What lab abnormalities are associated with hypophysitis and how are they managed?

Laboratory Abnormalities in Hypophysitis and Their Management

Hypophysitis is characterized by multiple hormone deficiencies, with central hypothyroidism and central adrenal insufficiency being the most common laboratory abnormalities, requiring prompt hormonal replacement therapy to prevent morbidity and mortality. 1

Common Laboratory Abnormalities

Pituitary Hormone Deficiencies

• Central Hypothyroidism: Low free T4 with low/normal TSH (>90% of cases) 1
• Central Adrenal Insufficiency: Low ACTH with low cortisol (>75% of cases) 1
• Hypogonadism: Low testosterone/estradiol with low/normal FSH/LH (50% of cases) 1
• Panhypopituitarism: Combination of multiple anterior pituitary hormone deficiencies (occurs in approximately 50% of patients) 1

Timing of Abnormalities

• Laboratory abnormalities typically appear 8-9 weeks after initiation of immune checkpoint inhibitors (particularly with anti-CTLA-4 therapy) 1
• Thyroid function abnormalities may be the first indication of hypophysitis during routine monitoring 1

Diagnostic Approach

Initial Laboratory Evaluation

When hypophysitis is suspected based on clinical findings (headache, fatigue) or abnormal thyroid function tests:

1. Morning hormone panel (preferably around 8 am): 1

   • Thyroid function: TSH, free T4
   • Adrenal function: ACTH, cortisol (or 1 mcg cosyntropin stimulation test)
   • Gonadal hormones:
     • Men: Testosterone, FSH, LH
     • Women: Estradiol, FSH, LH

2. Imaging: MRI of the sella with pituitary cuts 1

   • Look for pituitary enlargement, stalk thickening, suprasellar convexity, heterogeneous enhancement

Diagnostic Criteria

Proposed confirmation criteria for hypophysitis include: 1

• ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) + MRI abnormality, OR
• ≥2 pituitary hormone deficiencies (TSH or ACTH deficiency required) + headache/other symptoms

Management of Laboratory Abnormalities

Hormone Replacement Therapy

1. Central Adrenal Insufficiency: 1

   • First priority: Physiologic glucocorticoid replacement
   • In acute settings or with severe symptoms: High-dose steroids
   • Critical safety measure: All patients should obtain and carry a medical alert bracelet

2. Central Hypothyroidism: 1, 2

   • Levothyroxine 0.5-1.5 μg/kg/day (start at lower doses in elderly or those with cardiac history)
   • Important: Always start steroids BEFORE thyroid hormone replacement in patients with both adrenal insufficiency and hypothyroidism to prevent adrenal crisis

3. Hypogonadism: 1

   • Hormone replacement based on sex and symptoms
   • Not typically urgent compared to adrenal and thyroid replacement

Monitoring Protocol

1. Thyroid Function: 1

   • Monitor TSH and free T4 before each treatment cycle
   • A falling TSH across two measurements with normal or lowered T4 may suggest developing pituitary dysfunction

2. Adrenal Function: 1

   • Consider routine monitoring with early morning ACTH and cortisol levels
   • Schedule: Monthly for 6 months, then every 3 months for 6 months, then every 6 months for 1 year

3. Long-term Follow-up: 1

   • Both adrenal insufficiency and hypothyroidism typically represent long-term sequelae requiring lifelong hormonal replacement

Special Considerations

Thyroid Abnormalities Beyond Central Hypothyroidism

1. Thyroiditis and Thyrotoxicosis: 1

   • May present with high free T4 or T3 with low/normal TSH
   • Often self-limiting, leading to permanent hypothyroidism after approximately 1 month
   • Management: Beta-blockers for symptomatic relief; consider prednisolone 0.5 mg/kg for painful thyroiditis

2. Primary Hypothyroidism: 1, 2

   • High TSH with low free T4
   • Management: Levothyroxine replacement

Treatment Decisions

• For severe symptoms (severe headaches, vision changes, adrenal crisis): High-dose steroids 1
• For stable patients with hormone deficiencies: Physiologic hormone replacement 1
• When to withhold immunotherapy: Consider withholding if patient is unwell with symptomatic hypophysitis 1

Most patients with hypophysitis will require long-term hormone replacement therapy, as resolution of pituitary hormone deficiencies is uncommon, even though the pituitary enlargement on MRI typically resolves within two months 1.