Diagnosis and classification of autoimmune hypophysitis

doi:10.1016/j.autrev.2014.01.021

Autoimmunity Reviews

Volume 13, Issues 4–5, April–May 2014, Pages 412-416

https://doi.org/10.1016/j.autrev.2014.01.021 Get rights and content

Abstract

Autoimmmune hypophysitis (AH) is the consequence of an immune-mediated inflammation of the pituitary gland. The initial pituitary enlargement, secondary to infiltration and oedema, can evolve to remission, for spontaneous or pharmacological resolution of the inflammation, or evolve to progressive diffuse destruction with gland atrophy for fibrotic replacement, thus leading to various degrees of pituitary dysfunction. The autoimmune process against the pituitary gland is made evident by the appearance of circulating autoantibodies (APA), mainly detected by indirect immunofluorescence on cryostatic sections of human or primate pituitary. Among the target autoantigens recognized by APA are alpha-enolase, gamma-enolase, the pituitary gland specific factors (PGSF) 1 and 2 and corticotroph-specific transcription factor (TPIT). However, the low diagnostic sensitivity and specificity of APA for AH strongly limit the clinical use of this marker. AH should be considered in the differential diagnosis of non-secreting space-occupying lesions of sella turcica, to avoid misdiagnosis that may lead to an aggressive surgery approach, since endocrine dysfunction and the compressive effect may be transient.

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.

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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].
A 40-year-old female presented to the ED with a history of intermittent headaches since a vaginal delivery 8 days prior. Her pregnancy was unremarkable and was not complicated by pre-eclampsia. She did not present with signs or symptoms consistent with postdural puncture headache or pre-eclampsia. Her delivery was not complicated by hypotension or post-partum hemorrhage. By chance, she was found to be hyponatremic and admitted to internal medicine for further work-up. She was diagnosed with postpartum lymphocytic adenohypophysitis and treated with steroids. She was discharged with a steroid taper and had complete resolution on follow up.
Lymphocytic hypophysitis (LH), or commonly known as autoimmune hypophysitis, is a rare inflammatory condition affecting the pituitary gland. Acute LH can result in sudden death as demonstrated in some case reports. The most common symptom in >50% of cases is headache. First-line pharmacological treatment consists of high-dose corticosteroids and is effective in reducing pituitary size and improving endocrine insufficiency in 75% of cases.
LH is a potential cause of postpartum headache that can be easily screened for with history and routine bloodwork and has good outcomes with early intervention.
LH should be added to the differential for postpartum headaches presenting to the emergency department and routine blood work should be considered for all postpartum headaches.
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Hypophysitis is a heterogeneous condition that leads to inflammation of the sella and/or suprasellar region, potentially resulting in hormonal deficiencies and/or mass effects. A preponderance of hypophysitis subtypes have an underlying autoimmune aetiology. The overall incidence and prevalence of hypophysitis has dramatically increased over the past decade, mainly due to increased awareness of the condition in the medical community, improvements in imaging techniques, and a rise in the occurrence of certain forms of hypophysitis such as IgG4 hypophysitis (IgG4Hy) and immune checkpoint inhibitor induced hypophysitis (ICIHy). The clinical presentation varies from an asymptomatic condition to a fatal disease often as a result of electrolyte abnormalities due to glucocorticoid deficiency in the context of adrenal crisis from central adrenal insufficiency. Milder forms of hypophysitis are treated with replacement of deficient hormones while more acute presentations with mass effects require glucocorticoid therapy, immunosuppressive therapy or surgery. Timely diagnosis and interventions are keys to prevention of the lethal complications of this disease. In this review, we provide an update on the recent advances in the field of pituitary autoimmunity, with an emphasis on autoimmune hypophysitis and novel forms of hypophysitis such as anti-PIT1 hypophysitis, IgG4Hy and ICIHy.
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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.
The contribution of autoimmune phenomena to dysfunction of hypophysis or hypothalamus is far to be unraveled and also the specific pathways of hypophysitis are poorly understood until now, mostly for the pediatric population. Primary hypophysitis is rare in children and often regarded as an autoimmune disorder, following the evidence of lymphoplasmacytic infiltration in the pituitary gland, detection of anti-pituitary antibodies (APA) and anti-hypotalamus antibodies (AHA) by indirect immunofluorescence on cryostatic sections of human or primate hypophysis and hypothalamus, and coexistence with other autoimmune disorders. The rarity of this condition and the lack of ad hoc studies make hard any assessment of the real incidence of hypophysitis in pediatric patients, and also the role of APA and AHA has been poorly investigated in children with idiopathic hypopituitarism. Potential target autoantigens studied in autoimmune hypophysitis have been various pituitary-specific factors, chaperone proteins, alpha-enolase, secretogranins, chorionic somatomammotropin and intracellular transcription factors. Many clinical features both endocrine and neurologic or systemic can herald the onset of autoimmune hypophysitis. Antidiuretic hormone deficiency with central diabetes insipidus and growth retardation are the most significant presenting symptoms in children with hypophysitis, requiring a careful differential diagnosis with other causes of hypopituitarism, including tumors of the sellar region, differently from adults in whom adrenal insufficiency, hypogonadism, headache or diplopia might be the leading manifestations. Growth hormone deficiency is found in 3/4 of pediatric cases. Five histologic variants of primary hypophysitis have been described: lymphocytic, granulomatous, xanthomatous, IgG4-related and necrotizing: lymphocytic hypophysitis is the most frequent variant in the pediatric sceneries. Children with diagnosis of hypophysitis are also at risk of developing germinomas later in life, and require an extended follow-up in the long-term. Therapeutic options should be differentiated according to the rapidity of disease progression and modality of clinical onset, as acute pictures might require corticosteroids or immunosuppressant agents, while chronic forms may need a conservative management or appropriate hormone replacement therapies. This review updates and summarizes the most recent information related to the autoimmune involvement of hypophysis and hypothalamus in children, discusses the correlations between APA, AHA and disease activity, as well as the recommendations for treatment of primary hypophysitis from the pediatric perspective.
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Hypophysitis is a rare and potentially life-threatening disease, characterized by an elevated risk of complications, such as occurrence of acute central hypoadrenalism, persistent hypopituitarism, or extension of the inflammatory process to the neighboring neurological structures. In recent years, a large number of patients have been described as being affected by hypophysitis, due to the increased administration of immuno-chemotherapies. At the present time, the heterogeneous nature of hypophysitis diagnostic criteria and of the treatment protocols makes the management of affected patients difficult. We review the current data and evidence on primary and secondary hypophysitis, in order to suggest a diagnostic and therapeutic protocol that should be focused on a multidisciplinary approach, for reaching a prompt diagnosis and an appropriate and safe treatment.

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ReviewDiagnosis and classification of autoimmune hypophysitis

Abstract

Introduction

Section snippets

Epidemiology

Pathogenesis and histopathological findings

Clinical manifestations

Diagnostic criteria

Autoantigens and autoantibodies

Treatment

Lancet

Surg Neurol

Trends Endocrinol Metab

Lancet

J Immunol Methods

J Immunol Methods

J Autoimmun

Autoimmune hypophysitis

Endocr Rev

Lymphocytic hypophysitis: a rare or underestimated disease?

Eur J Endocrinol

Anterior hypophysitis and Hashimoto's disease in a woman

J Pathol Bacteriol

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

Review
Diagnosis and classification of autoimmune hypophysitis