Hypothyroidism

Causes (Etiology)

Primary Hypothyroidism (thyroid gland failure)

Transient Hypothyroidism

• Silent (postpartum) thyroiditis
• Subacute thyroiditis (de Quervain's)
• After radioiodine treatment (first 3-4 months)

Secondary / Central Hypothyroidism

• Pituitary or hypothalamic disease (low or normal/slightly elevated TSH with low free T4)

Epidemiology

• Mean annual incidence: up to 4 per 1000 women, 1 per 1000 men
• Subclinical hypothyroidism: 6-8% of women (10% over age 60) and 3% of men
• Typically presents between 30-50 years of age; mean age at diagnosis is 60 years
• Annual risk of progressing to overt hypothyroidism: ~4% when subclinical hypothyroidism is associated with positive TPO antibodies

Pathogenesis (Hashimoto's Thyroiditis)

• Marked lymphocytic infiltration with germinal center formation
• Atrophy of thyroid follicles with oxyphil (Hurthle cell) metaplasia, absence of colloid, and fibrosis
• Thyroid cell destruction is primarily mediated by CD8+ cytotoxic T cells; local cytokines (TNF, IL-1, IFN-γ) also contribute
• Autoantibodies include anti-TPO (thyroid peroxidase) and anti-thyroglobulin antibodies; these are markers of the disease but not necessarily the primary cause
• In atrophic thyroiditis: marked fibrosis, minimal lymphocytic infiltrate - represents end-stage Hashimoto's
• Genetic factors: HLA-DR3, DR4, DR5 in Caucasians; associations with PTPN22 and CTLA-4 polymorphisms; explains co-occurrence with type 1 DM, Addison's disease, pernicious anemia, and vitiligo

Clinical Features

Facial appearance in hypothyroidism: puffy, myxedematous features, periorbital edema, thickened skin.

Skin and Hair

• Dry skin, decreased sweating, thinning epidermis, hyperkeratosis
• Myxedema: increased dermal glycosaminoglycans trap water → non-pitting skin thickening
• Puffy face, periorbital edema, non-pitting pretibial edema
• Pallor with yellow tinge (carotene accumulation)
• Dry, brittle hair that falls out easily; thinning of outer third of eyebrows (Hertoghe's sign)
• Retarded nail growth

Metabolic and Weight

• Weight gain (mainly fluid retention) despite poor appetite
• Cold intolerance
• Fatigue and lethargy

Cardiovascular

• Bradycardia, reduced myocardial contractility, reduced stroke volume
• Increased peripheral resistance → diastolic hypertension
• Pericardial effusion (up to 30% of patients, rarely hemodynamically significant)
• Cool extremities (blood flow diverted from skin)

GI and Reproductive

• Constipation
• Decreased libido in both sexes
• Oligomenorrhea or amenorrhea in long-standing disease; menorrhagia at early stage
• Reduced fertility; increased miscarriage rate
• Mildly elevated prolactin (can cause galactorrhea)

Neuromuscular and Psychiatric

• Slowed cognition, poor concentration, poor memory
• Psychosis can occur ("myxedema madness")
• Carpal tunnel syndrome (common association)
• Cerebellar ataxia (rare)
• Delayed relaxation of tendon reflexes (classic sign)
• Muscle cramps, myalgia, weakness; elevated CK

Other

• Conductive and sensorineural deafness (fluid in middle ear)
• Normochromic normocytic or macrocytic anemia
• Hyponatremia (SIADH-like)
• Hyperlipidemia (elevated LDL cholesterol)

Laboratory Diagnosis

Secondary/Central hypothyroidism: TSH may be low, normal, or slightly elevated (bioinactive forms); free T4 is low. Do not rely on TSH alone - measure free T4.

Subclinical vs. Overt Hypothyroidism

Treatment

Standard Replacement: Levothyroxine (LT4)

• Starting dose: 1.6 µg/kg/day (full replacement); typical range 100-150 µg/day
• Adults <60 years without cardiac disease: start at 50-100 µg/day and titrate up
• Ideally taken 30 minutes before breakfast (food, calcium, iron, bile acid sequestrants all impair absorption)
• Goal: normalize TSH, ideally in the lower half of the reference range
• TSH response is gradual - recheck TSH 6-8 weeks after each dose change
• Adjust in 12.5-25 µg increments
• Clinical improvement may take months even after TSH normalization
• Once stable: annual TSH monitoring

Special Populations

Persistent Symptoms

• ~10-15% of patients have persistent symptoms despite euthyroid TSH - reasons unclear
• LT4 + liothyronine (T3) combinations: studied but benefit not confirmed in prospective trials
• Desiccated thyroid (USP) is not recommended (non-physiologic T3:T4 ratio)
• Liothyronine alone is not suitable for long-term replacement (short half-life, fluctuating T3 levels)

Causes of Elevated TSH Despite Treatment

• Poor adherence (most common - patients miss doses then take them before blood draw → normal T4 but high TSH)
• Malabsorption (celiac disease, atrophic gastritis, H. pylori gastritis, small bowel surgery)
• Oral estrogen, SERMs
• Drug interactions (ferrous sulfate, calcium carbonate, bile acid sequestrants, PPIs)

Myxedema Coma

• Almost always in the elderly
• Precipitants: sedatives, anesthetics, antidepressants, pneumonia, MI, CHF, GI bleeding, CVA, sepsis, cold exposure
• Features: depressed consciousness, seizures, hypothermia (as low as 23°C/74°F), bradycardia, hypoventilation, hyponatremia, hypoglycemia
• Treatment: IV LT4 (or T3), glucocorticoids (until adrenal insufficiency excluded), ICU supportive care

Congenital Hypothyroidism

• Incidence: ~1 in 2000-4000 newborns
• Causes: thyroid dysgenesis (65%), inborn errors of synthesis (30%), TSH-R antibody-mediated (5%)
• Most common treatable cause of mental retardation - neonatal screening programs are critical
• Transplacental maternal T4 provides partial support before fetal thyroid function begins

Key Associations

• Autoimmune polyendocrine syndromes: type 1 DM, Addison's disease, pernicious anemia, vitiligo
• Down syndrome and Turner syndrome have increased prevalence
• Drug-induced: checkpoint inhibitors are an increasingly recognized cause in oncology patients