximately 90% of patients with overt hypothyroidism have increased cholesterol and / or triglycerides 78 Lipids in Patient with Hypothyroidism Hypercholesterolemia (>200 mg/dL) Hypertriglyceridemia (>150 mg/dL) Hypercholesterolemia and mild Hyper TG N= 268 Normal Lipids 79 LDL-C Levels Increase With Increasing Hypothyroidism Grade 246 250 191 200 168 133 137 C 1 2 Basal TSH (mU/L) 1.1 3.0 8.6 LDL-C (mg/dL 144 150 100 50 0 Hypothyroidism Grade 3 4* 22.7 44.4 5† 63.7 80 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.” 81 Hypothyroidism and Depression • Depressive symptoms are common in hypothyroidism • Many hypothyroid patients fulfill DSM-IV criteria for a depressive disorder • Depressed patients may be more likely than normal individuals to be hypothyroid • All depressed patients should be evaluated for thyroid dysfunction 82 Hypothyroidism and Depression Depression Sleep decrease Suicidal ideation Weight change Delusions Hypothyroidism Constipation Decreased Conc. Decreased libido Depressed mood Diminished interest Weight increase Fatigue Bradycardia Cardiac and lipid Abnormalities Cold intolerance Hair and skin changes Delayed reflexes Goiter 83 Thyroxine in Depression 1. Thyroxine therapy is recommended for patients with depression who have persistently elevated serum TSH 2. Antidepressants may be less effective if thyroid function not normalized 84 Hypothyroidism and Infertility 1. Hypothyroidism associated with infertility, miscarriage, stillbirth 2. Infertility : Evaluate thyroid function, treat hypothyroidism 3. Equivocal results: Begin therapy; discontinue if no pregnancy for several months. 85 Suspect Hypothyroidism 1. 2. 3. 4. 5. 6. 7. 8. 9. Amenorrhea Oligomenorrhea Menorrhogia Galactorrhea Premature ovarian failure Infertility Decreased libido Precocious / delayed puberty Chronic urticaria 86 Hypothyroidism and Diabetes 1. Approximately 10% of patients with type 1 diabetes mellitus develop sub-clinical hypothyroidism 2. In diabetic patients - examine for goitre 3. TSH measurement at regular intervals 87 88 Algorithm for Hypothyroidism Measure TSH Elevated TSH Normal TSH Measure FT4 Considering Pituitary Normal Low Sub-clinical hypo No Yes Primary hypothyroid No tests TPO - Low TPO + TPO - T4 repl Annual FU TPO + Hashimoto Others Evaluate Pituitary Sick Euthyroid Drugs effect Measure FT4 Normal No tests 89 Hormone replacement 90 Many Causes, One Treatment • Goal : Normalize TSH level regardless of cause of hypothyroidism • Treatment : Once daily dosing with Levothyroxine sodium (1.6µg/kg/day) this comes to 100 mcg per day • Monitor TSH levels at 6 to 8 weeks, after initiation of therapy or dosage change 91 Many Causes, One Treatment • Treatment of choice is levothyroxin • Branded thyroxine recommended • Brand consistency recommended • No divided doses - illogical • Not recommended for use : Desiccated thyroid extract Combination of thyroid hormones T3 replacement except in Myxedema coma 92 Dosage Adjustments • Age (in elderly start with half dose) • Severity and duration of hypothyroidism (↑ dose) • Weight (0.5µg/kg/day ↑ upto 3.0µg/kg/day) • Malabsorption (requires ↑ dose) • Concomitant drug therapy (only on empty stomach) • Pregnancy ( 25% ↑ in dose), safe in lactating mother • Presence of cardiac disease (start alt. day Rx) 93 Start Low and Go Slow • 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 94 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 95 Drug Interactions • Malabsorption Syndromes • Reduced Absorption Cholestyramine resin Sucralfate Ferrous sulfate Soybean formula Aluminum hydroxide Colestipol hydrochloride Drugs that affect metabolism Rifampin Carbamazepine Phenytoin Phenobarbitol Amiodarone 96 Inappropriate Dosage Over-replacement risks • Reduced bone density / osteoporosis • Tachycardia, arrhythmia. atrial fibrillation • In elderly or patients with heart disease, angina, arrhythmia, or myocardial infarction2 Under-replacement risks • Continued hypothyroid state • Long-term end-organ effects of hypothyroidism • Increased risk of hyperlipidemia 97 Diet in Iodine deficiency • Iodized salt • Selenium supplementation • Avoid Cassava • Avoid cabbage (goitrogens) • Avoid formula milk • Fish, meat, milk & eggs 98 Special situations 99 Sub-clinical Hypothyroidism • Chronic autoimmune thyroiditis • Graves’ hyperthyroidism with radioiodine, surgery • Inadequate replacement therapy for hypothyroidism • Lithium carbonate therapy (for depressive illness) 100 Post-Partum Thyroiditis (PPT) Definition • Occurrence of hyperthyroidism and / or hypothyroidism during the postpartum period in women who were euthryroid during pregnancy At Highest Risk • Patients with type 1 diabetes, previous history of PPT or other autoimmune disease such as Hashimoto’s disease and Graves’ disease 101 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 ICU transfer, T3 100 µg IV sixth hourly, 500 µg of T4 , antibiotics, ventilation, hydrocortisone IV, passive warming, careful volume management 102 Sick Euthyroid Syndrome Total T3 reduced FT3 reduced Total T4 reduced FT4 Normal TSH Normal Clinically Euthyroid 103 The Commandments 104 The Commandments Highly suspect hypothyroidism All obese patients TSH a must Growth and pubertal delay For all pregnant -test TSH, FT4 Unexplained depression Postmenopausal 15% Hypothy TSH is the test in Hypothy. Start low and go slow TSH, FT4 to confirm Dx. Use Levothyroxine only Nine square magic Always on empty stomach Test cord blood for TSH Thyroxine - avoid empirical use 105 Question # 1 Should a serum TSH be a routine component of the periodic health exam in women? 106 Question # 2 What is the appropriate biochemical end point for adequate thyroid hormone replacement in hypothyroid patient? 107 Question # 3 Are there risks associated with over replacement? 108 Question # 4 Are all L-thyroxine products therapeutically equivalent? Should combination T4/T3 preparations be used? 109 Question # 5 What is the impact of pregnancy on Thyroxine replacement therapy in a hypothyroid women? 110 Question # 6 What is the impact of breast feeding on the management of maternal hypo and hyperthyroidism? 111 Question # 7 Should women with sub-clinical hypothyroidism be treated with L-Thyroxine? 112 Question # 8 Should euthyroid patient with benign thyroid nodules be placed on thyroid hormone suppression therapy? 113