EndocrinologyTier 2Disease (DEADMAN)

Hypothalamic–pituitary axis disorders - hypophysitis

Description

Inflammation of the pituitary +/- stalk +/- hypothalamus
Presents as hypopituitarism + a sellar mass, with headache out of proportion to size

Classification

Primary (autoimmune)
- Lymphocytic - commonest; anterior (adenohypophysitis), infundibuloneurohypophysitis, or panhypophysitis
- Granulomatous, xanthomatous, necrotising, plasmacytic (IgG4-related)
Secondary
- Drug-induced - checkpoint inhibitors (now the commonest cause seen by a physician)
- Systemic disease - sarcoidosis, granulomatosis with polyangiitis, Langerhans cell histiocytosis, IgG4-RD, TB, syphilis
- Adjacent lesion - Rathke cleft cyst, craniopharyngioma, germinoma

Hormone loss is not random
- Autoimmune/lymphocytic: ACTH and TSH lost first, gonadotrophins later
- Opposite to a compressing adenoma, where GH and gonadotrophins go first ("Go Look For The Adenoma": GH, LH/FSH, TSH, ACTH)

Checkpoint inhibitor hypophysitis - incidence by class

Agent class	Incidence
Anti-CTLA-4 (ipilimumab)	~3.2% (dose-dependent)
Anti-PD-1 (nivolumab, pembrolizumab)	~0.4%
Anti-PD-L1 (atezolizumab, durvalumab)	<0.1%
Combination CTLA-4 + PD-1	~6.4%

Anti-CTLA-4 hypophysitis: M>F, older, onset ~8-12 weeks after starting
Anti-PD-1 endocrinopathy is more often isolated ACTH deficiency, later onset (median ~4-6 months), and may present without a mass

Primary lymphocytic hypophysitis

Rare: ~1 per 9 million/yr
F>M ~4:1
Strong temporal link to late pregnancy and the postpartum period (adenohypophysitis)
IgG4-related hypophysitis: M>F, older

Lymphocytic - T-cell mediated infiltration of the gland, diffuse lymphoplasmacytic infiltrate -> oedema and enlargement -> later fibrosis and an empty sella
- Anti-pituitary antibodies described (poorly standardised, not diagnostic)
Checkpoint inhibitors
- CTLA-4 is constitutively expressed on human pituitary endocrine cells -> antibody binds -> type II/IV hypersensitivity, complement fixation
- Explains why CTLA-4 blockade causes hypophysitis while PD-1/PD-L1 blockade causes thyroiditis and T1DM more often
IgG4-RD - storiform fibrosis, obliterative phlebitis, IgG4+ plasma cells
Genetic predisposition: HLA-DQ8, DR53

Clinical

Headache - prominent, early, often precedes hormone deficiency
Fatigue, nausea, hypotension, hyponatraemia -> secondary adrenal insufficiency
Visual field defect (less common than with an adenoma of similar size)
Diabetes insipidus in ~15-20% of primary hypophysitis
- *Very rare in checkpoint-inhibitor hypophysitis - DI in a patient on immunotherapy should prompt a search for a pituitary metastasis* instead
Hyperprolactinaemia (stalk effect) or hypoprolactinaemia (gland destruction)

Biochemistry

9am cortisol + ACTH - low cortisol with inappropriately low/normal ACTH = secondary AI
- Short Synacthen may be falsely normal in the first 2-4 weeks - adrenals not yet atrophied
Central hypothyroidism: low fT4 with low or inappropriately normal TSH (never diagnose on TSH alone)
LH/FSH + testosterone/oestradiol, IGF-1, prolactin, Na, BGL
Paired serum/urine osmolality + Na if polyuric
IgG4, ACE, ANCA, CXR if primary/systemic cause suspected

MRI

Symmetrical pituitary enlargement with homogeneous enhancement
Thickened, enhancing stalk (non-deviated)
Loss of the posterior pituitary bright spot if DI
Dural tail; suprasellar extension
Versus adenoma: asymmetric, hypoenhancing relative to normal gland, stalk deviated
Checkpoint-inhibitor hypophysitis often shows only subtle enlargement, and the MRI may be normal by the time it is done

Checkpoint-inhibitor hypophysitis

Hormone replacement is the treatment. Immunotherapy usually continues.
Hydrocortisone replacement first - 10-15 mg mane, 5 mg midday (do not start thyroxine before)
- Sick-day rules, MedicAlert, emergency IM hydrocortisone
High-dose glucocorticoid (prednisolone ~1 mg/kg) only for mass effect, severe headache or visual compromise - no evidence it preserves pituitary function, and may blunt tumour response
Thyroxine once glucocorticoid replaced
Testosterone/oestrogen replacement as appropriate; GH generally deferred in active malignancy
Withhold immunotherapy only until clinically stable on replacement

Primary lymphocytic hypophysitis

Replace deficient axes - the same principle
High-dose glucocorticoid for mass effect or visual loss
- Relapse common on withdrawal
Second-line immunosuppression: azathioprine, methotrexate, rituximab (esp. IgG4-related)
Surgery reserved for diagnostic uncertainty or decompression - not therapeutic
Radiotherapy for refractory disease
IgG4-related: corticosteroids, then steroid-sparing agent or rituximab

Monitoring

Repeat pituitary axis testing at 4-6 weeks, then periodically
Repeat MRI at 4-8 weeks - failure of the mass to shrink questions the diagnosis

Ipilimumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab
Pregnancy and postpartum (lymphocytic adenohypophysitis)
Other autoimmune disease: Hashimoto's, Graves', T1DM, Addison's, coeliac, pernicious anaemia, APS
IgG4-related disease - pancreatitis, retroperitoneal fibrosis, sialadenitis
Sarcoidosis, granulomatosis with polyangiitis, Langerhans cell histiocytosis, Erdheim-Chester
TB, syphilis, fungal infection
Rathke cleft cyst (ruptured -> chemical hypophysitis)
Germinoma, craniopharyngioma, pituitary metastasis (breast, lung - classically present with DI)

ACTH deficiency is usually permanent (>80-90%)
Thyroid and gonadal axes recover in ~50% over months
Posterior pituitary function may recover in primary hypophysitis
MRI abnormality resolves in most within 1-2 months; late empty sella
Primary lymphocytic hypophysitis: spontaneous remission occurs, but permanent deficits in most

Complications

Adrenal crisis - the cause of death
- Risk peaks when an unrecognised case is stressed by infection, surgery or chemotherapy
Hyponatraemia
Visual loss from chiasmal compression
Infertility, osteoporosis, fatigue and reduced quality of life from under-replacement
Checkpoint-inhibitor hypophysitis does not predict poorer cancer outcome - some series suggest better survival

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