Hypothyroidism

Definition

Classification

Causes

Primary Hypothyroidism

• Hashimoto thyroiditis - the most common cause in the US and developed world. Antithyroid antibodies (especially TPO antibodies and thyroglobulin antibodies) attack thyroidal stroma, causing progressive fibrosis and declining T4 production. Female-to-male ratio 10-14:1, typically diagnosed in the fifth decade.

• Surgical ablation (thyroidectomy)
• Radioactive iodine (¹³¹I) therapy
• External radiation to head/neck

• Lithium (inhibits thyroid hormone release)
• Iodides (Wolff-Chaikoff effect)
• Amiodarone

• Thyroid dysgenesis (genetic defects in thyroid development)
• Dyshormonogenetic goiter (enzyme defects in hormone synthesis, e.g., deficient peroxidase, deficient iodide-trapping, deficient coupling)

• Riedel thyroiditis (IgG4-related disease; fibrosis of thyroid and surrounding structures; ~1/3 of patients develop hypothyroidism)

• Postpartum, sporadic, or subacute thyroiditis can cause transient hypothyroidism lasting 3-6 months

Secondary (Central) Hypothyroidism

• Pituitary failure - deficient TSH production
• Hypothalamic failure - deficient TRH production
• Suggested when TSH is low/normal with low FT4, without symptoms of thyrotoxicosis

Pathophysiology

1. Thyroid gland fails to produce adequate T4/T3
2. Loss of negative feedback on the pituitary/hypothalamus
3. TSH rises (in primary hypothyroidism)
4. Thyroid cells may be stimulated to grow (goiter), but without adequate substrate (iodine) or enzymes, hormone synthesis still fails
5. End result: decreased metabolic rate across all organ systems

Clinical Features

Congenital Hypothyroidism (Cretinism)

• Impaired skeletal and CNS development
• Severe irreversible intellectual disability (especially if maternal hypothyroidism occurs early in pregnancy, before fetal thyroid develops)
• Short stature, coarse facial features, protruding tongue, umbilical hernia
• Prevention: universal neonatal screening + iodine supplementation

Adult Hypothyroidism (Myxedema)

• Fatigue, lethargy, cold intolerance, weight gain
• Decreased sweating
• Generalized puffiness (myxedema - non-pitting edema from glycosaminoglycan deposition)

• Bradycardia, reduced cardiac output
• Diastolic hypertension
• Pericardial effusion
• Hypercholesterolemia (increased cardiovascular risk)

• Mental sluggishness, cognitive impairment
• Depression (may mimic primary psychiatric illness)
• Slow reflexes (prolonged relaxation phase)
• Peripheral neuropathy, carpal tunnel syndrome

• Cool, pale, dry, rough skin
• Hair loss, brittle hair
• Puffy face and periorbital edema
• Eyebrow thinning (lateral third - "Queen Anne's sign")
• Macroglossia

• Constipation (reduced GI motility)

• Menorrhagia, anovulation, infertility
• Galactorrhea (TRH stimulates prolactin)

• Muscle weakness, cramps, myalgia

Myxedema Coma (Severe/Emergency)

• Altered mental status / coma
• Hypothermia
• Bradycardia, hypotension
• Hyponatremia, hypoglycemia, hypercapnia

• IV levothyroxine (200-400 mcg loading dose) ± IV T3
• IV hydrocortisone (concurrent adrenal insufficiency must be treated)
• Supportive care (passive warming, airway management, fluid resuscitation)

Diagnosis

• Overt hypothyroidism: elevated TSH + low FT4
• Subclinical hypothyroidism: elevated TSH (typically 4.5-10 mIU/L) + normal FT4
• Central hypothyroidism: low/normal TSH + low FT4 - requires pituitary evaluation

Treatment

Levothyroxine (L-Thyroxine, T4) - First-Line

• Standard adult replacement dose: 1.6 mcg/kg/day
• Young, healthy adults: Can start at full replacement dose
• Elderly patients or those with cardiac disease: Start low (25-50 mcg/day) and titrate slowly to avoid precipitating angina or arrhythmia
• Monitoring: Serum TSH checked annually once stable; target TSH 0.5-2.5 mIU/L
• Taken on empty stomach, 30-60 min before breakfast; separate from calcium, iron, PPIs

Combination T4/T3 Therapy

• Considered in patients who remain symptomatic despite TSH in therapeutic range
• True T4-resistance is controversial
• If used, maintain TSH >1.0 mIU/L to avoid iatrogenic hyperthyroidism
• Not routinely recommended as first-line

Transient Hypothyroidism (e.g., post-thyroiditis)

• Usually resolves in 3-6 months
• Low-dose T4 may be used temporarily in symptomatic patients

Special Situations

• Pregnancy: Hypothyroidism must be aggressively treated; maternal hypothyroidism in early pregnancy (before fetal thyroid development) can cause irreversible fetal brain injury; TSH target <2.5 mIU/L in first trimester
• Subclinical hypothyroidism: Treat if TSH >10 mIU/L, symptomatic, or pregnant; individualize if TSH 4.5-10 mIU/L

Subclinical Hypothyroidism

• TSH mildly elevated (4.5-10 mIU/L), FT4 normal
• Affects 4-10% of the general population; 5-8% in pregnancy
• May be asymptomatic or have subtle symptoms
• Progression to overt hypothyroidism: ~2-4% per year (higher if TPO antibodies positive)

Key Associations