Primary Hypophysitis

Description

Primary hypophysitis refers to inflammation of the pituitary gland primarily, without a known triggering systemic or local disease. The condition can result in various forms of hypopituitarism due to functional impairment of the pituitary gland. This condition is distinct from secondary hypophysitis, which is caused by systemic diseases, infections or extension from adjacent anatomical structures such as Rathke’s cleft cysts, craniopharyngiomas or pituitary adenomas. Primary hypophysitis includes several histological subtypes each with unique clinical and radiographic presentations.

Subtype

• Lymphocytic hypophysitis (most common, typically occurs in females in the postpartum period)
• Granulomatous hypophysitis (often idiopathic but can be associated with systemic granulomatous diseases)
• Xanthomatous hypophysitis (very rare, characterised by lipid-laden macrophages)
• IgG4-related hypophysitis (part of the spectrum of IgG4-related disease, often associated with multi-organ involvement)
• Necrotising hypophysitis (rare, severe form with necrosis of the pituitary)

Pathogenesis

Hypophysitis is categorised based on the nature of the inflammatory cells that infiltrate the pituitary gland. The exact pathogenesis remains unclear, but it is generally thought to involve an abnormal immune response to various triggers.

• Lymphocytic Hypophysitis: This is the most common type of primary hypophysitis. It is believed to be an autoimmune disorder, where autoantibodies or T lymphocytes are directed against pituitary cell antigens. Pregnancy and the postpartum period are suspected to be precipitating factors, due to the expansion and increased activity of the pituitary gland during this time, which could expose hidden antigens to the immune system. Additionally, sex steroid hormones might enhance autoimmunity, which could explain the female predominance. The condition can also occur in individuals with other autoimmune diseases, suggesting shared genetic or environmental susceptibility.
• Granulomatous Hypophysitis: This rare form of hypophysitis is characterised by the presence of granulomas within the pituitary gland. The exact pathogenesis is unknown, but it may be a response to a non-identified infectious agent or an exaggerated immune response to pituitary antigens.
  • Possible secondary causes of granulomatous hypophysitis include tuberculosis, sarcoidosis, syphilis, Langerhans’ histiocytosis, granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis), and Rathke’s cleft cyst ruptur
• Xanthomatous Hypophysitis: This is an extremely rare subtype of hypophysitis, and its pathogenesis is unclear. It is hypothesised to be due to a response to an unknown inciting factor leading to accumulation of lipid-laden macrophages, forming xanthomas.
• IgG4-Related Hypophysitis: This form of hypophysitis is part of the spectrum of IgG4-related diseases, which are systemic disorders characterised by the presence of lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, fibrosis, and often, but not always, elevated serum IgG4 concentration. The exact pathogenesis is unknown, but it is believed to involve an immune response to an unidentified antigen, followed by an exaggerated fibrotic response.
• Necrotising Infundibulo-Hypophysitis: The pathogenesis of this extremely rare subtype is unclear. There is typically extensive necrosis and inflammation. It may be due to an aggressive immune response against an unknown antigen, leading to extensive tissue damage and cell death.

Epidemiology, Risk Factors & Associations

• Exact incidence is unknown due to the rarity of the condition and lack of large epidemiological studies.
• Female sex and pregnancy/postpartum state are the most significant risk factors (most common in females in the third trimester or early postpartum period).
• Some cases are associated with other autoimmune conditions such as Hashimoto’s thyroiditis and type 1 diabetes.

Clinical Features

Primary hypophysitis presents with a spectrum of symptoms categorised into mass effect, hypopituitarism, and systemic inflammation.

• Mass Effect: Symptoms include visual disturbances (bitemporal hemianopia) and headache due to pituitary gland enlargement and consequent compression of surrounding structures.
• Hypopituitarism: Symptoms depend on the deficient hormone and may include fatigue, weakness, irregular menstruation, decreased libido, and increased urination and thirst. The specific presentation varies depending on the part of the pituitary affected:
  • Adenohypophysitis (~65% of cases): Dysfunction of the anterior pituitary may lead to symptoms such as fatigue, weakness, amenorrhoea, impotence, and lactation failure due to deficiencies in hormones such as ACTH, TSH, LH, FSH, and PRL.
  • Infundibulo-neurohypophysitis (10%): Involvement of the posterior pituitary or the pituitary stalk can lead to diabetes insipidus, presenting with polyuria and polydipsia due to a deficiency of ADH (vasopressin).
  • Panhypophysitis (25%): Patients with this condition may present with symptoms of both anterior and posterior pituitary dysfunction.
• Systemic Inflammation: Non-specific symptoms like fever or malaise may be present. In IgG4-related hypophysitis, systemic disease manifestations, such as pancreatitis or retroperitoneal fibrosis, may be observed.

Specific subtype manifestations include:

• Lymphocytic Hypophysitis: Primarily affects late pregnant or postpartum women, leading to headaches, visual disturbances, and hormonal dysfunctions like amenorrhoea and galactorrhoea.
• Granulomatous Hypophysitis: May present with diabetes insipidus due to posterior pituitary or pituitary stalk involvement, along with other symptoms of hypopituitarism and mass effect.
• IgG4-Related Hypophysitis: Along with typical features, patients may have symptoms related to systemic IgG4-related disease affecting other organs.

Complications

The major complications of primary hypophysitis include:

• Hypopituitarism: Chronic or acute insufficiency of one or more pituitary hormones is a common complication. This can lead to a range of health problems depending on the specific hormones that are deficient.
• Pituitary Apoplexy: A rare but severe complication characterised by the sudden haemorrhage or infarction of the pituitary gland. Symptoms include a sudden onset headache, visual impairment, and altered consciousness. In the context of hypophysitis, this could be due to the inflammation leading to vascular compromise within the pituitary gland.

Pathological Features

Histopathology

• Macroscopic: Enlarged pituitary gland
• Microscopic: Infiltration by inflammatory cells, which may vary based on subtype

Serology

• Variable, may reveal elevated inflammatory markers, abnormal pituitary hormone levels

Biochemistry

• Hormone deficiencies may be detected in serum (e.g., low cortisol, thyroxine, sex hormones)

Radiological Features

General Features

• Enlarged pituitary gland with homogenous enhancement
• Thickening of the infundibulum (stalk) with loss of normal tapering can be a key imaging feature
• No cavernous sinus invasion unlike neoplasms
• Each subtype can have slightly different imaging features

CT

• Non-contrast: Iso- to hyperdense pituitary gland
• Contrast-enhanced: Homogenous enhancement

MRI

• T1WI: Hypointense to isointense pituitary gland
• T2WI: Hypointense or isointense
• T1 C+: Homogeneous enhancement, “bright spot” of the posterior pituitary may be lost
• DWI/ADC: Restricted diffusion is not typical

PET FDG

• FDG uptake can be variable but usually not significantly elevated

Diagnosis

The diagnosis of hypophysitis is typically made on the basis of clinical presentation, imaging findings, and evidence of pituitary hormone deficiencies. Histological confirmation via biopsy is considered the gold standard for diagnosis, but the invasive nature of the procedure often makes it impractical.

Differential Diagnosis

• Pituitary adenoma: No stalk thickening, may have a “dural tail” sign, can invade cavernous sinus, typically has microadenomas (<10mm) or macroadenomas (>10mm) presentation.
• Sarcoidosis: Systemic symptoms and other organ involvement, non-caseating granulomas can be seen on biopsy.
• Langerhans cell histiocytosis: More common in children, lytic bone lesions, often multisystem disease.

Management

Treatment strategies can be diverse. In mild cases, watchful waiting may be employed. Use of glucocorticoids and other immunosuppressants may be necessary, along with hormone replacement therapy for pituitary deficiencies. Surgical intervention can be indicated in cases of significant mass effect, but is generally considered a last resort due to the potential for complications.