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Hypothyroidism - Comprehensive Notes for MUHS PG Medicine Theory Exam

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1. DEFINITION

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2. EPIDEMIOLOGY

• Prevalence: ~2-5% in iodine-sufficient areas; higher in women and elderly
• Female:Male ratio approximately 10:1
• Hashimoto's thyroiditis is the most common cause in iodine-sufficient countries
• Iodine deficiency remains the most common cause worldwide (~2 billion people affected)

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3. CLASSIFICATION & ETIOLOGY

A. PRIMARY HYPOTHYROIDISM (>95% of cases - pathology at thyroid level)

B. SECONDARY HYPOTHYROIDISM (pituitary pathology - deficient TSH)

• Hypopituitarism: tumours, pituitary surgery/irradiation, Sheehan's syndrome, infiltrative disorders
• Isolated TSH deficiency or inactivity
• Drugs: bexarotene, mitotane

C. TERTIARY HYPOTHYROIDISM (hypothalamic - deficient TRH)

• Tumours, trauma, infiltrative disorders, Prader-Willi syndrome

D. TRANSIENT HYPOTHYROIDISM

• Silent thyroiditis including postpartum thyroiditis
• Subacute (de Quervain's) thyroiditis
• After 131I treatment or subtotal thyroidectomy for Graves' disease

IMPORTANT DRUG CAUSES TO REMEMBER FOR EXAM:

• Amiodarone - contains 37% iodine by weight; causes both hypo- and hyperthyroidism (Jod-Basedow effect for hyper-, Wolff-Chaikoff effect for hypo-)
• Lithium - inhibits thyroid hormone synthesis and release
• Checkpoint inhibitors - increasingly important in modern oncology practice

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4. PATHOGENESIS

HPT Axis

• Hypothalamus secretes TRH → stimulates pituitary to secrete TSH → stimulates thyroid to produce T3 and T4
• T3 and T4 provide negative feedback on both hypothalamus and pituitary
• In PRIMARY hypothyroidism: low T4 → loss of negative feedback → elevated TSH (sensitive early marker)
• In SECONDARY/TERTIARY: TSH is low or inappropriately normal despite low T4

Thyroid Hormone Physiology

• Thyroid produces mostly T4 (prohormone); peripheral conversion to T3 (active form) by deiodinases
• T3 is ~3-4x more potent than T4
• T3 acts on nuclear receptors to regulate gene transcription
• Type 3 deiodinase inactivates T3 and T4 (important in sick euthyroid syndrome)

Myxedema Pathophysiology

• Reduced thyroid hormone leads to accumulation of glycosaminoglycans and hyaluronic acid in skin, subcutaneous tissue, and viscera
• Results in non-pitting edema (myxedema) - characteristic coarsening of features
• Affects every organ system due to reduced metabolic rate

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5. CLINICAL FEATURES

A. CONGENITAL HYPOTHYROIDISM / CRETINISM

• Impaired skeletal and CNS development
• Severe mental disability (irreversible if untreated)
• Short stature
• Coarse facial features
• Protruding tongue (macroglossia)
• Umbilical hernia
• Pot-belly
• Hoarse cry

B. ADULT HYPOTHYROIDISM (MYXEDEMA)

• Non-pitting edema (periorbital puffiness, swollen hands/feet)
• Bradycardia
• Dull slow speech, "Donald Duck" voice
• Hung-up deep tendon reflexes (slow relaxation phase - pathognomonic)
• Carpal tunnel syndrome (median nerve compression by mucinous deposits)
• Yellow tinge to skin (carotenemia - impaired carotene conversion to Vit A)
• Dry, rough, doughy skin

• Bradycardia, low cardiac output
• Cardiomegaly due to pericardial effusion (bottle-shaped heart on CXR)
• Elevated total cholesterol and LDL (accelerated atherosclerosis)
• ECG: low voltage complexes, prolonged QT interval, flattened/inverted T waves

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6. HASHIMOTO'S THYROIDITIS (Most Common Cause in Iodine-sufficient Areas)

Pathogenesis

• Autoimmune destruction of thyroid
• Loss of self-tolerance to thyroid antigens
• CD8+ cytotoxic T lymphocytes destroy follicular cells
• CD4+ Th cells promote B cell antibody production

Autoantibodies

1. Anti-TPO (anti-thyroid peroxidase) - most sensitive; present in >95%
2. Anti-Tg (anti-thyroglobulin) - less specific
3. Anti-TSH receptor (blocking type) - contribute to hypothyroidism

Histology (Robbins)

• Dense lymphocytic infiltration with germinal center formation
• Follicular atrophy with Hurthle cell (oxyphilic) metaplasia of follicular epithelium
• Reduced colloid

Clinical

• Painless diffuse enlargement of thyroid (rubbery, non-tender goiter)
• Progressive hypothyroidism
• May pass through transient hyperthyroid phase ("Hashitoxicosis")
• Associated with other autoimmune diseases: Type 1 DM, Addison's disease, pernicious anemia, Sjogren's, SLE
• Slightly increased risk of primary thyroid lymphoma (B-cell NHL)

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7. INVESTIGATIONS

A. Thyroid Function Tests

• Primary hypothyroidism: TSH >4.12 mIU/L (upper limit of normal)
• Overt hypothyroidism: elevated TSH + low free T4
• Subclinical hypothyroidism: elevated TSH + normal free T4 and T3

B. Antibody Tests

• Anti-TPO antibodies: elevated in Hashimoto's (>95%)
• Anti-Tg antibodies
• TSH-R blocking antibodies (in some)

C. Other Lab Findings

• Raised cholesterol and LDL (cardiovascular risk)
• Normochromic normocytic anemia (most common) or macrocytic (if coexistent pernicious anemia)
• Raised serum CK (from muscles)
• Raised serum LDH
• Hyponatremia (dilutional, from impaired free water excretion)
• Elevated prolactin (TRH stimulates prolactin; causes galactorrhea)
• ECG: low voltage, prolonged QT, bradycardia, flat T waves

D. Imaging

• Thyroid ultrasound: heterogeneous texture in Hashimoto's, reduced vascularity
• Radioisotope scan: not typically needed in hypothyroidism
• CXR: cardiomegaly (pericardial effusion), pleural effusion
• Echo: pericardial effusion confirmation

E. Neonatal Screening

• TSH (or T4) on day 3-5 of life (heel prick/Guthrie test)
• Elevated TSH in congenital hypothyroidism

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8. SUBCLINICAL HYPOTHYROIDISM

• Definition: Elevated TSH + normal free T4, with no or minimal symptoms
• Prevalence: 4-10% of population; more common in women and elderly
• Progression to overt hypothyroidism: ~5% per year; faster if anti-TPO positive (up to 4.5% per year)

When to treat:

• TSH >10 mIU/L: treat regardless
• TSH 4.5-10 mIU/L: treat if:
  • Symptoms present
  • Anti-TPO antibodies positive
  • Pregnancy or trying to conceive
  • Dyslipidemia
  • Aged <65 years with cardiovascular risk factors
• Note: In elderly (>65-70 years), mild TSH elevation (4.5-7 mIU/L) may be physiologically acceptable and treatment can be harmful

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9. SPECIAL SITUATIONS

A. Hypothyroidism in Pregnancy

• TSH targets during pregnancy (ATA 2017 guidelines):
  • 1st trimester: <2.5 mIU/L
  • 2nd/3rd trimester: <3.0 mIU/L
• Maternal hypothyroidism in 1st trimester - risk of severe fetal neurological impairment
• LT4 dose must be increased 25-30% as soon as pregnancy is confirmed (increased T4 binding to TBG due to estrogen, and increased volume of distribution)
• Postpartum thyroiditis: silent thyroiditis occurring 1-12 months post delivery; biphasic course (hyperthyroid then hypothyroid); most resolve spontaneously

B. Hypothyroidism with Cardiac Disease

• Start LT4 at very low dose (12.5-25 μg/day)
• Increase slowly every 6-8 weeks
• Risk: unmasking coronary artery disease or precipitating angina/MI
• Cardiac surgery should not be delayed if urgent

C. Elderly Patients

• Lower starting doses (25-50 μg/day)
• Slower titration
• TSH target slightly higher (1.0-4.0 mIU/L acceptable)

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10. MYXEDEMA COMA

Definition

• Extreme, life-threatening decompensation of severe hypothyroidism
• Mortality: 20-40% despite intensive treatment
• Rare but a classic exam/viva topic

Precipitating Factors (the "SIICCC" mnemonic):

• S - Sedatives/anesthetics/antidepressants
• I - Infection (pneumonia, sepsis)
• I - Ischemia (MI, CVA, GI bleed)
• C - Cold exposure
• C - Cardiac failure
• C - Non-compliance with thyroid medication

Clinical Features:

• Hypothermia (can be as low as 23°C / 74°F)
• Altered consciousness/coma (reduced level of consciousness, seizures)
• Bradycardia and hypotension
• Hypoventilation - hypoxia and hypercapnia (major pathogenic mechanism)
• Hyponatremia (dilutional)
• Hypoglycemia
• All features of severe hypothyroidism (myxedematous facies, absent DTRs, etc.)

Management of Myxedema Coma:

• External warming only if temperature <30°C (space blankets to prevent heat loss; active warming risks cardiovascular collapse)
• Hypertonic saline or IV glucose for severe hyponatremia or hypoglycemia
• Avoid hypotonic IV fluids (worsens water retention)
• Broad-spectrum antibiotics (infection is common trigger)
• Reduce sedative doses (impaired drug metabolism)
• Treat precipitating cause

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11. TREATMENT

A. Levothyroxine (LT4) - FIRST LINE

• Full replacement: 1.6 μg/kg body weight/day
• Typical adult dose: 100-150 μg/day (oral, ideally 30 min before breakfast)
• Starting dose in young healthy adults: 50-100 μg/day
• Starting dose in elderly/cardiac disease: 12.5-25 μg/day

• TSH rechecked after 6-8 weeks of any dose change
• Adjust in 12.5-25 μg increments
• Target TSH: lower half of reference range (typically 0.5-2.5 mIU/L)
• Annual TSH monitoring once stable

• T4 is converted to active T3 by peripheral deiodinases (physiologically appropriate)
• Long half-life (7 days) - missed doses can be doubled next day

B. Causes of Increased LT4 Requirement

• Malabsorption: Celiac disease, small bowel surgery, atrophic gastritis, H. pylori gastritis
• Drug interactions: Cholestyramine (bile acid sequestrants), ferrous sulfate, calcium, antacids (separate by 4h), proton pump inhibitors
• Drug metabolism increase: Phenytoin, carbamazepine, rifampicin (induce cytochrome P450)
• Increased TBG: Oral estrogen (OCPs, HRT)
• Poor compliance (most common in patient taking >200 μg/day with high TSH)

C. Why NOT to Use T3 Alone

• Short half-life (1 day) - requires 3-4 doses daily
• Fluctuating T3 levels
• Not recommended for long-term replacement

D. Combination LT4 + LT3

• Multiple RCTs have failed to show superiority over LT4 alone
• Not routinely recommended
• May be considered in patients with persistent symptoms on LT4 monotherapy

E. Desiccated Thyroid Extract (DTE)

• Not recommended: nonphysiologic T3:T4 ratio
• 10-15% of patients have persistent symptoms despite normal TSH - ongoing area of research

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12. SUMMARY TABLE - KEY DIFFERENTIATORS

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13. HIGH-YIELD EXAM POINTS (MUHS PG)

1. Most common cause worldwide - iodine deficiency; in iodine-sufficient areas - Hashimoto's thyroiditis
2. Best screening test - serum TSH
3. Most sensitive indicator of thyroid status in primary hypothyroidism = TSH
4. Hung-up ankle reflex (delayed relaxation) - pathognomonic sign
5. Hertoghe's sign - loss of outer 1/3 of eyebrow
6. Pericardial effusion - causes cardiomegaly without cardiac failure (clear lungs on CXR)
7. Myxedema coma treatment - IV T4 loading dose 200-400 μg + hydrocortisone + ventilatory support
8. Hashimoto's histology - lymphocytic infiltration + germinal centers + Hurthle cell metaplasia
9. Anti-TPO antibodies - most sensitive marker of autoimmune thyroid disease
10. Subclinical hypothyroidism - treat if TSH >10 or symptomatic or pregnant or anti-TPO positive
11. LT4 starting dose - 50-100 μg in young healthy; 12.5-25 μg in elderly/cardiac
12. Pregnancy - increase LT4 dose by 25-30% as soon as confirmed; 1st trimester target TSH <2.5
13. Amiodarone - can cause both hypo and hyperthyroidism; check TFTs before and during treatment
14. Congenital hypothyroid screening - TSH on day 3-5 (Guthrie test)
15. Cretinism + maternal iodine deficiency in 1st trimester - irreversible severe mental disability

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• Harrison's Principles of Internal Medicine 22E (2025), Chapter 395 - Hypothyroidism
• Robbins & Kumar Basic Pathology, Chapter 18 - Endocrine System
• Sabiston Textbook of Surgery, Chapter on Thyroid

Recent evidence note: A 2026 systematic review and meta-analysis (PMID 42095176) identified predictive factors for permanent hypothyroidism after subacute thyroiditis - large goiter size, elevated initial TSH, low T4, and prolonged course are risk factors. Worth knowing for theory.