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Pathophysiology of Hypothyroidism

Hypothyroidism is a condition in which the thyroid gland fails to produce or secrete sufficient thyroid hormone (T3 and T4) to meet the metabolic demands of peripheral tissues. - Rosen's Emergency Medicine

1. Classification by Level of Defect

Type	Level of Defect	TSH	Free T4
Primary (99% of cases)	Thyroid gland itself	↑ (elevated)	↓ (low)
Secondary (Central)	Pituitary - deficient TSH secretion	Low/normal	↓ (low)
Tertiary (Central)	Hypothalamus - deficient TRH secretion	Low/normal	↓ (low)

In primary hypothyroidism, loss of negative feedback by T3/T4 on the hypothalamus and pituitary leads to elevated TRH and TSH. In secondary/tertiary forms, the axis fails at a higher level, so TSH is not elevated. - Robbins & Kumar Basic Pathology

2. Causes and Their Mechanisms

A. Autoimmune (Most Common in Iodine-Sufficient Regions)

Hashimoto Thyroiditis is the leading cause in developed countries (female:male ratio 10:1 to 20:1, peak 45-65 years). The mechanisms of thyroid destruction include:

CD8+ cytotoxic T lymphocytes - directly kill thyroid epithelial cells
CD4+ T helper cells - activate macrophages, which damage follicles through cytokine-mediated inflammation
Circulating autoantibodies (anti-thyroid peroxidase, anti-thyroglobulin) are present in nearly all patients
Progressive lymphocytic infiltration leads to follicular atrophy and fibrosis - Robbins & Kumar Basic Pathology

B. Iodine Deficiency (Most Common Worldwide)

Iodine (~50 mg/year) is required for synthesis of T3 and T4. Without it:

Thyroxine and T3 production falls
Loss of negative feedback on the pituitary - TSH rises markedly
TSH drives thyroid cell hyperplasia and colloid accumulation - endemic goiter forms (gland can enlarge 10-20x)
Despite gland enlargement, hormone production remains insufficient - Guyton & Hall Medical Physiology

C. Enzyme/Synthesis Defects (Dyshormonogenesis)

Several enzymatic failures can block hormone synthesis:

Deficient iodide-trapping - iodine not adequately pumped into thyroid cells
Deficient peroxidase system - iodides cannot be oxidized to active iodine (this is also the mechanism of Wolff-Chaikoff effect from excess iodine and drugs like lithium)
Defective coupling of iodinated tyrosines - MIT and DIT cannot form T3/T4
Deficiency of deiodinase - iodine not recovered from MIT/DIT for reutilization - Guyton & Hall Medical Physiology

D. Iatrogenic Causes

Surgical thyroidectomy - direct loss of thyroid tissue
Radioactive iodine (RAI) therapy - radiation-induced destruction
Drugs: Lithium (blocks thyroid hormone release), excess iodides (Wolff-Chaikoff effect), amiodarone - Robbins & Kumar Basic Pathology; Sabiston Textbook of Surgery

3. The HPT Axis Feedback Loop in Primary Hypothyroidism

Hypothalamus → TRH ↑↑
        ↓
Anterior Pituitary → TSH ↑↑
        ↓
Thyroid gland (damaged/dysfunctional)
        → T3/T4 ↓↓ (insufficient output)
        → No negative feedback → cycle perpetuates

The hallmark lab finding is elevated TSH + low free T4. TSH is the most sensitive screening test because it rises early, before free T4 falls below normal range (subclinical hypothyroidism: elevated TSH but normal T4). - Rosen's Emergency Medicine; Sabiston Textbook of Surgery

4. Downstream Pathophysiological Effects

Thyroid hormones regulate nearly every organ system. Their deficiency causes a global hypometabolic state:

System	Mechanism	Effect
Metabolism	Decreased Na-K ATPase activity, reduced oxygen consumption	Low BMR (reduced 30-50% in myxedema), cold intolerance, weight gain
Cardiovascular	Reduced cardiac contractility, HR, and CO; increased cholesterol	Bradycardia, decreased cardiac output, decreased blood volume, dyslipidemia, atherosclerosis
Neuromuscular	Slowed nerve conduction, impaired muscle metabolism	Fatigue, somnolence (sleeping 12-14 hrs/day), muscle sluggishness, delayed deep tendon reflexes
Skin/connective tissue	Accumulation of hyaluronic acid + chondroitin sulfate in interstitium	Myxedema - non-pitting edema, periorbital puffiness, coarse dry skin, hair loss
GI	Decreased gut motility	Constipation
Reproductive	Altered steroid hormone metabolism	Menstrual irregularity, anovulation
Voice	Myxedematous infiltration of laryngeal tissue	Hoarse, husky, "froglike" voice
Mental	Reduced cerebral oxygen use	Mental sluggishness, depression, psychosis ("myxedema madness")

Guyton & Hall Medical Physiology

5. Myxedema - The Extreme Presentation

Myxedema is the most severe form of untreated or decompensated hypothyroidism. The hallmark is non-pitting, generalized edema caused by:

"Greatly increased quantities of hyaluronic acid and chondroitin sulfate bound with protein form excessive tissue gel in the interstitial spaces...the edema is the non-pitting type." - Guyton & Hall Medical Physiology

Myxedema crisis (coma) occurs when chronic hypothyroidism is decompensated by an acute stressor (infection, trauma, surgery). Features:

Altered mental status/coma
Hypothermia
Bradycardia
Hyponatremia
Cardiomegaly, pericardial effusion
Hypotension/shock - Sabiston Textbook of Surgery

Patient with myxedema showing periorbital puffiness, broad coarse facial features, and edematous appearance

Myxedema - note periorbital bagginess and coarsened facial features (Guyton & Hall)

6. Special Populations

Congenital Hypothyroidism (Cretinism)

Fetus depends on maternal T3/T4 in early pregnancy (before fetal thyroid develops)
Maternal hypothyroidism in this window causes severe fetal brain damage
Clinical features: intellectual disability, growth failure, short stature, protruding tongue, umbilical hernia, coarse facial features
Later in pregnancy (after fetal thyroid is established), maternal hypothyroidism has less impact on brain development - Robbins & Kumar Basic Pathology

Subclinical Hypothyroidism

TSH elevated, but free T4 is still within normal range
Affects 4-10% of the general population, 5-8% in pregnancy
Represents early/compensated primary hypothyroidism - Rosen's Emergency Medicine

7. Diagnostic Correlation

Finding	Mechanism
TSH ↑	Loss of T3/T4 negative feedback on pituitary
Free T4 ↓	Insufficient thyroid hormone production
Elevated cholesterol	Reduced LDL receptor expression, decreased hepatic cholesterol excretion in bile
Hyponatremia	SIADH-like state, increased ADH sensitivity
Elevated CK	Muscle involvement in myxedema
Macrocytic anemia	Impaired B12 absorption (associated autoimmune gastritis in Hashimoto)

Sources: Robbins & Kumar Basic Pathology; Guyton and Hall Textbook of Medical Physiology; Sabiston Textbook of Surgery; Rosen's Emergency Medicine

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