Lymphocytic Hypophysitis

Lymphocytic hypophysitis is autoimmune inflammation of the pituitary gland, mainly the anterior lobe (adenohypophysitis), with infundibuloneurohypophysitis and panhypophysitis as variants.

It is rare, about 1 case in 9,000,000 people each year. The classic patient is a woman in late pregnancy or the first postpartum months, and men present later in life. Other autoimmune disease is common.

Immune checkpoint inhibitor hypophysitis (with ipilimumab, nivolumab and pembrolizumab) is the most common secondary form. Natural history varies: mass effect may resolve spontaneously, but ACTH deficiency often persists.

Pathophysiology.

Lymphocytic infiltration with plasma cells and fibrosis damages hormone secreting cells. Antipituitary antibodies are unreliable for diagnosis.

ACTH deficiency is the most common, then thyroid stimulating hormone and gonadotrophin deficiency. Prolactin may be high or low. Diabetes insipidus occurs in infundibular forms.

• Headache, fatigue, nausea and visual disturbance.
• Adrenal insufficiency, hypothyroidism, amenorrhoea, lactation failure postpartum and, with posterior involvement, polyuria and thirst.

Red flags.

• Adrenal crisis: hypotension, hyponatraemia, hypoglycaemia.
• Progressive visual field loss or reduced acuity.

• MRI: diffuse symmetric gland enlargement with homogeneous enhancement, a thickened stalk, loss of the posterior bright spot and a dural tail. Rapid change on serial imaging favours hypophysitis over an adenoma.
• Morning cortisol: under 100 nmol/L (3.6 micrograms/dL) strongly suggests deficiency, and over 400 nmol/L (about 14.5 micrograms/dL) makes it unlikely. A short tetracosactide 250 micrograms test is used for intermediate values (peak cortisol under about 450 nmol/L, assay dependent, indicates deficiency).
• Free thyroxine with thyroid stimulating hormone (low or inappropriately normal), LH, FSH, sex steroids, prolactin, IGF-1, serum sodium, and paired serum and urine osmolality.
• Exclude other causes: IgG4 level, serum angiotensin converting enzyme, ANCA, tuberculosis and syphilis serology, and biopsy if atypical or progressive.

Differential diagnosis.

• Pituitary adenoma and apoplexy.
• Sheehan syndrome (postpartum infarction).
• Sarcoidosis, granulomatosis with polyangiitis, IgG4-related disease and tuberculosis.
• Langerhans cell histiocytosis, germinoma, craniopharyngioma, lymphoma and metastasis.
• Immune checkpoint inhibitor effect.

• Replace deficits. Hydrocortisone 15 to 25 mg daily in two or three divided doses (for example 10 mg on waking, 5 mg at noon, 5 mg in the late afternoon). Double the dose for fever or illness, and give hydrocortisone 100 mg intramuscularly or intravenously for vomiting or collapse. Issue a steroid alert card.
• Start levothyroxine only after glucocorticoid cover: about 1.6 micrograms/kg daily (25 to 50 micrograms in older adults or heart disease), adjusted to free thyroxine in the mid to upper reference range because thyroid stimulating hormone cannot be used. Desmopressin 100 micrograms orally at night for diabetes insipidus, titrated to 100 to 200 micrograms two to three times daily with sodium checks.
• Mild disease: observe with repeat MRI and visual fields.
• Visual threat, severe headache or progression: prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg) tapered over 6 to 8 weeks, or intravenous methylprednisolone 1 g daily for 3 days for acute visual loss. Surgical decompression if visual loss persists or the diagnosis is uncertain.
• Relapse: azathioprine, methotrexate or rituximab.
• Checkpoint inhibitor hypophysitis: replace hormones and continue the immunotherapy if the patient is stable. Use high dose steroids only for mass effect.

Special groups. Pregnancy and breastfeeding: hydrocortisone and levothyroxine are compatible. Adjust replacement in pregnancy and give stress cover in labour.

Monitoring. Pituitary function at 3, 6 and 12 months then yearly. MRI at 3 months then at 6 to 12 months. Visual fields during active disease.

Referral and escalation. Endocrinology for all cases; neurosurgery and ophthalmology for visual loss. Same day review for adrenal crisis.