What is autoimmune hypophysitis in an adult patient with a history of autoimmune disorders or recent immunotherapy?

What is Autoimmune Hypophysitis?

Autoimmune hypophysitis is an immune-mediated inflammation of the pituitary gland that causes pituitary enlargement and hormone deficiencies, occurring either as a primary autoimmune condition or secondary to immunotherapy (particularly anti-CTLA-4 agents), systemic autoimmune diseases, or IgG4-related disease. 1, 2

Pathophysiology and Classification

Autoimmune hypophysitis results from inflammatory infiltration of the pituitary gland by lymphocytes with variable degrees of fibrosis, leading to pituitary cell destruction and subsequent hypopituitarism 3. The condition can be classified by:

• Histopathological subtypes: Lymphocytic hypophysitis (most common, primarily affects pregnant women), granulomatous, xanthomatous, and IgG4-related hypophysitis (occurs frequently in men with systemic IgG4 disease) 4, 2
• Anatomical location: Adenohypophysitis, infundibuloneurohypophysitis, or panhypophysitis 2
• Etiology: Primary autoimmune versus secondary (immunotherapy-induced, systemic disease-related) 2, 5

Incidence Patterns by Immunotherapy Type

The incidence varies dramatically based on immune checkpoint inhibitor (ICI) regimen:

• Anti-PD(L)1/anti-CTLA-4 combination therapy: 9-10% incidence 1, 4
• Anti-CTLA-4 monotherapy (ipilimumab): 2-6% at standard doses (3 mg/kg), up to 16% at higher doses (10 mg/kg) 1
• Anti-PD-1 monotherapy: <1% incidence 1
• Anti-PD-L1 monotherapy: <0.1% incidence 1

Timing of onset: Anti-CTLA-4-induced hypophysitis typically occurs within 3-4 months of therapy initiation, while anti-PD-1-related cases present later (median 6 months) 1

Clinical Presentation

The presenting features include:

• Headache: Occurs in 85% of patients and requires immediate evaluation to differentiate from cerebral metastases, leptomeningeal disease, or cerebrovascular events 6, 1
• Fatigue: Present in 66% of cases, often related to adrenal insufficiency 6
• Visual disturbances: Result from mass effect on the optic chiasm 1, 4
• Endocrine deficiencies: Manifesting as hypothyroidism, hypocortisolism, hypogonadism (low testosterone in men, amenorrhea in premenopausal women) 1
• Diabetes insipidus: Uncommon (approximately 7% of cases); when present, should prompt consideration of alternative diagnoses such as metastatic disease or germinoma 6, 4

Diagnostic Workup

Mandatory Laboratory Evaluation

Obtain a morning (9 AM) hormonal panel before administering any steroids to avoid interference with results 6, 4:

• Adrenal axis: ACTH and cortisol (9 AM or random if patient is unstable) 1, 6
• Thyroid axis: TSH and free T4 1, 6
• Gonadal axis: LH, FSH, testosterone (men), estradiol (premenopausal women) 1, 6
• Growth hormone axis: IGF-1 1, 6
• Additional: Prolactin, glucose, HbA1c 6

Key diagnostic pattern: A falling TSH across two measurements with normal or lowered T4 suggests pituitary dysfunction and mandates weekly cortisol monitoring 1

Imaging Requirements

MRI of the sella with pituitary cuts is mandatory for all suspected cases 6, 4. Characteristic findings include:

• Symmetrical pituitary enlargement 6
• Homogeneous enhancement after gadolinium administration 6
• Thickened pituitary stalk (in some cases) 2

Diagnostic Confirmation Criteria

The Endocrine Society proposes two pathways for diagnosis without biopsy 6, 4:

1. ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) plus MRI abnormality, OR
2. ≥2 pituitary hormone deficiencies (TSH or ACTH deficiency required) plus headache and other symptoms

Differential Diagnosis Considerations

Rule out the following before diagnosing primary autoimmune hypophysitis 6:

• Infectious etiologies (tuberculosis, syphilis, fungal infections)
• Granulomatous diseases (sarcoidosis, Wegener's granulomatosis)
• IgG4-related disease
• Pituitary adenomas
• Metastatic disease
• Germinoma (especially if diabetes insipidus is present)

Autoantibody Testing Limitations

Anti-pituitary antibodies (APA) can be detected by indirect immunofluorescence, with target autoantigens including alpha-enolase, gamma-enolase, pituitary gland-specific factors (PGSF) 1 and 2, and TPIT 7. However, the low diagnostic sensitivity and specificity of APA strongly limit their clinical utility 7. Newer markers such as anti-rabphilin 3A are under investigation but are not yet commercially available and lack consistent diagnostic value 2.

Management Principles

Hormone Replacement Therapy

Physiological hormone replacement is the cornerstone of management, not high-dose steroids 4:

• Hydrocortisone 20/10 mg if morning cortisol is low 1, 4
• Critical safety rule: Always replace cortisol for at least 1 week before initiating levothyroxine to prevent adrenal crisis 1, 4
• Levothyroxine 50-100 mcg/day (or 0.5-1.5 μg/kg) after ensuring adequate cortisol replacement, starting low in elderly patients or those with cardiac history 1, 4
• Monitor TSH and free T4 every 1-2 weeks initially 1, 4
• Testosterone or estrogen replacement should be considered if levels are low 1

Glucocorticoid Therapy for Mass Effect

High-dose steroids are reserved exclusively for severe neurological symptoms due to mass effect (headaches, visual disturbances), not for treating the hormonal deficiency itself 1, 4, 2. Importantly, high-dose steroids do not reverse the hormonal deficiency resulting from hypophysitis 1.

Immunotherapy Management

• Continue ICI therapy for asymptomatic or mild cases (grade 1) 1
• Withhold ICI for grade 2 or higher hypophysitis until symptoms are controlled 1
• Permanent discontinuation is rarely necessary; most patients can resume ICI after stabilization with hormone replacement 1

Surgical Intervention

Surgery should be limited to specific scenarios 4:

• Severe compressive symptoms with progressive deterioration
• Lack of response to medical treatment with progressive visual deterioration
• Preferred approach: Standard transnasal route 4

Immunosuppressive Therapies

For refractory cases or when glucocorticoids and/or surgery fail 4, 2:

• Rituximab: Most commonly used immunosuppressant with successful response in approximately two-thirds of patients, particularly effective in B-cell predominant hypophysitis 4, 8
• Alternative agents: Azathioprine, methotrexate, cyclosporine A, mycophenolate 4, 2

Patient Safety Measures

All patients with adrenal insufficiency must 4:

• Obtain and wear a medical alert bracelet
• Receive education on "sick day" rules (doubling or tripling hydrocortisone during illness)
• Have a prescription for emergency parenteral steroid use

Prognosis

Hypophysitis usually results in acute and persistent pituitary hormone deficiency requiring long-term replacement 2. The initial pituitary enlargement can evolve to remission with spontaneous or pharmacological resolution of inflammation, or progress to diffuse destruction with gland atrophy and fibrotic replacement 7. Hormone replacement is typically lifelong in most cases 1, 4.