What is the most likely etiology of hypothyroidism in a patient with a history of Hodgkin lymphoma treated with upper thoracic radiation?

Radiation-Induced Hypothyroidism

The most likely etiology of Khadija's hypothyroidism is radiation-induced thyroid damage from her upper thoracic radiation therapy for Hodgkin lymphoma. 1, 2

Primary Mechanism: Direct Radiation Injury to the Thyroid Gland

Radiation-induced hypothyroidism occurs in approximately 50-60% of patients who receive neck or upper mediastinal irradiation for Hodgkin lymphoma, making this the predominant cause in her case. 1, 2, 3 The pathophysiology involves:

• Direct parenchymal cell damage to thyroid follicular cells from ionizing radiation 4
• Vascular injury to the thyroid gland's blood supply, leading to ischemic damage 4
• Autoimmune reactions triggered by radiation exposure, though her negative TSI argues against this mechanism 4

Dose-Volume Relationship and Risk Factors

The risk of developing hypothyroidism is directly related to the radiation dose and volume of thyroid tissue exposed:

• When >62.5% of the thyroid gland receives ≥30 Gy, the risk of hypothyroidism increases to 70.8%, compared to only 11.5% when this threshold is not exceeded 5
• Upper thoracic/mediastinal radiation fields for Hodgkin lymphoma typically deliver mean doses >10 Gy to the thyroid gland 2
• Approximately half of radiation-induced hypothyroidism cases occur within the first 5 years after therapy, though onset can be delayed up to 10 years or more 1, 2, 4

Laboratory Pattern Confirms Primary Hypothyroidism

Her laboratory results demonstrate central hypothyroidism (low TSH, low T4, low T3), which is unusual and warrants additional consideration:

• The typical pattern after thyroid irradiation is PRIMARY hypothyroidism (elevated TSH with low T4/T3) in 20-30% of patients 4
• Her low TSH with low thyroid hormones suggests either:
  • Pituitary/hypothalamic dysfunction from radiation scatter to the hypothalamic-pituitary axis, though less common with thoracic fields 2
  • Early evolution of thyroid failure where TSH has not yet compensated
  • Laboratory timing issues requiring repeat testing

Clinical Presentation Aligns with Hypothyroidism

Her symptoms are classic for hypothyroid state regardless of mechanism:

• Fatigue and exercise intolerance despite maintained fitness regimen 2, 3
• Cold intolerance 2
• Weight gain despite unchanged nutrition 2
• Menorrhagia (heavy periods) 2
• Dry, coarse skin on examination 2

Alternative Etiologies to Consider (But Less Likely)

While radiation injury is the primary etiology, other contributing factors in Hodgkin lymphoma survivors include:

• Chemotherapy effects: ABVD (her likely regimen) does not typically cause direct thyroid dysfunction, unlike alkylating agents 1
• Autoimmune thyroiditis: Her negative TSI makes Graves' disease unlikely, though other autoimmune processes could theoretically contribute 4
• Secondary malignancy or recurrence: Must always be considered but her recent scan was clear 2, 3

Critical Diagnostic Pitfall

Do not attribute her low TSH to hyperthyroidism or dismiss her symptoms as "cancer-related fatigue" without thorough thyroid evaluation. 2, 3 The combination of low TSH with low thyroid hormones requires:

• Immediate repeat thyroid function tests (TSH, free T4, free T3) to confirm the pattern 2
• Consider pituitary function testing if central hypothyroidism is confirmed (morning cortisol, IGF-1, prolactin, LH/FSH) 2
• Thyroid ultrasound to assess for structural changes, nodules, or volume loss 1, 4

Surveillance Recommendations for Hodgkin Lymphoma Survivors

Annual TSH screening is recommended for all patients who received neck or mediastinal radiation, with more frequent monitoring if abnormalities are detected 1, 2 This should have been initiated within 1-2 years post-treatment and continued lifelong 2