Hypothyroidism

Overview

Classification & Etiology

Over 95% of cases are primary hypothyroidism.

Primary Hypothyroidism – Key Causes

• Goitrous form (Hashimoto's thyroiditis) or atrophic form (atrophic thyroiditis)
• Characterized by anti-TPO and anti-thyroglobulin antibodies
• Lymphocytic infiltration → progressive destruction of follicular cells
• The autoimmune process gradually reduces thyroid function: first a compensated phase (subclinical hypothyroidism, normal T4 with elevated TSH), then overt hypothyroidism as T4 falls and TSH rises (typically TSH >10 mIU/L) (Harrison's, p. 10696)

• Post-radioiodine ablation (for Graves' disease or thyroid cancer)
• Post-thyroidectomy (total or subtotal)
• External beam radiation to the neck

• Amiodarone (iodine-rich; inhibits T4→T3 conversion)
• Lithium (inhibits thyroid hormone synthesis and release)
• Immune checkpoint inhibitors (anti-PD-1, anti-CTLA-4) — immune-related hypothyroidism
• Interferon-alpha, sunitinib

Pathophysiology

1. Reduced thyroid hormone (T3/T4) → disinhibition of hypothalamic-pituitary axis → elevated TSH
2. T3 (active form) acts on nuclear receptors regulating metabolism, thermogenesis, cardiac contractility, CNS development, and lipid metabolism
3. Deficiency leads to reduced basal metabolic rate, accumulation of glycosaminoglycans (myxedema), hyperlipidemia, and bradycardia

Clinical Features

Symptoms

• General: fatigue, weight gain, cold intolerance, lethargy
• Skin/hair: dry skin, hair thinning/loss, brittle nails, facial puffiness
• Cardiovascular: bradycardia, dyspnea on exertion, pericardial effusion
• GI: constipation, anorexia, macroglossia
• Neuropsychiatric: cognitive slowing, depression, poor concentration, paresthesias (carpal tunnel syndrome)
• Musculoskeletal: muscle cramps, myalgia, proximal myopathy
• Reproductive: menorrhagia, anovulation, infertility, decreased libido

Signs

• Bradycardia
• Periorbital/facial puffiness (myxedema)
• Non-pitting edema
• Delayed relaxation of deep tendon reflexes ("hung reflexes")
• Goiter (in Hashimoto's) or absent thyroid tissue (atrophic form)
• Hoarse voice, dry coarse skin, carotenemia (yellow tinge)

Diagnosis

Step 1 — TSH Screening (best initial test)

• TSH is the most sensitive screening test for primary hypothyroidism
• If TSH is elevated, confirm with free T4

Step 2 — Additional Tests

• Anti-TPO antibodies: positive in ~95% of Hashimoto's thyroiditis; confirms autoimmune etiology
• Anti-thyroglobulin antibodies: less specific, may be positive
• Thyroid ultrasound: heterogeneous echotexture in Hashimoto's; not routinely required for diagnosis
• CBC: normocytic or macrocytic anemia may be present
• Lipid panel: hypercholesterolemia (LDL elevated) is common
• CK: elevated in hypothyroid myopathy
• Prolactin: may be mildly elevated (TRH stimulates prolactin)

Management

Overt Hypothyroidism

• Take on an empty stomach, 30–60 min before food
• Avoid co-administration with calcium, iron, PPI, soy (impair absorption)

Subclinical Hypothyroidism

Special Populations

• Pregnancy: TSH target <2.5 mIU/L in first trimester (uncontrolled hypothyroidism risks miscarriage, preeclampsia, fetal neurodevelopmental impairment); increase levothyroxine dose ~25–30% on pregnancy confirmation
• Congenital hypothyroidism: Treat immediately after birth to prevent cretinism (irreversible intellectual disability); neonatal TSH screening is standard
• Myxedema coma (see below): ICU management required

Myxedema Coma (Severe/Decompensated Hypothyroidism)

1. IV levothyroxine 200–400 mcg loading dose, then 50–100 mcg/day IV
2. IV liothyronine (T3) may be added cautiously (faster onset)
3. IV hydrocortisone 50–100 mg q8h (empirically cover for adrenal insufficiency before thyroid hormone replacement)
4. Mechanical ventilation if needed
5. Passive rewarming
6. Treat precipitating cause

Complications of Untreated Hypothyroidism

Differential Diagnosis

• Depression (mimics cognitive/affective symptoms)
• Chronic fatigue syndrome / fibromyalgia
• Nephrotic syndrome (low T4 due to protein loss, but TSH normal)
• Euthyroid sick syndrome (low T3/T4 with normal/low TSH in critical illness)
• Anemia
• Congestive heart failure (edema, fatigue overlap)

Key Takeaways

• TSH is the best screening test; low free T4 confirms overt disease
• Hashimoto's thyroiditis is the most common cause in developed nations
• Levothyroxine is the treatment of choice; dose-adjusted by TSH at 6–8 week intervals
• Pregnancy and myxedema coma are critical scenarios requiring urgent management
• Subclinical hypothyroidism with TSH >10 should generally be treated; the 4.5–10 range requires individualized decision-making

Cold Intolerance in Hypothyroidism

Mechanism

• Mitochondrial oxidative phosphorylation
• Na⁺/K⁺-ATPase activity (a major heat-generating process)
• Thermogenin (UCP1) expression in brown adipose tissue

1. Decreased BMR — less metabolic heat is generated
2. Reduced sympathetic tone — blunted thermogenic response to cold
3. Impaired peripheral vasoconstriction regulation — diminished ability to conserve core body temperature
4. Decreased cardiac output — less heat distribution via circulation

Clinical Context

Differential Diagnosis of Cold Intolerance

Evaluation

1. TSH — single best screening test for hypothyroidism
2. Free T4 — confirm overt vs. subclinical disease if TSH is elevated
3. CBC — rule out anemia
4. Iron studies / ferritin — rule out iron deficiency
5. Fasting glucose / HbA1c — if autonomic neuropathy is suspected
6. Clinical exam: pulse rate, skin/hair texture, DTR relaxation, blood pressure, peripheral pulses

Treatment Implications