What are the key considerations in the differential diagnosis and treatment of hypothyroidism, particularly in patients with a history of autoimmune disorders or those taking medications such as lithium or amiodarone?

Differential Diagnosis for Hypothyroidism

Primary Hypothyroidism (Most Common)

Hashimoto's thyroiditis (chronic autoimmune thyroiditis) is the leading cause of hypothyroidism in iodine-sufficient areas, characterized by lymphocytic infiltration and elevated anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin antibodies 1, 2.

Autoimmune Causes

• Hashimoto's thyroiditis presents with gradual thyroid destruction, elevated TSH, low free T4, and positive anti-TPO antibodies in most cases 1, 2
• Type 1 diabetes mellitus significantly increases risk of autoimmune thyroid disease, requiring regular thyroid monitoring 1
• Family history of thyroid disease indicates genetic predisposition and warrants screening 1

Iatrogenic Causes

• Previous radioactive iodine therapy for hyperthyroidism commonly results in permanent hypothyroidism 1, 3
• Thyroid surgery (total or partial thyroidectomy) causes immediate or delayed hypothyroidism 3, 2
• External neck radiation for head and neck cancer damages thyroid tissue 1

Drug-Induced Hypothyroidism

Amiodarone causes hypothyroidism in 2-10% of patients through multiple mechanisms: it inhibits peripheral conversion of T4 to T3, releases large amounts of inorganic iodine (37% iodine by weight), and may directly damage thyroid tissue 4, 5.

• Lithium carbonate inhibits thyroid hormone synthesis and secretion 3, 5
• Immune checkpoint inhibitors (anti-PD-1/PD-L1 therapy) cause thyroid dysfunction in 6-20% of patients 6, 2
• Interferon therapy can trigger autoimmune thyroiditis 5
• Anti-thyroid drugs (methimazole, propylthiouracil) when used for hyperthyroidism 5
• Iodine excess paradoxically inhibits thyroid hormone synthesis (Wolff-Chaikoff effect) 5

Nutritional Deficiency

• Iodine deficiency remains the most common cause worldwide, though rare in developed countries 1, 3, 2

Secondary (Central) Hypothyroidism

Pituitary or hypothalamic disorders cause low or inappropriately normal TSH with low free T4, distinguishing it from primary hypothyroidism where TSH is elevated 6, 7.

• Pituitary adenomas compress normal pituitary tissue, reducing TSH production 3
• Pituitary surgery or radiation damages TSH-producing cells 3
• Sheehan syndrome (postpartum pituitary necrosis) 3
• Hypothalamic disorders reduce TRH secretion 3
• Critical consideration: Always rule out concurrent adrenal insufficiency before treating central hypothyroidism, as thyroid hormone replacement can precipitate life-threatening adrenal crisis 6

Transient Causes (Reversible)

• Recovery from destructive thyroiditis (subacute, postpartum, or immune checkpoint inhibitor-induced) shows temporarily elevated TSH that normalizes in 30-60% of cases 6, 1
• Severe nonthyroidal illness transiently suppresses or elevates TSH during acute phase 6, 7
• Recent levothyroxine dose adjustments require 6-8 weeks to reach steady state 6

Consumptive Hypothyroidism

• Massive hemangiomas (infantile hepatic hemangiomas) express type 3 deiodinase, which rapidly degrades thyroid hormone 7

Resistance Syndromes (Rare)

• TSH receptor resistance causes elevated TSH with normal or high free T4, mimicking primary hypothyroidism 7
• Thyroid hormone resistance shows elevated TSH and free T4 together 7

Laboratory Interferences (Pseudo-Hypothyroidism)

• Heterophilic antibodies cause falsely elevated TSH in immunoassays 1, 7
• Bioinactive TSH molecules show elevated immunoreactive TSH without biological activity 1, 7
• Biotin interference (high-dose supplementation >5 mg/day) affects some TSH assays 7

Key Demographic Risk Factors

• Advanced age: Prevalence increases to 20% in women over 60 years 1
• Female sex: Women have 5-8 times higher risk than men 1, 8
• Black race: One-third the prevalence compared to whites 9, 1
• Postpartum period: High-risk window for thyroid dysfunction 1
• Down syndrome: Elevated risk with overlapping clinical features 1

Critical Diagnostic Pitfalls to Avoid

• Never diagnose based on single TSH measurement: 30-60% of elevated TSH values normalize spontaneously on repeat testing after 3-6 weeks 6, 1
• Always measure free T4 with TSH: Distinguishes subclinical (normal T4) from overt (low T4) hypothyroidism and identifies central hypothyroidism 6
• Consider medication history: Amiodarone effects persist for weeks to months after discontinuation due to its 58-day half-life 4
• Rule out adrenal insufficiency in central hypothyroidism: Start corticosteroids 1 week before levothyroxine to prevent adrenal crisis 6
• Recognize age-adjusted TSH ranges: TSH naturally increases with age; values up to 5-6 mIU/L may be acceptable in elderly patients 6