ReviewDiagnosis and classification of autoimmune hypophysitis
Introduction
Lymphocytic hypophysitis (LH) is an inflammatory disorder affecting anterior (lymphocytic adenohypophysitis, LAH), posterior (lymphocytic infundibuloneurohypophysitis, LINH) or both (lymphocitic panhypophysitis, LPH) pituitary lobes [1], [2]. It is also commonly referred to as “autoimmune hypophysitis” (AH), because its epidemiological, histomorphological and clinical features are suggestive for an autoimmune pathogenesis [1], [2]. The flogistic destruction can be self-limiting or result in permanent endocrine/neurological dysfunction, and even in potentially life-threatening complications. The first description of pituitary autoimmunity was made in 1962 by Goudie and Pinkerton [3], as an autoptycal finding of extensive lymphocytic infiltrate of anterior pituitary in a young woman affected by Hashimoto's thyroiditis, dead for circulatory shock one year after her second delivery. However, it is likely that some cases of end-stage hypophysitis among Sheehan's original series of patients from the early 1900s [4] may have included cases of lymphocytic hypophysitis. In addition, Carpenter's review of Schmidt's syndrome from 1964 [5] included at least two patients studied in 1930s with autoimmune polyendocrine syndrome and lymphoid infiltration of the hypophysis. After the first enunciation by Goudie and Pinkerton, autoimmune hypophysitis has been referred to in the literature with a variety of different names, though the most common terms remain LH/LAH, or LINH when diabetes insipidus (DI) is associated. Nevertheless, though evidence of global glandular involvement has been documented from 1991, to consider LAH and LINH as aspects of the same nosologic entity with a common pathogenesis is still challenging, because of their different structural, histological and onthogenetic characteristics.
The gold standard for unequivocal diagnosis remains pituitary biopsy, but similarly to what occurred for other endocrine autoimmune diseases, the search for pituitary autoantibodies, with the aim of developing accurate and non-invasive diagnostic tests of the disease, is very active.
The demonstration of the existence of pituitary autoantibodies was first provided in 1965 [6] in sera from patients with Sheehan's syndrome, by using a complement consumption test. From 1970 [7], several case reports have documented the same histo-pathological features, though limited to infundibulum stem and neurohypophyseal tissue, in patients presenting with diabetes insipidus.
Section snippets
Epidemiology
The prevalence and incidence of LH are not known with precision. Discrepancies in the way diagnosis is formulated, e.g. pituitary biopsy vs. clinical picture, make it problematic to generate accurate epidemiological estimates. AH is considered a rare condition, although reported with increasing frequency in the last years. The extrapolated incidence on overall population is low, approximately 1 in 9 million/year [1], but probably underestimated. LAH is more common in women and has an
Pathogenesis and histopathological findings
LH is thought to have in many cases an autoimmune origin [1], [2], [3]. Association with other autoimmune diseases has been reported in 25–50% of cases [1], [15], [16], [17], [18]. The most common association is with Hashimoto's thyroiditis (with an estimated frequency of 7–8%) [3], [15], [19], but LH has been diagnosed in patients with Graves' disease [18], [20], Addison's disease [21], type 1 diabetes mellitus [16], [18], atrophic gastritis [18], [22], systemic lupus erythematosus [23], [24],
Clinical manifestations
Clinical findings may vary according to the rapidity of progression of the disease process. LH is predominant in females, with a female:male ratio of 6:1 [1], and disease presents at a younger age in females than in males [2]. In addition, there is a strong association with pregnancy. LH may present as an acute, subacute or chronic condition. Acute manifestation of LH is similar to that of a non-secretory pituitary tumour with adrenocorticotrophin (ACTH) deficiency and secondary adrenal
Diagnostic criteria
AH should be suspected in females presenting with pituitary enlargement in the peri-partum, or with pituitary dysfunction and underlying autoimmunity and in all patients with a rapidly growing pituitary mass. Although definitive diagnosis can be achieved only by histology on trans-sphenoidal biopsy specimen, non-invasive diagnosis can be putatively assessed by MRI and endocrinological deficit pattern. Distinctive radiological characteristics of AH are summarized in Table 2. In LAH, the mass,
Autoantigens and autoantibodies
Currently, the most widely used method to detect anti-pituitary autoantibodies (APA) is indirect immunofluorescence on cryostatic sections of human or primate pituitary [2]. However, the clinical use of this assay type is strongly limited by a low diagnostic sensitivity and a low diagnostic specificity, APA being detected also in healthy control subjects, in patients with pituitary adenomas and in patients with endocrine autoimmune diseases with no clinical or imaging signs of lymphocytic
Treatment
Available treatment strategies are symptomatic, aiming at reducing pituitary size. The type of treatment is mainly dictated by rapidity of onset and severity of symptoms and signs. Neurosurgery has been so far the most common treatment [1]. It provides a definitive histological diagnosis and promptly relieves compressive symptoms that are the primary indication for surgical approach. Surgery is also indicated in those cases where diagnosis of a pituitary adenoma or tumour cannot be ruled out.
References (71)
- et al.
Autoantibodies in Sheehan's syndrome
Lancet
(1965) - et al.
Lymphocytic adenohypophysitis: an immunohistochemical study
Surg Neurol
(1991) - et al.
Autoimmune hypophysitis
Trends Endocrinol Metab
(1997) - et al.
Autoantibodies to prolactin-secreting cells of human pituitary
Lancet
(1975) - et al.
Detection of anti-pituitary autoantibodies by immunoblotting
J Immunol Methods
(1993) - et al.
Radioimmunoassays for glutamic acid decarboxylase (GAD65) and GAD65 autoantibodies using 35S or 3H recombinant human ligands
J Immunol Methods
(1995) - et al.
Placenta suppresses experimental autoimmune hypophysitis through soluble TNF receptor 1
J Autoimmun
(2012) - et al.
Autoimmune hypophysitis
Endocr Rev
(2005) - et al.
Lymphocytic hypophysitis: a rare or underestimated disease?
Eur J Endocrinol
(2003) - et al.
Anterior hypophysitis and Hashimoto's disease in a woman
J Pathol Bacteriol
(1962)
The syndrome of hypopituitarism
Q J Med
Schmidt's syndrome (thyroid and adrenal insufficiency). A review of the literature and a report of fifteen new cases including ten instances of coexisting diabetes mellitus
Medicine (Baltimore)
Chronic hyponatremia associated with inflammation of neurohypophysis
J Endocrinol Metab
Primary hypophysitis: clinical-pathological correlations
Eur J Endocrinol
Lymphocytic hypophysitis
Horm Res
Hypophysitis in surgical and autoptical specimens
Acta Neuropathol (Berl)
Lymphocytic hypophysitis: light and electron microscopic findings and correlation to clinical appearance
Endocr Pathol
Lymphocytic and granulomatous hypophysitis: experience with nine cases
Neurosurgery
Primary hypophysitis: a single-center experience in 16 cases
J Neurosurg
Lymphocytic and granulocytic hypophysitis: a single center experience
Br J Neurosurg
Lymphocytic hypophysitis. Report of 3 new cases and review of the literature
Medicine (Baltimore)
Lymphocytic adenohypophysitis and lymphocytic adenoinfundibuloneurohypophysitis
Endocr J
Clinical case seminar: lymphocytic hypophysitis: clinicopathological findings
J Clin Endocrinol Metab
Cytosolic autoantigens in lymphocytic hypophysitis
J Clin Endocrinol Metab
Peripartum hypopituitarism and lymphocytic hypophysitis
QJM
Lymphocytic hypophysitis in a patient with Graves' disease
J Endocrinol Invest
Lymphoid hypophysitis in a patient with lymphoid thyroiditis, lymphoid adrenalitis, and idiopathic retroperitoneal fibrosis
Arch Pathol Lab Med
Lymphocytic hypophysitis. Associated with antiparietal cell antibodies and vitamin B12 deficiency
Arch Intern Med
A case of lymphocytic infundibuloneurohypophysitis associated with systemic lupus erythematosus
J Endocrinol Invest
A case of systematic lupus erythematosus with autoimmune hypophysitis
Nippon Naika Gakkai Zasshi
Hypertrophic cranial pachymeningitis and lymphocytic hypophysitis in Sjogren's syndrome
Neurology
A case of autoimmune hypophysitis associated with asymptomatic primary biliary cirrhosis
Endocr J
Autoimmune hepatitis associated with thyroiditis and hypophysitis. A case report
Gastroenterol Hepatol
Severe autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy in an adolescent girl with a novel AIRE mutation: responsive to immunosuppressive therapy
J Clin Endocrinol Metab
The spectrum and significance of primary hypophysitis
J Clin Endocrinol Metab
Cited by (74)
Nonpituitary Sellar Masses
2022, The PituitaryPostpartum headache: A broader differential
2021, American Journal of Emergency MedicineCitation Excerpt :Unlike other pituitary masses that typically present with vision changes, the most common symptom in LH is headache (>50% of cases) [3]. Extension of the inflammatory process to the surrounding structures may occur and extension into the cavernous sinus is responsible for headache and dipoplia from cranial nerve 3,4 and 6 palsies [2]. The earliest hormonal deficiency in the disease is ACTH and they can present with delayed signs of glucocorticoid deficiency such as hyponatremia [5].
Hypophysitis: An update on the novel forms, diagnosis and management of disorders of pituitary inflammation
2019, Best Practice and Research: Clinical Endocrinology and MetabolismAutoimmune phenomena involving the pituitary gland in children: New developing data about diagnosis and treatment
2019, Autoimmunity ReviewsCitation Excerpt :The final search retrieved 95 articles, of which 11 were exclusively related to pediatric patients: these studies were critically analyzed for the present review. Lymphocytic hypophysitis has been reported in patients affected by other autoimmune diseases [10], such as Hashimoto's thyroiditis [11–13], Graves' disease [14,15], Addison's disease [16], diabetes mellitus type 1 [17], atrophic gastritis [11,18], systemic lupus erythematosus [19,20], Sjögren's syndrome [21], primary biliary cirrhosis [22], autoimmune hepatitis [23], and autoimmune polyendocrine syndrome type I/autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (or APECED) [24]. The association of lymphocytic hypophysitis with other autoimmune disorders is usually considered as a frank proof of an autoimmune pathogenesis for hypophysitis, and indeed, according to Rose and Bona criteria [25], the association with other diseases having a clear autoimmune nature is a circumstantial evidence of the autoimmune etiology of the disease.
Other Pituitary Conditions and Pregnancy
2019, Endocrinology and Metabolism Clinics of North AmericaThe Changing Clinical Spectrum of Hypophysitis
2019, Trends in Endocrinology and Metabolism