What is the differential diagnosis for a 41-year-old female patient presenting with symptoms suggestive of hypothyroidism, such as fatigue, cold sensitivity, ridged fingernails, and periorbital darkening?

Differential Diagnosis for Hypothyroidism

Primary Hypothyroidism (Most Common)

Autoimmune thyroiditis (Hashimoto's disease) is the predominant cause of hypothyroidism in iodine-sufficient areas, accounting for up to 85% of cases. 1, 2

Autoimmune Causes

• Hashimoto's thyroiditis - characterized by lymphocytic infiltration, gradual thyroid destruction, and presence of anti-thyroid peroxidase (anti-TPO) antibodies with reduced echogenicity on ultrasound 3, 2
• Postpartum thyroiditis - transient hypothyroidism following pregnancy in women with underlying autoimmune thyroid disease 1

Iatrogenic Causes

• Radioactive iodine therapy - for previous hyperthyroidism treatment, can cause chronic or transient hypothyroidism 4
• Thyroid surgery - post-thyroidectomy for thyroid cancer, nodules, or hyperthyroidism 4
• External beam radiation - neck radiation for head and neck cancers 1
• Immune checkpoint inhibitors - thyroid dysfunction occurs in 6-20% of patients on anti-PD-1/PD-L1 therapy or combination immunotherapy 5
• Amiodarone - antiarrhythmic medication causing thyroid dysfunction 1

Nutritional Deficiency

• Iodine deficiency - the most common cause worldwide in areas without iodine supplementation 2, 4

Congenital Causes

• Congenital hypothyroidism - present from birth, requiring early detection and treatment 4

Secondary (Central) Hypothyroidism (Rare)

Central hypothyroidism results from pituitary or hypothalamic dysfunction, presenting with low or inappropriately normal TSH alongside low free T4. 4, 5

Pituitary Causes

• Hypophysitis - most commonly seen with anti-CTLA-4 antibody therapy (ipilimumab), occurring in ≤10% at 3 mg/kg and up to 17% at 10 mg/kg 6
• Pituitary adenoma - mass effect causing TSH deficiency 6
• Pituitary surgery or radiation - iatrogenic pituitary damage 6
• Sheehan syndrome - postpartum pituitary necrosis 6

Hypothalamic Causes

• Hypothalamic infiltration - from tumors, granulomatous disease, or histiocytosis 6
• Cranial radiation - affecting hypothalamic-pituitary axis 6

Transient Hypothyroidism

Between 30-60% of elevated TSH levels normalize spontaneously on repeat testing, indicating transient thyroid dysfunction. 7, 5

Causes of Transient Elevation

• Recovery phase from thyroiditis - subacute or silent thyroiditis with temporary TSH elevation 5, 7
• Acute illness or hospitalization - non-thyroidal illness syndrome transiently suppressing or elevating TSH 5
• Recent iodine exposure - from CT contrast or other sources 5
• Medication effects - various drugs can transiently affect thyroid function 6

Key Clinical Features to Distinguish Causes

For Primary Hypothyroidism

• Elevated TSH with low free T4 indicates overt primary hypothyroidism 1, 4
• Positive anti-TPO antibodies confirm autoimmune etiology and predict 4.3% annual progression risk versus 2.6% in antibody-negative patients 5
• Reduced thyroid echogenicity on ultrasound supports Hashimoto's thyroiditis 3

For Central Hypothyroidism

• Low or inappropriately normal TSH with low free T4 suggests pituitary/hypothalamic dysfunction 4, 5
• MRI findings - pituitary enlargement, stalk thickening, or suprasellar masses in hypophysitis 6
• Multiple pituitary hormone deficiencies - >75% have both central hypothyroidism and adrenal insufficiency 6

For Your Patient's Presentation

Given the constellation of fatigue, cold sensitivity, ridged fingernails, and periorbital darkening in a 41-year-old female:

• Measure TSH and free T4 to distinguish between subclinical (normal T4) and overt (low T4) hypothyroidism 5
• Check anti-TPO antibodies to confirm autoimmune etiology if TSH is elevated 5
• Consider medication history - particularly immune checkpoint inhibitors, amiodarone, or recent iodine exposure 1, 5
• Evaluate for other autoimmune conditions - patients with autoimmune thyroiditis have increased risk of concurrent autoimmune diseases 5

Critical Diagnostic Pitfall

Never assume hypothyroidism is permanent without reassessment - transient thyroiditis can cause elevated TSH that resolves spontaneously in 30-60% of cases, and treating based on a single elevated value risks unnecessary lifelong therapy 5, 7