IgG4-Related Hypophysitis

IgG4-related hypophysitis is pituitary and stalk involvement in IgG4-related disease, characterised by IgG4-positive plasma cell infiltration and storiform fibrosis.

It is rare and affects men more often than women, usually in the sixth decade. Many patients have other organ involvement (pancreas, salivary and lacrimal glands, retroperitoneum, kidney and biliary tree).

It overlaps with lymphocytic hypophysitis and is confirmed by histology or by the presence of IgG4-related disease in another organ.

Pathophysiology.

T helper 2 and regulatory T cell activity drives IgG4-positive plasma cell infiltration, fibrosis and obliterative phlebitis, damaging the stalk and the anterior and posterior lobes.

• Headache, polyuria and thirst (diabetes insipidus), fatigue and features of anterior hypopituitarism.
• Visual loss is uncommon. Systemic features: swelling of salivary or lacrimal glands, jaundice, back or flank pain and weight loss.

Red flags.

• Visual loss or adrenal crisis.
• Obstructive jaundice or hydronephrosis from other organ disease.

• MRI: thickened stalk or sellar mass with enhancement.
• Serum IgG4 (raised, 1.35 g/L or more, in many patients, but normal in a minority).
• Whole body CT or PET-CT to find other organ disease. Biopsy of an accessible lesion: over 10 IgG4-positive plasma cells for each high power field, IgG4 to IgG ratio over 40% and storiform fibrosis.
• Pituitary hormones, serum sodium and osmolality, and a water deprivation or desmopressin test if diabetes insipidus is suspected.

Differential diagnosis.

• Lymphocytic hypophysitis and pituitary adenoma.
• Granulomatosis with polyangiitis, sarcoidosis, tuberculosis and histiocytosis.
• Germinoma, lymphoma and metastasis.

• Prednisolone 0.6 mg/kg daily (usually 30 to 40 mg) for 2 to 4 weeks, then reduce by 5 mg every 1 to 2 weeks to a maintenance dose of 5 to 10 mg, continuing low dose treatment for up to 3 years to limit relapse.
• Steroid sparing treatment for relapse or intolerance: rituximab 1 g intravenously on days 1 and 15, azathioprine 2 to 2.5 mg/kg daily (check thiopurine methyltransferase), mycophenolate mofetil 1 to 2 g daily, or methotrexate.
• Replace deficits: hydrocortisone 15 to 25 mg daily in two or three divided doses with stress cover, levothyroxine after glucocorticoid, and desmopressin 100 micrograms orally at night, titrated to 100 to 200 micrograms two to three times daily with sodium checks. Diabetes insipidus often persists.

Monitoring. IgG4 and MRI at 3 months, organ imaging, pituitary function and serum sodium every 3 to 6 months. Watch for relapse on steroid reduction.

Referral and escalation. Endocrinology and rheumatology (or clinical immunology). Urgent review for visual loss.