Lymphocytic Hypophysitis 

Lymphocytic Hypophysitis 

  • Lymphocytic hypophysitis is a rare primary autoimmune disease characterized by
    • Inflammation and infiltration of the anterior pituitary gland, posterior pituitary gland-pituitary stalk, or both in the acute setting
    • Fibrosis in the chronic stages of the disease
  • Presentation is due to mass effect (headache, visual abnormalities) and/or pituitary dysfunction as a consequence of inflammation
  • It is important to recognize hypophysitis because failure to treat hormonal deficiencies, such as adrenal insufficiency, can result in death
  • Diagnosis can be made presumptively in the setting of symptoms and signs suggestive of hypophysitis, in the presence of radiologic signs consistent with hypophysitis, and at the exclusion of other etiologies relevant to the clinical presentation
  • If the diagnosis remains unclear, a definitive diagnosis can be obtained by performing a transsphenoidal biopsy of the pituitary10
  • Treatment of mass effect is dependent on the severity of compressive symptoms at presentation, with observation for patients with mild symptoms and high dose glucocorticoids or surgery for those with moderate to severe symptoms1011
  • Hormonal deficiencies should be identified and, if appropriate, replaced1011
  • Cortisol should be replaced prior to thyroid hormone to avoid precipitation of adrenal crisis13
  • Patients may present in adrenal crisis, which requires immediate treatment13
  • Close clinical, biochemical, and radiologic follow-up is needed to determine response to treatment and to assess for recurrence

Alarm Signs and Symptoms

  • Unilateral or bilateral loss of vision; complete or temporal loss of vision
  • Development of double vision
  • Worsening headache
  • Hypophysitis is an inclusive term for any condition that leads to inflammation of the pituitary, neuroinfundibulum, or both
  • Hypophysitis can be categorized according to:
    • Etiology (primary or secondary)
    • Anatomic distribution of radiologic findings
      • Involvement of the anterior pituitary (adenohypophysitis), posterior pituitary (neurohypophysis) and pituitary stalk (infundibulum) (infundibulo-neurohypophysitis), or both (panhypophysitis)
    • Histopathologic subtype (lymphocytic, granulomatous, IgG, xanthomatous, and necrotizing)
  • Primary hypophysitis is hypothesized to be of autoimmune origin whereas secondary hypophysitis is caused by inflammation induced by medication, infection, tumor, or infiltration by a systemic condition (eg, systemic IgG4 disease)
  • The most common cause of primary autoimmune hypophysitis is lymphocytic hypophysitis
  • It is important to recognize hypophysitis because failure to treat hormonal deficiencies, such as adrenal insufficiency, can result in death

Epidemiology

  • Lymphocytic hypophysitis is rare and accounts for 0.24% to 0.8% of surgical pituitary specimens, with an estimated annual incidence of 1 per 9 million per year1
  • A recent systematic review and meta-analysis of 33 studies, which included 591 unique patients, revealed that 72% of cases were female2
  • The average age at presentation is 40 years2
  • There is an association with pregnancy23
    • In historical cohorts (prior to 2005), 57% of cases identified were associated with pregnancy
    • With the inclusion of contemporary cohorts (2010 – present), this association has decreased to 15% to 20%
    • The change in prevalence over time is thought to be due to increasing knowledge regarding lymphocytic hypophysitis and, therefore, the ability to identify cases outside of pregnancy

Etiology and Risk Factors

What causes Lymphocytic Hypophysitis?

  • Lymphocytic hypophysitis is believed to be autoimmune in etiology and is characterized predominantly by a lymphocyte and plasma cell inflammatory infiltrate in the acute setting and fibrosis in the chronic stages of disease4
  • It remains unclear if adenohypophysitis, infundibulo-neurohypophysitis , or panhypophysitis are separate entities or different expressions of the same pathological process
  • A target antigen has not been identified, but several have been proposed, including a-enolase, growth hormone, and pituitary gland specific factors 1 and 2

Risk Factors

What increases the risk of Lymphocytic Hypophysitis?

  • Pregnancy5
    • In pregnancy associated hypophysitis, 56% of cases developed during pregnancy and the vast majority (68.7%) occurred during the third trimester
    • Among those with a postpartum onset, most occurred in the first month after delivery
  • HLA haplotype expression
    • In a study of 15 patients with lymphocytic hypophysitis, expression of both HLA Dq8 and DR53 was seen in 73% of patients compared with the estimated background prevalence of 1% to 10% in patients of a similar ethnic background6
  • Autoimmune conditions
    • There is a high prevalence (up to 44%) of other autoimmune conditions among those with lymphocytic hypophysitis,7 with autoimmune thyroiditis (Hashimoto or Graves disease) being the most prevalent

Diagnosis

Approach to Diagnosis

  • A high degree of clinical suspicion is necessary as clinical and radiologic findings often overlap with those of a pituitary adenoma
  • A diagnosis of lymphocytic hypophysitis can be made noninvasively when a patient presents with suggestive symptoms and signs, including consistent radiologic findings of hypophysitis, and secondary causes have been excluded
  • The diagnosis should be suspected in an individual if:
    • Symptoms are suggestive of anterior and/or posterior pituitary dysfunction
    • Severe headaches and visual disturbance are reported
    • The patient has a history of autoimmune disease and incidental MRI findings of pituitary and/or infundibulum enlargement
    • Symptoms are associated with pregnancy, in particular
  • Scoring systems using a combination of clinical and radiologic variables have been developed to help differentiate hypophysitis from a pituitary adenoma89
  • If lymphocytic hypophysitis is suspected:
    • Perform a biochemical assessment to identify pituitary dysfunction
    • Perform an MRI of the pituitary to identify inflammation of the pituitary and/or neuroinfundibulum10
    • Perform additional investigations to exclude other causes of pituitary masses or secondary causes of hypophysitis. The extent of further investigations is dependent on the clinical context. For example, further imaging (such as a fluorodeoxyglucose PET/CT scan or CT scans of the chest, abdomen, and pelvis) is warranted in a smoker with weight loss, a chronic cough, and a sellar mass to exclude malignancy with metastatic disease to the pituitary
    • Consider referral to endocrinology for further investigation and management
  • If, despite the above investigations, the diagnosis remains uncertain or unclear, a diagnostic biopsy should be done for definitive diagnosis1011

Workup

History

  • Patients can present with:
    • Neurological symptoms related to mass effect: headache (43%), visual field defects (23%), and/or ophthalmoplegia due to cranial nerve defects (4%)2
    • Pituitary hormone deficiencies that may result in various symptoms
  • Patients can also present without symptoms and with an MRI showing pituitary and/or infundibulum enlargement
  • Patients may present acutely in adrenal crisis with signs and symptoms that can include hypotension, fever, nausea, vomiting, abdominal pain, postural dizziness, loss of consciousness, and/or pallor
  • Lymphocytic hypophysitis can be associated with other autoimmune conditions, with the most common being autoimmune thyroiditis, type 1 diabetes, rheumatoid arthritis, and Sjögren syndrome
  • Assess for secondary causes of lymphocytic hypophysitis (eg, medication exposures, history of malignancy, sarcoidosis, Langerhans cell histiocytosis, infection

Physical Examination

  • There are no specific diagnostic features of lymphocytic hypophysitis on physical examination
  • Findings consistent with neurological compromise related to mass effect include:
    • Bitemporal hemianopsia due to optic chiasm involvement
    • Oculomotor (third), trochlear (fourth), and abducens (sixth) cranial nerve palsies due to cavernous sinus compromise
  • Pituitary hormone deficiencies may result in various physical examination findings

Laboratory Tests

  • Laboratory testing should be performed to assess for pituitary dysfunction and to rule out potential etiologies in the differential diagnosis
  • Testing for pituitary dysfunction should be performed in all patients with suspected hypophysitis
  • The most important hormonal axis to assess is the cortisol axis because untreated adrenal insufficiency is associated with increased mortality
    • Assessment for secondary adrenal insufficiency:
      • Obtain early morning (8:00 AM) serum cortisol, serum DHEA-sulfate, and plasma ACTH12
        • Cortisol levels less than 3 mcg/dL are indicative of adrenal insufficiency; cortisol levels greater than 15 mcg/dL exclude adrenal insufficiecy13
        • If cortisol levels are between 3 mcg/dL and 15 mcg/dL, confirmatory dynamic testing using one of several tests, including cosyntropin testing and insulin tolerance testing, could be performed 13
    • Assessment for central hypothyroidism
      • Obtain a free thyroxine (free T4) and a TSH level131415
        • A free thyroxine level below the lower limit of the reference range with a TSH that is normal/low, or even slightly above the reference range, is consistent with central hypothyroidism
    • Additional hormonal evaluations to assess for anterior pituitary dysfunction include morning (8:00 AM – 10:00 AM ) total testosterone (in males) or estradiol (in females), LH (luteinizing hormone) and FSH (follicle stimulating hormone), serum prolactin concentration, and insulin like growth factor-113
    • Assessment for arginine vasopressin deficiency (formerly known as central diabetes insipidus16)
      • Arginine vasopressin deficiency is defined as hypotonic polyuria due to arginine vasopressin deficiency
      • First confirm the presence of polyuria, which is often mistaken for urinary frequency, by measuring 24 hour urine volume
        • Polyuria is defined as more than 2.5 to 3 L of urine in 24 hours17
      • Obtain a serum chemistry panel to exclude other causes of polyuria (eg, hypergylcemia, hypercalcemia, hypokalemia) and to identify hypernatremia
      • For confirmation, additional testing can be performed such as an overnight water deprivation test, a formal water deprivation test, or a combiation of both with measurement of fasting urine osmolality, serum sodium, serum osmolality, and measurement of weight171819
        • Urine osmolality greater than 700 to 800 mOsm/kg at any time without desmopressin treatment excludes arginine vasopressin deficiency17
  • Additional laboratory tests to rule out other potential etiologies
    • The extent of additional testing is dependent on the clinical presentation of the patient and may include the following:1011
      • Interferon gamma release assay or tuberculin skin testing to assess for tuberculosis
      • Serum IgG4 level measurement to assess for IgG4 related disease
      • Serum ACE level and chest radiograph to assess for sarcoidosis
      • Molecular analysis of blood for BRAF, MAPK-ERK pathway, or cyclin D1 mutations seen in Langerhans cell histiocytosis
      • Tumor markers such as AFP (alpha fetoprotein) and hCG can be measured in serum or in cerebrospinal fluid when an intracranial germinoma is suspected
  • Several studies have suggested measurement of antipituitary and antihypothalamic antibodies, as the frequency of positivity is higher among those with autoimmune hypophysitis (n=19; 68.4% and 68.4%, respectively) compared with healthy controls (n=50; 14% and 24%, respectively) or those with nonfunctioning pituitary adenomas (n=100; 22% and 8%, respectively).20 While detection of antipituitary antibodies and antihypothalamic antibodies may be supportive, these tests are not readily clinically available, difficult to perform, and not diagnostic

Imaging Studies

  • MRI of the pituitary, with and without contrast, is used to exclude the presence of a neoplastic, infiltrative, inflammatory, or vascular processes and to identify imaging characteristics that are most consistent with hypophysitis238
    • Common radiologic findings seen in acute lymphocytic hypophysitis include:
      • Homogenous enhancement following contrast administration
      • Medium to high enhancement following gadolinium contrast administration
      • Symmetrical pituitary enlargement
      • Suprasellar extension
      • Pituitary stalk thickening
      • Loss of posterior pituitary bright spot
    • In the chronic phase of lymphocytic hypophysitis, empty or partial empty sella can be seen on MRI
  • If there is concern for metastatic disease, further imaging, such as a CT chest, abdomen, and pelvis or fluorodeoxyglucose PET/CT scan, should be ordered to identify a primary malignancy

Diagnostic Procedures

  • When visual symptoms are present or radiologic findings identify compression or abutment of the optic chiasm, the patient should be referred to ophthalmology for formal evaluation of visual fields10
  • If a diagnosis is unclear, a lumbar puncture should be done, if it is safe to do so, to assess for alternative etiologies1011
    • Cerebral spinal fluid should be sent for analysis, culture, cytology, alpha-fetoprotein, hCG, molecular analysis, and flow cytometry
  • If the diagnosis is uncertain, a definitive diagnosis can be obtained by performing a transsphenoidal biopsy of the pituitary1011

Possible presenting symptoms in adults with pituitary hormone deficiencies

Hormone deficiencyPresenting symptoms
Adrenocorticotropic hormoneAcute: weakness, lethargy, dizziness, vomiting, loss of consciousness

Chronic: weight loss, nausea, abdominal pain, diarrhea, joint and muscular aches and pain
Thyroid stimulating hormoneFatigue, weight gain, cold intolerance, edema, hair loss, constipation
Growth hormoneIncreased fat, decreased lean muscle mass, fatigue
Gonadotropins: luteinizing hormone and follicle stimulating hormoneFemales: absence of menstruation, low libido, infertility

Males: erectile dysfunction, low libido, infertility
ProlactinMilky breast discharge (hyperprolactinemia) or absence of lactation after childbirth (hypoprolactinemia)
Arginine vasopressin (also known as vasopressin, antidiuretic hormone)Excess urination and thirst

Differential Diagnosis

Differential Diagnosis: Lymphocytic hypophysitis

ConditionDescriptionDifferentiated by
Sellar/parasellar tumors:
Pituitary adenoma
Craniopharyngioma
Rathke cleft cyst
Meningioma
Metastasis
Sellar parasellar masses

The most common differential diagnosis is a pituitary adenoma
Radiologic appearance (eg, Rathke cleft cyst is cystic on MRI) and clinical course (eg, metastases are progressive)

Definitive diagnosis is obtained pathologically
Lymphoproliferative disease:
Lymphoma
Plasmacytoma
Neoplastic proliferative disease can be systemic or primary intracranialFlow cytometry of blood or CSF, CT chest, abdomen and pelvis or fluorodeoxyglucose PET/CT scan, biopsy
Infiltrative disease:
Langerhans cell histiocytosis
Erdheim-Chester disease
Sarcoidosis
Histiocytosis:

Proliferative disease of the mononuclear phagocytic system affecting bone, skin, lungs, and pituitary

Sarcoidosis:

Inflammatory multisystem disease characterized by noncaseating granulomas
Histiocytosis:

Skeletal survey, bone scan, fluorodeoxyglucose PET/CT scan, V600E BRAF in peripheral blood or CSF

Sarcoidosis:

ACE level in serum or cerebrospinal fluid, chest radiography, biopsy of lesions with noncaseating granulomas
IgG4 related diseaseCan be primary (isolated) or systemic, leading to pancreatitis, retroperitoneal fibrosis, infiltration of salivary or parotid gland, or lymphadenopathyIgG4 levels, CT of the chest, abdomen, and pelvis, biopsy
Infectious disease:
Tuberculosis
Bacterial or fungal disease
Infections that may be systemic or localizedTuberculosis:

Interferon gamma release assay or tuberculin skin testing

Bacterial or fungal disease: Blood cultures, CSF analysis, culture, or polymerase chain reaction test for mycobacterium
Medication:
Immune check point inhibitors
Interferon
Secondary hypophysitis due to immune check point inhibitor or interferon useRecent exposure to checkpoint inhibitor or other culprit medication
Vasculitis:
Granulomatosis with polyangiitis
Antineutrophil cytoplasmic autoantibody associated vasculitides of small vessels with variable presentation depending on the organ effectedElevated erythrocyte sedimentation rate and c-reactive protein, positive ANCA (antineutrophil cytoplasmic antibodies) testing
Paraneoplastic disease:
Anti-PIT-1 (pituitary-specific transcription factor 1)
Anti-T-PIT (pituitary-restricted transcription factor)
Specific hormonal deficiencies in the absence of other causes (genetic or structural) and associated with tumorPIT-1:

Thyroid, growth hormone, and prolactin deficiency

T-PIT:

Isolated adrenocorticotropin hormone deficiency

Anti-pituitary-specific transcription factor 1 or anti- T-PIT antibodies

Most commonly associated with thymoma

Treatment

Approach to Treatment

  • Lymphocytic hypophysitis is a rare entity and data regarding treatment outcomes are limited to case reports, case series, and small prospective studies, therefore, management guidelines are lacking and rely on expert opinion
  • Comprehensive care should be provided by a multidisciplinary team composed of endocrinology, neurosurgery, ophthalmology, neuroradiology, and other specialties, depending on presenting or developing symptoms, in conjunction with the primary care clinician. For example, ophthalmology can provide supportive care using prisms for ophthalmoplegia
  • Treatment should be considered under 2 categories: addressing inflammation, with treatment being directed according to the severity of symptoms or signs, and replacing pituitary deficiencies
  • Severity of presentation can be determined by the gravity of neurological sequalae. Those with mild compressive symptoms can be observed, whereas those with moderate to severe compressive symptoms (eg, severe headache, visual loss, or ophthalmoplegia) are treated with high dose glucocorticoids (rather than replacement doses) or surgery1011

Nondrug and Supportive Care

  • Although no guidelines currently exist, close observation is typically recommended for: 10
    • Patients with mild symptoms at presentation or improving symptoms on follow-up
    • Patients likely to be adversely affected by high dose glucocorticoids
    • Patients who decline treatment
  • Secondary adrenal insufficiency
    • The Endocrine Society’s clinical practice guidelines for hormonal replacement in hypopituitarism in adults recommend that all patients receive detailed information on their disease and recommendations regarding glucocorticoid adjustment requirements for stressful situations. In addition, the guidelines recommend that patients carry an emergency card, bracelet or necklace, and glucocorticoids for emergency administration13

Drug Therapy

  • Addressing inflammation of the pituitary
    • High dose glucocorticoids are recommended when moderate to severe symptoms are present (eg, visual abnormalities or severe unremitting headache)1011
      • Different doses, types, and durations of high dose glucocorticoids have been employed and no consensus exists as to the optimal type of glucocorticoid, dose, or duration of treatment
      • Prednisone/prednisolone is a common oral agent used in the literature, with initial doses ranging from 20 mg daily to 1 mg/kg daily2
      • Recently, 1 g of IV methylprednisolone for 3 days, followed by 60 mg of oral prednisone for 1 month, followed by a taper of 5 mg per week was associated with higher complete hormonal recovery compared with those who were clinically observed, but similar outcomes were seen in terms of improvements in mass effect21
    • Steroid sparing immunosuppressants (eg, azathioprine, methotrexate, and rituximab) have been used for disease relapse following glucocorticoid taper or for disease recurrence following glucocorticoid cessation
  • Replacing pituitary deficiencies
    • Pituitary deficiencies, particularly adrenal insufficiency and central hypothyroidism, should be treated.1011 Importantly, if deficiencies are identified, glucocorticoid replacement should precede thyroid hormone replacement to avoid adrenal crisis13
  • Patients presenting in adrenal crisis require immediate treatment with parenteral hydrocortisone13

Treatment Procedures

  • Surgery is recommended when:1011
    • Diagnosis is uncertain OR
    • Hypophysitis is progressive, recurrent, or recalcitrant to medical therapy OR
    • Medical therapy is contraindicated
  • Transsphenoidal approach is typically employed

Follow-up

Monitoring

  • Monitoring components are similar regardless of the treatment plan selected
  • Initial follow-up can be every 1 to 3 months, however, the frequency of follow-up is dependent on the development of symptoms, with less frequent follow-up when stability or improvement is demonstrated
  • Patients should be evaluated for:
    • Worsening or development of new neurological symptoms (eg, headache, visual defects, cranial nerve palsies) detected through patient reported symptoms or on physical examination
    • Development of new pituitary dysfunction, clinically and biochemically
    • Stability, regression, or progression of inflammatory lesion, radiologically (MRI)
  • If visual deficits are identified on presentation, the patient should be seen by ophthalmology for regular visual field assessments to identify improvement, stability, or worsening of visual fields
  • No published guidelines exist, but some experts recommend a repeat MRI in 1 to 3 months, depending on severity, to monitor initial response to therapy with less frequent imaging directed by findings (improvement or stability)

Complications

  • Loss of vision
  • Double vision/ophthalmoplegia due to cranial nerve involvement
  • Development of new pituitary deficits

Prognosis

  • Given increased knowledge and recognition, overall prognosis is good
  • Fatalities associated with hypophysitis are attributable to unrecognized pituitary dysfunction, however, outcomes have improved with increased awareness

References

1.Caturegli P et al. Autoimmune hypophysitis. Endocr Rev. 2005;26(5):599-614.

Reference

2.Donegan D et al. Outcomes of initial management strategies in patients with autoimmune lymphocytic hypophysitis: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2022;107(4):1170-1190

Reference

3.Ju JS et al. Clinical presentation and magnetic resonance imaging characteristics of lymphocytic hypophysitis: a systematic review with meta-analysis. Arch Med Sci. 2023;19(4):976-986.

Reference

4.Fehn M et al. Lymphocytic hypophysitis: light and electron microscopic findings and correlation to clinical appearance. Endocr Pathol. 1998;9(1):71-78.

Reference

5.Honegger et al. Pregnancy-related hypophysitis revisited. Eur J Endocrinol. 2023;188(2):lvad003.

Reference

6.Heaney AP et al. HLA Markers DQ8 and DR53 are associated with lymphocytic hypophysitis and may aid in differential diagnosis. J Clin Endocrinol Metab. 2015;100(11):4092-4097.

Reference

7.Tirosh A et al. Variations in clinical and imaging findings by time of diagnosis in females with hypopituitarism attributed to lymphocytic hypophysitis. Endocr Pract. 2016;22(4):447-453.

Reference

8.Gutenberg A et al. A radiologic score to distinguish autoimmune hypophysitis from nonsecreting pituitary adenoma preoperatively. AJNR Am J Neuroradiol. 2009;30(9):1766-1772.

Reference

9.Wright K et al. Preoperative differentiation of hypophysitis and pituitary adenomas using a novel clinicoradiologic scoring system. Pituitary. 2022;25(4):602-614.

Reference

10.Donegan D et al. Hypophysitis. Endocr Pract. 2022;28(9):901-910.

Reference

11.Langlois F et al. The growing spectrum of a rare pituitary disease. J Clin Endocrinol Metab. 2022;107(1):10-28.

Reference

12.Karaca Z et al. Investigation of the hypothalamo-pituitary-adrenal (HPA) axis: a contemporary synthesis. Rev Endocr Metab Disord. 2021;22(2):179-204.

Reference

13.Fleseriu M et al. Hormonal replacement in hypopituitarism in adults: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(11):3888-3921.

Reference

14.Beck-Peccoz P et al. Central hypothyroidism – a neglected thyroid disorder. Nat Rev Endocrinol. 2017;13(10):588-598.

Reference

15.Persani L et al. 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism. Eur Thyroid J. 2018;7(5):225-237.

Reference

16.Arima H et al. Changing the name of diabetes insipidus: a position statement of the Working Group for Renaming Diabetes Insipidus. J Clin Endocrinol Metab. 2022;108(1):1-3.

Reference

17.Tomkins M et al. Diagnosis and management of central diabetes insipidus in adults. J Clin Endocrinol Metab. 2022;107(10):2701-2715.

Reference

18.Christ-Crain et al. Diagnosis and management of diabetes insipidus for the internist: an update (Review). J Intern Med. 2021;290: 73-87.

Reference

19.Pedrosa W et al. A combined outpatient and inpatient overnight water deprivation test is effective and safe in diagnosing patients with polyuria-polydipsia syndrome. Endocr Pract. 2018;24(11):963-972.

Reference

20.Chiloiro S et al. Markers of humoral and cell-mediated immune response in primary autoimmune hypophysitis: a pilot study. Endocrine. 2021;73(2):308-315.

Reference

21.Krishnappa B et al. Early pulse glucocorticoid therapy and improved hormonal outcomes in primary hypophysitis. Neuroendocrinology. 2022;112(2):186-195.

Reference

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