BASICS
DESCRIPTION
- A rare autoimmune disease that occurs when the pituitary gland is infiltrated with lymphocytes and plasma cells, leading to impaired hormonal secretion
- Patients present with varying degrees of pituitary hormonal impairment or enlargement.
- Cause is usually unknown.
- The most common form affects the anterior pituitary and causes hypopituitarism.
- Less commonly affects the infundibulum or posterior pituitary, causing diabetes insipidus and hyperprolactinemia
EPIDEMIOLOGY
- Predominantly seen in women: female > male (6:1)
- Strong association with pregnancy, most frequently occurring in the gestational or postpartum period
- Females tend to present at a younger age (35 years) than do males (45 years).
Incidence
- Annual incidence estimated at 1 case per 9 million
- Thought to be underestimated because of the following:
- Frequency of case reports are increasing
- Undiagnosed cases due to indolent disease
Prevalence
- Uncommon
- Found in <1% of all surgical pituitary samples
ETIOLOGY AND PATHOPHYSIOLOGY
- Most commonly caused by an autoimmune infiltration that includes an admixture of T and B lymphocytes with plasma cells
- Causes extrasellar pituitary enlargement
- CD8 T cells mediate the attack on pituitary cells.
- Antipituitary antibodies are considered markers of the T-cell mediation and are detectable in serum.
- It is unknown if antipituitary antibodies play a pathogenic role.
- Can also be caused by an inflammatory process
- Initially leads to symptoms consistent with a pituitary mass effect (similar to pituitary adenoma)
- Followed by fibrosis and shrinkage, causing differing degrees of hypopituitarism
- Extension of the inflammatory process into the posterior pituitary and up into the neurohypophysis leads to diabetes insipidus, which is more common in males.
- With complete progression, panhypopituitarism occurs with an empty sella turcica.
- Autoimmune
- Inflammatory
Genetics
- Patients often have family history of autoimmunity.
- HLA DR4 allele
- HLA DR5 allele
- Can be associated with antibody to PIT1 (POU1F1).
RISK FACTORS
- Female gender
- Pregnancy
- Pregnant type 1 diabetics are at even higher risk.
- Personal or family history of autoimmune disease
- May be associated with viral infections, particularly meningoencephalitis
- CTLA-4 antibody cancer treatment (e.g., ipilimumab or tremelimumab)
GENERAL PREVENTION
None
COMMONLY ASSOCIATED CONDITIONS
- Aseptic meningitis: unknown if simple association or causal
- Other autoimmune polyendocrinopathies are the following:
- Hashimoto thyroiditis; Graves disease is most common.
- Addison disease, type 1 diabetes mellitus, central diabetes insipidus, chronic atrophic gastritis, polyglandular autoimmune disease type 1, systemic lupus erythematosus, Sj Άgren syndrome, autoimmune hepatitis, pernicious anemia, and primary biliary cirrhosis
DIAGNOSIS
HISTORY
- Four categories of symptoms are the following: pituitary enlargement, hypopituitarism, diabetes insipidus, and hyperprolactinemia (1)[C].
- Initial presentation is most often related to pituitary enlargement and includes the following:
- Headache
- Visual field changes, often with bitemporal hemianopsia due to chiasmal compression (2)[C]
- Decreased acuity, diplopia (3)[C]
- 3rd, 4th, or 6th cranial nerve palsies
- As the disease progresses, patients have varying symptoms of adrenal insufficiency, hypothyroidism, or hypogonadism secondary to anterior pituitary failure including (4)[C] the following:
- Hypotension
- Dizziness
- Temperature intolerance
- Fatigue
- Weight fluctuations
- Loss of libido
- Impotence
- Amenorrhea
- Hypoglycemia
- Other symptoms are due to diabetes insipidus from posterior pituitary failure:
- The least common symptoms are due to hyperprolactinemia with the following:
- Galactorrhea
- Amenorrhea
- Oligomenorrhea
PHYSICAL EXAM
Physical exam is usually normal, but patients may have subtle findings, such as mild changes in blood pressure, weight, temperature, and visual field deficit testing.
DIFFERENTIAL DIAGNOSIS
- Gestational hypopituitarism
- Sheehan syndrome
- Pituitary adenoma
- Pituitary dysgerminoma
- Langerhans cell histiocytosis
- Rathke cysts
- Granulomatous hypophysitis such as neurosarcoidosis, tuberculosis, and Wegener granulomatosis
- Xanthomatous hypophysitis
DIAGNOSTIC TESTS & INTERPRETATION
In lymphocytic (autoimmune) hypophysitis, the hormone deficiency pattern consists of early deficiency of thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) with relative sparing of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and growth hormone (GH) secretion. This is in contrast to the hormone loss pattern of macroadenomas (which is typically the sequential loss of GH, LH/FSH, and later TSH and ACTH) (2)[C].
Initial Tests (lab, imaging)
- Cortisol
- TSH
- Free T3 and T4
- ACTH stimulation test
- Acutely, ACTH deficiency with low levels of cortisol, which may be the first and only element of hypopituitarism
- Testosterone
- Prolactin
- MRI with and without gadolinium contrast (1)[C]
- Usually reveals symmetric pituitary enlargement with suprasellar extension that can displace the optic chiasm
- With gadolinium, there is intense homogeneous pituitary enhancement.
- Strip of enhancement along the dura mater, known as the "dural tail. "
- Thickened infundibulum
Follow-Up Tests & Special Considerations
- Other autoimmune testing: ANA, antithyroglobulin antibody, antithyroperoxidase antibody, antipituitary antibody (4)[C]
- MRI findings can be difficult to differentiate from a pituitary adenoma. Thus, the detection of high antipituitary antibody titers would suggest lymphocytic hypophysitis (3)[C].
- FSH and LH levels are often normal.
- GH deficiency, if present, is usually the last deficit.
- Insulin tolerance testing, IGF
- Bone morphogenic proteins and urine osmolality to detect diabetes insipidus if the posterior pituitary is involved.
- The disease is often classified as suspected, biopsy proven, subacute, or chronic.
Diagnostic Procedures/Other
Gold standard for diagnosis is transsphenoidal pituitary biopsy.
Test Interpretation
- Gross pathology shows significant pituitary atrophy.
- Histopathology (3)
- An inflammatory process with diffuse infiltration of T and B lymphocytes with plasma cells within the anterior pituitary
- Lymphocytes can aggregate to form lymphoid follicles with germinal centers associated with areas of atrophic pituitary cells.
- There can be occasional eosinophils, macrophages, histiocytes, mast cells, remnant pituitary cells, and reactive fibrosis.
TREATMENT
- Spontaneous remission can occur (3)[C].
- With acute presentation, the immediate concern is to treat the underlying hypopituitarism, decrease mass effect to preserve vision, reduce inflammation, and exclude pituitary tumor (1)[C].
- Conservative management is more likely to be successful in subacute cases presenting with hypopituitarism and a resolving pituitary mass.
- Because spontaneous remission has been reported, many endocrinologists and neurosurgeons advocate a conservative approach, with or without a trial of immunosuppression.
MEDICATION
First Line
- High-dose steroids as immunosuppressive agents reported to reduce the mass effect in some patients:
- Most often includes methylprednisolone therapy of 120 mg/day for 2 weeks, then tapering doses over 1 month
- Methylprednisolone has been tried up to lymphocytotoxic doses of 1 g for 3 days.
- High-dose methylprednisolone pulse therapy of 500 mg/day for 2 days followed by taper and maintenance dosing appears to be useful for both therapy and to diagnose patients with overlapping findings of adenoma. Patients often require long-term low-dose maintenance therapy of 10 mg/day.
- Glucocorticoids can reduce the size of the pituitary mass and act as a replacement for adrenal function.
Second Line
- Dopamine agonists (bromocriptine or cabergoline) can treat hyperprolactinemia and improve visual field changes, but long-term impact on the course of the disease is unproven.
- Desmopressin (DDAVP) if diabetes insipidus is present
- Other immunosuppressive drugs: methotrexate, azathioprine, cyclophosphamide, cyclosporine (1, 2, 3, 4)[C]
ISSUES FOR REFERRAL
- When the diagnosis of lymphocytic hypophysitis is presumed, the patient should be referred to an endocrinologist for evaluation and management of hormone replacement.
- Neurosurgical referral should be considered.
- Ophthalmology referral should be considered for complete visual field testing.
ADDITIONAL THERAPIES
- Hypopituitarism must be corrected with appropriate hormone replacement therapy.
- Low-dose stereotactic pituitary radiotherapy can be used in patients resistant to conventional therapy (4)[C].
SURGERY/OTHER PROCEDURES
- Indications for surgical intervention (4)[C]:
- Need for definitive diagnosis
- Mass reduction when visual compromise does not improve rapidly with medical therapy
- For recurrent mass effects despite treatment
- Need for tissue sample
- Surgical complications include the following:
- Bleeding
- Cerebrospinal fluid leaks
- Diabetes insipidus
- Permanent hypopituitarism
- Rarely, recurrence of the inflammatory mass requires a second surgery to alleviate symptoms.
- Patients who present with hypopituitarism, diabetes insipidus, or hyperprolactinemia rarely benefit from surgery because the defects are due to pituitary destruction, not compression.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Careful follow-up of hormone levels to determine appropriate hormone replacement, serial visual field testing, and annual imaging are recommended.
PROGNOSIS
- Spontaneous recovery of pituitary function with mass reduction can occur.
- Transient hypopituitarism can be due to a compression of the pituitary cells by the inflammatory infiltrate or edema.
- In some cases, the natural disease course is characterized by cycles of remission and relapse.
- Permanent hypopituitarism, if it occurs, requires lifelong hormonal replacement therapy.
- ACTH deficiency rarely leads to acute adrenal insufficiency in lymphocytic hypophysitis.
COMPLICATIONS
Usually the result of long-term steroid use, such as osteoporosis, diabetes, cataracts, cushingoid features, weight gain, and bilateral femoral head necrosis
REFERENCES
11 Caturegli P, Newshaffer C, Olivi A, et al. Autoimmune hypophysitis. Endocr Rev. 2005;26(5):599 " 614.22 Singhal S, Sing H, Furlong K, et al. Lymphocytic hypophysitis. JHN J. 2010;5(2):16 " 19.33 De Bellis A, Ruocco G, Battaglia M. Immunological and clinical aspects of lymphocytic hypophysitis. Clin Sci (Lond). 2008;114(6):413 " 421.44 Iuliano SL, Laws ER. The diagnosis and management of lymphocytic hypophysitis. Expert Rev Endocrinol Metab. 2011;6(60):777 " 783.
ADDITIONAL READING
- Falorni A, Minarelli V, Bartoloni E, et al. Diagnosis and classification of autoimmune hypophysitis. Autoimmun Rev. 2014;13(4 " 5):412 " 416.
- Smith CJ, Bensing S, Burns C, et al. Identification of TPIT and other novel autoantigens in lymphocytic hypophysitis: immunoscreening of a pituitary cDNA library and development of immunoprecipitation assays. Eur J Endocrinol. 2012;166(3):391 " 398.
- Takahashi Y. Autoimmune hypophysitis: new developments. Handb Clin Neurol. 2014;124:417 " 422.
CODES
ICD10
E23.0 Hypopituitarism
ICD9
253.2 Panhypopituitarism
SNOMED
- Lymphocytic hypopituitarism
- Lymphocytic hypophysitis of pregnancy (disorder)
CLINICAL PEARLS
- Suspect lymphocytic hypophysitis in patients presenting with headache and visual field impairments during or soon after pregnancy.
- Lymphocytic hypophysitis is characterized by the presence of other autoimmune diseases, antipituitary antibodies, and symptomatic improvement with immunosuppressive therapy.
- Medical management with sequential MRI is the preferred therapeutic approach.
- Lymphocytic hypophysitis is associated with varied outcomes, including remission, a relapsing and remitting course, or chronic disease.