What is the diagnostic workup for Autoimmune Hypophysitis (Lymphocytic)?

Diagnostic Workup for Autoimmune (Lymphocytic) Hypophysitis

The diagnostic workup requires comprehensive hormonal evaluation with morning cortisol, ACTH, TSH, free T4, gonadal hormones (testosterone in men, estradiol in premenopausal women, FSH, LH), combined with MRI of the sella with pituitary cuts, and confirmation requires either ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) plus MRI abnormality, or ≥2 pituitary hormone deficiencies (TSH or ACTH deficiency required) with headache and other symptoms. 1, 2

Initial Clinical Assessment

Key Presenting Features to Identify

• Headache occurs in 85% of patients and is the most common presenting symptom 3
• Fatigue is present in 66% of cases 3
• Visual disturbances from mass effect, though less common than headache 3, 4
• Symptoms of hormone deficiencies: cold intolerance, weakness, menstrual irregularities, decreased libido 5, 6
• Diabetes insipidus occurs in only 7-16.7% of cases and should prompt consideration of other diagnoses if prominent 1, 5

Critical Context to Elicit

• Pregnancy or postpartum status: 57% of lymphocytic adenohypophysitis cases occur during pregnancy or postpartum 4, 6
• Other autoimmune conditions: present in 18-25% of patients with autoimmune hypophysitis 4, 7
• Recent immunotherapy exposure: particularly anti-CTLA-4 agents (ipilimumab) which cause hypophysitis in up to 17% at high doses 3, 1

Mandatory Laboratory Evaluation

Morning Hormonal Panel (Preferably 8 AM)

All tests should be performed before administering steroids to avoid interference with results 3, 2:

• Adrenal axis: ACTH and cortisol (or 1 mcg cosyntropin stimulation test if baseline cortisol is 3-15 mg/dL) 3, 2
• Thyroid axis: TSH and free T4 3, 2
• Gonadal axis: testosterone in men, estradiol in premenopausal women, FSH, LH 3, 2
• Prolactin: may be elevated or deficient 4, 6
• IGF-1: to assess growth hormone status 2
• Glucose and HbA1c: for glycemic monitoring 3, 2

Characteristic Hormonal Pattern

The pattern of hormone deficiency in autoimmune hypophysitis differs from typical pituitary adenomas 4, 6:

• ACTH deficiency is typically the earliest and most frequent (75% of cases), unlike pituitary adenomas where gonadotropins are usually affected first 5, 4, 6
• TSH deficiency occurs in 58% 5
• Gonadotropin deficiency in 50% 5
• Central hypothyroidism presents with low free T4 and low/normal TSH (not elevated TSH as in primary hypothyroidism) 3, 2

Imaging Requirements

MRI of the Sella with Pituitary Cuts

MRI with gadolinium contrast is mandatory for all suspected cases 3, 1:

Characteristic MRI Findings in Autoimmune Hypophysitis

• Symmetrical pituitary enlargement in 91.7% of cases 5
• Homogeneous enhancement after gadolinium in 91.7% 5
• Stalk thickening in 87.5% 5
• Suprasellar extension in 87.5% 5
• Loss of posterior pituitary bright spot (T1 hyperintensity) in 71.5% 5
• Dural tail sign: enhancement of adjacent dura 6
• Undisplaced stalk despite thickening, contrasting with pituitary adenomas which typically displace the stalk 4

Diagnostic Confirmation Criteria

Two pathways exist for diagnosis without biopsy 1, 2:

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

When Pituitary Biopsy Is Indicated

Biopsy is not routinely necessary if clinical, hormonal, and radiological features are characteristic 1, 4. However, consider biopsy when 4, 7:

• Diagnosis remains uncertain despite complete workup
• Progressive visual deterioration despite medical management
• Inability to distinguish from pituitary adenoma or other sellar masses
• Atypical presentation requiring definitive diagnosis

Additional Diagnostic Considerations

Antipituitary Antibodies

• Detected in up to 70% of biopsy-proven cases but not specific enough for routine diagnostic use 7
• Their role remains investigational and should not guide clinical decision-making 6, 7

Exclusion of Secondary Causes

Rule out other causes of hypophysitis before diagnosing primary autoimmune hypophysitis 5:

• Infectious etiologies (tuberculosis, syphilis, fungal)
• Granulomatous diseases (sarcoidosis, Wegener's granulomatosis)
• IgG4-related disease (check serum IgG4 levels in appropriate clinical context) 1
• Metastatic disease
• Recent immunotherapy exposure (checkpoint inhibitor-induced hypophysitis is a distinct entity) 3, 1

Critical Pitfalls to Avoid

Timing of Steroid Administration

Never start thyroid hormone replacement before ensuring adequate cortisol replacement, as this can precipitate life-threatening adrenal crisis 1, 2. If both deficiencies are present, initiate hydrocortisone at least 1 week before starting levothyroxine 1.

Acute Adrenal Insufficiency

ACTH deficiency can present as acute secondary adrenal insufficiency as the first manifestation, carrying high mortality if unrecognized 6. Maintain high clinical suspicion in patients presenting with unexplained hypotension, hyponatremia, or hypoglycemia.

Misdiagnosis as Pituitary Adenoma

The symmetrical, homogeneous enhancement pattern with undisplaced but thickened stalk helps distinguish hypophysitis from adenomas, which typically show asymmetric growth and stalk displacement 5, 4. However, definitive distinction may require biopsy in ambiguous cases.

Diabetes Insipidus as Red Flag

While diabetes insipidus can occur in lymphocytic infundibuloneurohypophysitis, its presence—especially as a prominent feature—should prompt consideration of metastatic disease, germinoma, or other infiltrative processes rather than typical autoimmune hypophysitis 3, 1.