AUTREV-01506; No of Pages 5 Autoimmunity Reviews xxx (2014) xxx–xxx
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Review
Diagnosis and classification of autoimmune hypophysitis Alberto Falorni a, Viviana Minarelli a, Elena Bartoloni b, Alessia Alunno b, Roberto Gerli b,⁎ a b
Section of Internal Medicine and Endocrine and Metabolic Sciences, Italy Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy
a r t i c l e
i n f o
Article history: Accepted 13 November 2013 Available online xxxx Keywords: Anti-pituitary autoantibodies Diabetes insipidus Enolase Lymphocytic hypophysitis Hypopituitarism Hyperprolactinemia
a b s t r a c t 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. © 2014 Elsevier B.V. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . 2. Epidemiology . . . . . . . . . . . . . . 3. Pathogenesis and histopathological findings . 4. Clinical manifestations . . . . . . . . . . 5. Diagnostic criteria . . . . . . . . . . . . 6. Autoantigens and autoantibodies . . . . . . 7. Treatment . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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1. 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
⁎ Corresponding author at: Rheumatology Unit, Department of Medicine, University of Perugia, Via E. Dal Pozzo, I-06122 Perugia, Italy. Tel./fax: +39 075 5783975. E-mail address: [email protected] (R. Gerli).
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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.
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Please cite this article as: Falorni A, et al, Diagnosis and classification of autoimmune hypophysitis, Autoimmun Rev (2014), http://dx.doi.org/ 10.1016/j.autrev.2014.01.021
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A. Falorni et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
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. 2. 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 established, strong association with late pregnancy and postpartum (from 30 to 70% of cases) [1,2,8,9]. Mean age is third-fourth decade. No strict female predisposition is reported for LINH and LPH, though a weak female predisposition has been reported for LPH [1]. In large series of pituitary surgery, LH accounted for approximately 0.24 to 0.88% of cases [1,10]. However, these estimates may represent only those cases that presented more acutely. In the largest series of 2500 surgical pituitary cases, collected in Germany between 1970 and 1996 [10,11], LH was identified in 6 cases (0.24%). Honegger et al. [12] found 7 cases of hypophysitis among 2362 pituitary cases (0.3%). Similarly, a review of 2000 pituitary cases from Virginia, US [13] identified 16 patients with hypophysitis, but only in 10 a definitive diagnosis of LH was made according to a pituitary biopsy. Higher frequencies were observed in a study from Nottingham (0.8%) [14] and in a study from the Johns Hopkins Hospital (0.88%) [1]. 3. Pathogenesis and histopathological findings LH is thought to have in many cases an autoimmune origin [1–3]. Association with other autoimmune diseases has been reported in 25–50% of cases [1,15–18]. 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], Sjögren's syndrome [25], primary biliary cirrhosis [26], autoimmune hepatitis [27] or autoimmune polyendocrine syndrome type I/autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) [28]. The autoimmune process likely targets specific pituitary cell sub-types, with early selective loss of ACTH, FSH/LH or TSH secreting cells and subsequent triggering of an unselective destruction of the gland. Concerning the association with pregnancy, both changes in immunologic system modulation and in pituitary volume or its blood supply may play a major role [1]. At autopsy, the pituitary gland of patients with LH showed significant atrophy [17], associated with secondary atrophy of adrenal glands. At neurosurgery, pituitary tissue is more often fibrous, adherent to surrounding structures and dura mater. At histopathology, LH is characterized by extensive lympho-plasmacytic infiltration of anterior pituitary. Inflammatory cells are T and B cells with a proportion of plasma cells and occasional eosinophils, macrophages, histiocytes [10,11,29–31] and mast cells [32]. T-cells predominate over B-cell infiltrates in areas characterized by lymphoid follicles. The CD4+/CD8+ cell ratio has been described to be 2:1, or greater, in most cases [11,32–36]. Preferential expression of
activated CD8+ T cells was observed in pregnant women with a short duration of disease symptoms [30]. 4. 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 insufficiency. The rapidity and severity of disease progression explain cases of sudden death reported in the literature [37,38]. The reasons why ACTH deficiency is more common and precocious in LH than in pituitary adenoma are unclear. Acute LH is also often characterized by TSH deficiency and rarely may also present with symptoms of pituitary apoplexy [39]. Subacute LH is typically observed in young women during pregnancy or post-partum [18,19]. In this scenario, symptoms and signs are those of a pituitary mass that resolves at follow-up. The MRI typically demonstrates an increased hypophysis with uniform enhancement after magnetic contrast administration with possible extension to the hypothalamus. Hormonal changes are much less dramatic than in the acute manifestation of the disease. Prolactin may be increased, normal or reduced in approximately equal proportions [1,40]. In the case of hyperprolactinemia, differential diagnosis with a prolactinoma may be challenging. In contrast with what was observed in other pathological conditions of the pituitary gland, such as brain trauma or irradiation [41,42], in which GH deficiency is one of the first deficits, secretion of GH is more frequently preserved in subacute LH. In acute or subacute LH, extension of the inflammatory process to the surrounding structures may occur. Involvement of the cavernous sinus is responsible for headache and diplopia, associated with third, fourth or six cranial nerve palsies. Dural involvement is often observed at MRI scans and may require differential diagnosis with hyperthrophic cranial pachymeningitis [25]. Significantly higher lymphomonocytic pleocytosis was observed at an analysis of cerebrospinal fluid in patients with suspected LH as compared to patients with documented pituitary adenoma [43], which suggests a possible association with aseptic meningitis. Diagnosis of chronic LH is more problematic. Rarely pituitary biopsy is proposed in this scenario. The availability of an accurate autoantibody assay would be instrumental for the correct diagnosis of many chronic cases. In chronic LH, postinflammatory fibrosis may lead to pituitary gland atrophy and empty sella at MRI scan. A complicating factor is heterogeneity of empty sella syndrome. Nevertheless, isolated ACTH or TSH deficiency has been documented in patients with empty sella syndrome and autoimmune endocrinopathies. In contrast, pituitary tumours tend to cause more often isolated GH or isolated gonadotroph dysfunction. Taken together these clinical findings indirectly suggest that at least a proportion of cases of empty sella and of isolated ACTH or TSH deficiency may have an autoimmune origin. In summary, clinical findings of LH can be divided into three groups, as reported in Table 1. Their relative frequency varies depending on whether anterior, posterior or both pituitary lobes are involved. Most patients present with symptoms related to compressive and inflammatory effects of enlarged pituitary on sellar and parasellar structures, as headache, present in over 50% of cases at diagnosis [8,9]. Among the symptoms of hypopituitarism, those ascribable to hypogonadism and hyperprolactinemia are reported with various frequencies [1,8]. With the exception of lactating women, hyperprolactinemia does not occur commonly and may be secondary to stalk compression, impaired dopamine effect for inflammation, immunological destruction of lactotrophs with PRL release, or supposed PRL-secretion stimulating autoantibodies [33]. As discussed above, symptoms of hypocorticolism are frequently
Please cite this article as: Falorni A, et al, Diagnosis and classification of autoimmune hypophysitis, Autoimmun Rev (2014), http://dx.doi.org/ 10.1016/j.autrev.2014.01.021
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Table 1 Clinical manifestations of AH.
1) Pituitary enlargement
2) Anterior pituitary defects
3) Infundibulum/posterior pituitary defect 4) Stalk impairment
Effects
Symptoms
Distension of dura madre Compression of optic chiasm Expansion in cavernous sinus Hypocortisolism Hypothyroidism Hypogonadism Hypoprolactinemia Diabetes Insipidus Hyperprolactinemia
Headache Visual field, acuity reduction Cranial nerves palsy (rare) Hypotension, hypoglycaemia Fatigue, mixedema, bradycardia Impotence, decreased libido Impaired lactation Polyuria, polydipsia Amenorrhea/galactorrhea
reported. Symptoms related to diabetes insipidus, reported with an overall frequency that varies from 20% to 48% [8,9], are constantly present in LINH and LPH, due to direct a infundibulo-neurohypophyseal damage, but can also occur in LAH as a consequence of stalk compression [9] and impaired vasopressin transport. Partial or complete impairment of one or more hormonal axes is almost invariably present in all cases: more often basal hypocortisolism, reduced gonadotrophins with or without low levels of testosterone and estrogens and hypothyroidism. A transient thyreotoxicosis during the early stage of Hashimoto's thyroiditis is possible. Mono-hormonal deficits are rare and affect, in descending order of frequency: ACTH, FSH-LH, TSH, PRL and GH [1,2,8,9]. Natural history of AH is unpredictable, from spontaneous recovery with remission of clinical, laboratoristic and imaging data [1,44–46] to permanent hormonal/neurological impairment or even death, mostly because of adrenal insufficiency. Some authors reported a recurrence after pharmacological improvement [47] and biochemical and imaging long-term follow-up is recommended. LINH is often self-limiting. 5. 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, typically isointense in T1-weighted sequences, is shaped as a triangle or dumbbell, and has often a suprasellar extension. In cases presenting with diabetes insipidus, MRI can be negative at first stages. Common features are posterior lobe swelling and stalk thickening [8,48], associated with loss of neurohypophyseal pre-contrast hyperintensity and alteration of early enhancement pattern, that are probably due to vascular alterations [48]. Atrophy with empty sella is not uncommon. 6. 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 Table 2 Differential imaging features in AH and pituitary adenoma.
Pre-contrast mass aspect Cystic aspect Anterohypophyseal postcontrast enhancement Sellar floor Hypocortisolism
AH
Adenoma
Symmetric enlargement Rare Rapid — uniform intense
Asymmetric enlargement Frequent Slow less intense
Intact Hypotension, hypoglycaemia
Depressed–eroded Displaced
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 hypophysitis. The use of a four-layer immunofluorescence technique has enabled the first demonstration of prolactin cell-specific autoantibodies [49]. Subsequently, ACTH cell-specific autoantibodies were also demonstrated, especially in patients with Cushing's disease or isolated ACTH deficiency. In these latter patients, ACTH-cell autoantibodies seem to be directed against aspartil protease [50]. In a recent Italian study [51], APA were detected in 4 of 27 (15%) patients with isolated ACTH deficiency, 4 of 20 (20%) with isolated GH deficiency and 5 of 19 (26%) with hypogonadotrophyc hypogonadism. Discrimination of the immunofluorescent pattern may improve the diagnostic and predictive value of APA for pituitary dysfunction [52]. In a study of 149 APApositive patients, clinical signs of hypopituitarism were present only in those cases presenting an isolated pituitary cell immunostaining, but not on those cases were all pituitary cells were aspecifically stained [52]. In a large study of Polish patients with ACTH deficiency [53], 51% had another autoimmune disease and 85% resulted positive for thyroid autoantibodies. Immunoblotting detected autoantibodies against a 36 kDa pituitary cytosolic autoantigen in 18% of the patients compared to 3% healthy control sera [54]. The presence of 36 kDa autoantibodies was significantly associated with the presence of thyreoglobulin autoantibodies [54]. A Japanese study detected autoantibodies to a 22 kDa cytosolic pituitary protein, subsequently identified as GH, in 78% of 9 patients with isolated ACTH deficiency [55]. The same autoantibodies were also found in 73% of patients with LH, of whom 88% had a GH deficiency [55]. GH-secreting cell autoantibodies have been detected in some patients with Turner's syndrome, partial GH deficiency or idiopathic GH deficiency [56], but their role is still controversial. A controversial topic is the diagnostic value of pituitary autoantibodies in empty sella syndrome. Empty sella syndrome is certainly heterogeneous and the link between this condition and LH is still unclear, especially in those cases with normal pituitary function. In a Swedish study of 30 patients with empty sella syndrome (15 of whom with type 2 diabetes or impaired glucose tolerance and central obesity) [57] high-titer pituitary autoantibodies were not detected. However, it must be noted that in that study only 13% of patients had pituitary dysfunction, which indicates that patients with empty sella syndrome and normal pituitary function are unlikely to have had prior hypophysitis. Insufficient information is available to derive any conclusive estimate of the proportion of patients with empty sella syndrome and pituitary dysfunction who have had autoimmune hypophysitis. Using immunoblotting, autoantibodies to a 45 kDa pituitary-specific membrane protein were detected in 1/19 patients with idiopathic GH deficiency and empty sella syndrome [58]. In addition, another patient had autoantibodies to a 43 kDa membrane protein. Pituitary-specific autoantibodies to 43 kDa, 49 kDa and 68 kDa membrane proteins were also detected by Nishiki et al. [59] in 5/13 patients with LH, 1/12 with LINH, but in none of 4 patients with isolated ACTH deficiency.
Please cite this article as: Falorni A, et al, Diagnosis and classification of autoimmune hypophysitis, Autoimmun Rev (2014), http://dx.doi.org/ 10.1016/j.autrev.2014.01.021
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In subsequent studies, the 49 kDa protein was purified, sequenced and identified as α-enolase, the first pituitary autoantigen recognized by human autoantibodies [60]. However, α-enolase is widely expressed in several human tissues and α-enolase autoantibodies have a very low diagnostic specificity for lymphocytic hypophysitis. Anti-enolase antibodies have been found in several patients with non-organ-specific autoimmunity, but also in 20% of patients with pituitary adenoma and 5–10% healthy control subjects [18]. More recently, also gamma-enolase has been recognized as a target of pituitary autoantibodies [61]. Interestingly, gamma-enolase is expressed in both the pituitary and the placenta, thus providing a theoretical basis for the strong association between pituitary autoimmunity and pregnancy. The use of radioligand binding assays [62] has led to several studies in organ-specific autoimmune diseases. This technique has shown the presence of autoantibodies against pituitary gland specific factor 1a (PGSF1a) in 33% patients with biopsy-proven LH and in 20% patients with isolated ACTH deficiency [63]. PGSF2 autoantibodies were detected in 14% patients with suspected LH or LINH. Anti-GH antibodies were present in 25% patients with LH and in 6% patients with other autoimmune diseases. No patients with pituitary adenomata showed reactivity to either PGSF1a or PGSF2, but PGSF1a autoantibodies were found in 77% patients with rheumatoid arthritis [64]. However, no information is available on pituitary hormone function in these latter patients and it is not possible to understand at present whether these results are due to a lack of specificity of this autoantibody marker or to a high diagnostic sensitivity for a subtle pituitary dysfunction. Immunoscreening of a pituitary cDNA expression library, followed by retesting using a radioligand binding assay with in vitro translated radiolabelled autoantigen, confirmed PGSF1a, PGSF2 and neuronspecific enolase (NSE) as autoantigen target of autoantibodies in LH. In the same study, autoantibodies to corticotroph-specific transcription factor (TPIT) were detected in 9/86 (10%) LH patients and in 1/90 healthy control sera [65]. Recently, the Italian Autoimmune Hypophysitis Network Group has studied 95 patients with anti-pituitary autoantibodies (APA) and autoimmune hypophysitis for the presence of anti-hypothalamus antibodies (AHA) [66]. AHA were detected by immunofluorescence and positive samples were retested by double immunofluorescence to identify the hypothalamic cells targeted by the immune reaction. AHA were positive in 20/95 (21%) patients. They immunostained arginine vasopressin (AVP)-secreting cells in 13 of the 20 positive cases. Clinical or subclinical diabetes insipidus was demonstrated in all AVP cell antibody-positive patients. These results, though from a limited number of patients, may be interpreted to indicate that AVP antibodies may help in the identification of patients with clinical or subclinical diabetes insipidus. The detection of AHA targeting CRH-secreting cells in patients with GH/ACTH deficiency, but with APA specifically directed to GH-secreting cells, suggest a combined autoimmune aggression to both the pituitary and the hypothalamus in a proportion of patients with a clinical diagnosis of LH. Although the research on pituitary autoantibodies is constantly growing, at present the clinical applicability of these immune markers in the routine diagnosis and management of patients with lymphocytic hypophysitis is limited by a very low diagnostic sensitivity and specificity and by conflicting results generated by different methods. 7. 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. It is rarely effective in resolving endocrine dysfunctions,
with the exception of hyperprolactinemia-related hypogonadism [8]. So far, post-surgical follow-up reports have been short-term and have shown both recovery and recurrences [67,68], with significant incidence of iatrogenic hypopituitarism, especially diabetes insipidus [1,9,67]. For these reasons, most authors suggest to limit its indications, favouring a more conservative treatment [8,67]. Among pharmacologic therapies, high dose glucocorticoids are reported both as a first line (e.g. 20–60 mg/d prednisone [68,69], 120 mg/d methylprednisolone [43]) or as second instance after neurosurgery, effective in reducing pituitary size in 75% of cases [8] and in improving endocrine dysfunction [43]. Other reported pharmacologic treatments include azatioprine, used in a patient with a recurring, inoperable mass [70] and methotrexate [67,69]. Efficacy of radiotherapy is controversial [1]. Conservative management is advocated in most subacute forms of the disease, and could consist of steroidal treatment, monitoring for endocrinological status (with possible hormonal replacement and dopaminergic treatment of hyperprolactinemia) and MRI, leaving surgery in the case of lack of response and worsening of symptoms. Finally, we note a recent mouse model of autoimmune hypophysitis [71].
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Please cite this article as: Falorni A, et al, Diagnosis and classification of autoimmune hypophysitis, Autoimmun Rev (2014), http://dx.doi.org/ 10.1016/j.autrev.2014.01.021
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[51] De Bellis A, Pane E, Bellastella G, Sinisi AA, Colella C, Giordano R, et al. Italian Autoimmune Hypophysitis Network Study. Detection of antipituitary and antihypothalamus antibodies to investigate the role of pituitary or hypothalamic autoimmunity in patients with selective idiopathic hypopituitarism. Clin Endocrinol (Oxf) 2011;75:361–6. [52] Bellastella G, Rotondi M, Pane E, Dello Iacovo A, Pirali B, Dalla Mora L, et al. Predictive role of the immunostaining pattern of immunofluorescence and the titers of antipituitary antibodies at presentation for the occurrence of autoimmune hypopituitarism in patients with autoimmune polyendocrine syndromes over a 5-year follow-up. J Clin Endocrinol Metab 2010;95:3750–7. [53] Kasperlik-Zaluska AA, Czarnocka B, Czeck W. Autoimmunity as the most frequent cause of idiopathic secondary adrenal insufficiency: report of 111 cases. Autoimmunity 2003;36:155–9. [54] Bensing S, Kasperlik-Zaluska AA, Czarnocka B, Crock PA, Hulting A. Autoantibodies against pituitary proteins in patients with adrenocorticotropin-deficiency. Eur J Clin Investig 2005;35:126–32. [55] Takao T, Nanamiya W, Matsumoto R, Asaba K, Okabayashi T, Hashimoto K. Antipituitary antibodies in patients with lymphocytic hypophysitis. Horm Res 2001;55:288–92. [56] Bottazzo GF, McIntosh C, Stanford W, Preece M. Growth hormone cell antibodies and partial growth hormone deficiency in a girl with Turner's syndrome. Clin Endocrinol 1980;12:1–9. [57] Bensing S, Rorsman F, Crock P, et al. No evidence for autoimmunity as a major cause of the empty sella syndrome. Exp Clin Endocrinol Diabetes 2004;112:231–5. [58] Crock P, Salvi M, Miller A, Wall J, Guyda H. Detection of anti-pituitary autoantibodies by immunoblotting. J Immunol Methods 1993;162:31–40. [59] Nishiki M, Murakami Y, Ozawa Y, Kato Y. Serum antibodies to human pituitary membrane antigens in patients with autoimmune lymphocytic hypophysitis and infundibuloneurohypophysitis. Clin Endocrinol (Oxf) 2001;54:327–33. [60] O'Dwyer DT, Smith AI, Matthew ML, Andronicos NM, Ranson M, Robinson PJ, et al. Identification of the 49-kDa autoantigen associated with lymphocytic hypophysitis as α-enolase. J Clin Endocrinol Metab 2002;87:752–7. [61] O'Dwyer DT, Clifton V, Hall A, Smith R, Robinson PJ, Crock PA. Pituitary autoantibodies in lymphocytic hypophysitis target both gamma- and alpha-enolase — a link with pregnancy? Arch Physiol Biochem 2002;110:94–8. [62] Falorni A, Örtqvist E, Persson B, Lernmark Å. Radioimmunoassays for glutamic acid decarboxylase (GAD65) and GAD65 autoantibodies using 35S or 3H recombinant human ligands. J Immunol Methods 1995;186:89–99. [63] Tanaka S, Tatsumi KI, Kimura M, et al. Detection of autoantibodies against the pituitary-specific proteins in patients with lymphocytic hypophysitis. Eur J Endocrinol 2002;147:767–75. [64] Tanaka S, Tatsumi KI, Tomita T, et al. Novel autoantibodies to pituitary gland specific factor 1a in patients with rheumatoid arthritis. Rheumatology (Oxf) 2003;42:353–6. [65] Smith CJ, Bensing S, Burns C, Robinson PJ, Kasperlik-Zaluska AA, Scott RJ, 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;166:391–8. [66] De Bellis A, Sinisi AA, Pane E, Dello Iacovo A, Bellastella G, Di Scala G, et al. Italian Autoimmune Hypophysitis Network Group. Involvement of hypothalamus autoimmunity in patients with autoimmune hypopituitarism: role of antibodies to hypothalamic cells. J Clin Endocrinol Metab 2012;97:3684–90. [67] Leung GK, Lopes MB, Thorner MO, Vance ML, Laws Jr ER. Primary hypophysitis: a single-center experiences in 16 cases. J Neurosurg 2004;101:71–286. [68] Nishioka H, Ito H, Fukushima C. Recurrent lymphocytic hypophysitis: case report. Neurosugery 1997;41:684–6. [69] Tubridy N, Saunders D, Thom M, Asa SL, Powell M, Plant GT, et al. Infundibulohypophysitis in a man presenting with diabetes insipidus cavernous sinus involvement. J Neurol Neurosurg Psychiatry 2001;71:798–801. [70] Lecube A, Francisco G, Roderiguez D, Ortega A, Codina A, Hernandez C, et al. Lymphocytic hypophysitis successfully treated with azathioprine: first case report. J Neurol Neurosurg Psichiatry 2003;74:1581–3. [71] Landek-Salgado MA, Rose NR, Caturegli P. Placenta suppresses experimental autoimmune hypophysitis through soluble TNF receptor 1. J Autoimmun 2012;38:J88–96.
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Review
Diagnosis and classification of autoimmune hypophysitis Alberto Falorni a, Viviana Minarelli a, Elena Bartoloni b, Alessia Alunno b, Roberto Gerli b,⁎ a b
Section of Internal Medicine and Endocrine and Metabolic Sciences, Italy Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy
a r t i c l e
i n f o
Article history: Accepted 13 November 2013 Available online xxxx Keywords: Anti-pituitary autoantibodies Diabetes insipidus Enolase Lymphocytic hypophysitis Hypopituitarism Hyperprolactinemia
a b s t r a c t 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. © 2014 Elsevier B.V. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . 2. Epidemiology . . . . . . . . . . . . . . 3. Pathogenesis and histopathological findings . 4. Clinical manifestations . . . . . . . . . . 5. Diagnostic criteria . . . . . . . . . . . . 6. Autoantigens and autoantibodies . . . . . . 7. Treatment . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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1. 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
⁎ Corresponding author at: Rheumatology Unit, Department of Medicine, University of Perugia, Via E. Dal Pozzo, I-06122 Perugia, Italy. Tel./fax: +39 075 5783975. E-mail address: [email protected] (R. Gerli).
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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.
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Please cite this article as: Falorni A, et al, Diagnosis and classification of autoimmune hypophysitis, Autoimmun Rev (2014), http://dx.doi.org/ 10.1016/j.autrev.2014.01.021
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A. Falorni et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
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. 2. 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 established, strong association with late pregnancy and postpartum (from 30 to 70% of cases) [1,2,8,9]. Mean age is third-fourth decade. No strict female predisposition is reported for LINH and LPH, though a weak female predisposition has been reported for LPH [1]. In large series of pituitary surgery, LH accounted for approximately 0.24 to 0.88% of cases [1,10]. However, these estimates may represent only those cases that presented more acutely. In the largest series of 2500 surgical pituitary cases, collected in Germany between 1970 and 1996 [10,11], LH was identified in 6 cases (0.24%). Honegger et al. [12] found 7 cases of hypophysitis among 2362 pituitary cases (0.3%). Similarly, a review of 2000 pituitary cases from Virginia, US [13] identified 16 patients with hypophysitis, but only in 10 a definitive diagnosis of LH was made according to a pituitary biopsy. Higher frequencies were observed in a study from Nottingham (0.8%) [14] and in a study from the Johns Hopkins Hospital (0.88%) [1]. 3. Pathogenesis and histopathological findings LH is thought to have in many cases an autoimmune origin [1–3]. Association with other autoimmune diseases has been reported in 25–50% of cases [1,15–18]. 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], Sjögren's syndrome [25], primary biliary cirrhosis [26], autoimmune hepatitis [27] or autoimmune polyendocrine syndrome type I/autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) [28]. The autoimmune process likely targets specific pituitary cell sub-types, with early selective loss of ACTH, FSH/LH or TSH secreting cells and subsequent triggering of an unselective destruction of the gland. Concerning the association with pregnancy, both changes in immunologic system modulation and in pituitary volume or its blood supply may play a major role [1]. At autopsy, the pituitary gland of patients with LH showed significant atrophy [17], associated with secondary atrophy of adrenal glands. At neurosurgery, pituitary tissue is more often fibrous, adherent to surrounding structures and dura mater. At histopathology, LH is characterized by extensive lympho-plasmacytic infiltration of anterior pituitary. Inflammatory cells are T and B cells with a proportion of plasma cells and occasional eosinophils, macrophages, histiocytes [10,11,29–31] and mast cells [32]. T-cells predominate over B-cell infiltrates in areas characterized by lymphoid follicles. The CD4+/CD8+ cell ratio has been described to be 2:1, or greater, in most cases [11,32–36]. Preferential expression of
activated CD8+ T cells was observed in pregnant women with a short duration of disease symptoms [30]. 4. 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 insufficiency. The rapidity and severity of disease progression explain cases of sudden death reported in the literature [37,38]. The reasons why ACTH deficiency is more common and precocious in LH than in pituitary adenoma are unclear. Acute LH is also often characterized by TSH deficiency and rarely may also present with symptoms of pituitary apoplexy [39]. Subacute LH is typically observed in young women during pregnancy or post-partum [18,19]. In this scenario, symptoms and signs are those of a pituitary mass that resolves at follow-up. The MRI typically demonstrates an increased hypophysis with uniform enhancement after magnetic contrast administration with possible extension to the hypothalamus. Hormonal changes are much less dramatic than in the acute manifestation of the disease. Prolactin may be increased, normal or reduced in approximately equal proportions [1,40]. In the case of hyperprolactinemia, differential diagnosis with a prolactinoma may be challenging. In contrast with what was observed in other pathological conditions of the pituitary gland, such as brain trauma or irradiation [41,42], in which GH deficiency is one of the first deficits, secretion of GH is more frequently preserved in subacute LH. In acute or subacute LH, extension of the inflammatory process to the surrounding structures may occur. Involvement of the cavernous sinus is responsible for headache and diplopia, associated with third, fourth or six cranial nerve palsies. Dural involvement is often observed at MRI scans and may require differential diagnosis with hyperthrophic cranial pachymeningitis [25]. Significantly higher lymphomonocytic pleocytosis was observed at an analysis of cerebrospinal fluid in patients with suspected LH as compared to patients with documented pituitary adenoma [43], which suggests a possible association with aseptic meningitis. Diagnosis of chronic LH is more problematic. Rarely pituitary biopsy is proposed in this scenario. The availability of an accurate autoantibody assay would be instrumental for the correct diagnosis of many chronic cases. In chronic LH, postinflammatory fibrosis may lead to pituitary gland atrophy and empty sella at MRI scan. A complicating factor is heterogeneity of empty sella syndrome. Nevertheless, isolated ACTH or TSH deficiency has been documented in patients with empty sella syndrome and autoimmune endocrinopathies. In contrast, pituitary tumours tend to cause more often isolated GH or isolated gonadotroph dysfunction. Taken together these clinical findings indirectly suggest that at least a proportion of cases of empty sella and of isolated ACTH or TSH deficiency may have an autoimmune origin. In summary, clinical findings of LH can be divided into three groups, as reported in Table 1. Their relative frequency varies depending on whether anterior, posterior or both pituitary lobes are involved. Most patients present with symptoms related to compressive and inflammatory effects of enlarged pituitary on sellar and parasellar structures, as headache, present in over 50% of cases at diagnosis [8,9]. Among the symptoms of hypopituitarism, those ascribable to hypogonadism and hyperprolactinemia are reported with various frequencies [1,8]. With the exception of lactating women, hyperprolactinemia does not occur commonly and may be secondary to stalk compression, impaired dopamine effect for inflammation, immunological destruction of lactotrophs with PRL release, or supposed PRL-secretion stimulating autoantibodies [33]. As discussed above, symptoms of hypocorticolism are frequently
Please cite this article as: Falorni A, et al, Diagnosis and classification of autoimmune hypophysitis, Autoimmun Rev (2014), http://dx.doi.org/ 10.1016/j.autrev.2014.01.021
A. Falorni et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
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Table 1 Clinical manifestations of AH.
1) Pituitary enlargement
2) Anterior pituitary defects
3) Infundibulum/posterior pituitary defect 4) Stalk impairment
Effects
Symptoms
Distension of dura madre Compression of optic chiasm Expansion in cavernous sinus Hypocortisolism Hypothyroidism Hypogonadism Hypoprolactinemia Diabetes Insipidus Hyperprolactinemia
Headache Visual field, acuity reduction Cranial nerves palsy (rare) Hypotension, hypoglycaemia Fatigue, mixedema, bradycardia Impotence, decreased libido Impaired lactation Polyuria, polydipsia Amenorrhea/galactorrhea
reported. Symptoms related to diabetes insipidus, reported with an overall frequency that varies from 20% to 48% [8,9], are constantly present in LINH and LPH, due to direct a infundibulo-neurohypophyseal damage, but can also occur in LAH as a consequence of stalk compression [9] and impaired vasopressin transport. Partial or complete impairment of one or more hormonal axes is almost invariably present in all cases: more often basal hypocortisolism, reduced gonadotrophins with or without low levels of testosterone and estrogens and hypothyroidism. A transient thyreotoxicosis during the early stage of Hashimoto's thyroiditis is possible. Mono-hormonal deficits are rare and affect, in descending order of frequency: ACTH, FSH-LH, TSH, PRL and GH [1,2,8,9]. Natural history of AH is unpredictable, from spontaneous recovery with remission of clinical, laboratoristic and imaging data [1,44–46] to permanent hormonal/neurological impairment or even death, mostly because of adrenal insufficiency. Some authors reported a recurrence after pharmacological improvement [47] and biochemical and imaging long-term follow-up is recommended. LINH is often self-limiting. 5. 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, typically isointense in T1-weighted sequences, is shaped as a triangle or dumbbell, and has often a suprasellar extension. In cases presenting with diabetes insipidus, MRI can be negative at first stages. Common features are posterior lobe swelling and stalk thickening [8,48], associated with loss of neurohypophyseal pre-contrast hyperintensity and alteration of early enhancement pattern, that are probably due to vascular alterations [48]. Atrophy with empty sella is not uncommon. 6. 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 Table 2 Differential imaging features in AH and pituitary adenoma.
Pre-contrast mass aspect Cystic aspect Anterohypophyseal postcontrast enhancement Sellar floor Hypocortisolism
AH
Adenoma
Symmetric enlargement Rare Rapid — uniform intense
Asymmetric enlargement Frequent Slow less intense
Intact Hypotension, hypoglycaemia
Depressed–eroded Displaced
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 hypophysitis. The use of a four-layer immunofluorescence technique has enabled the first demonstration of prolactin cell-specific autoantibodies [49]. Subsequently, ACTH cell-specific autoantibodies were also demonstrated, especially in patients with Cushing's disease or isolated ACTH deficiency. In these latter patients, ACTH-cell autoantibodies seem to be directed against aspartil protease [50]. In a recent Italian study [51], APA were detected in 4 of 27 (15%) patients with isolated ACTH deficiency, 4 of 20 (20%) with isolated GH deficiency and 5 of 19 (26%) with hypogonadotrophyc hypogonadism. Discrimination of the immunofluorescent pattern may improve the diagnostic and predictive value of APA for pituitary dysfunction [52]. In a study of 149 APApositive patients, clinical signs of hypopituitarism were present only in those cases presenting an isolated pituitary cell immunostaining, but not on those cases were all pituitary cells were aspecifically stained [52]. In a large study of Polish patients with ACTH deficiency [53], 51% had another autoimmune disease and 85% resulted positive for thyroid autoantibodies. Immunoblotting detected autoantibodies against a 36 kDa pituitary cytosolic autoantigen in 18% of the patients compared to 3% healthy control sera [54]. The presence of 36 kDa autoantibodies was significantly associated with the presence of thyreoglobulin autoantibodies [54]. A Japanese study detected autoantibodies to a 22 kDa cytosolic pituitary protein, subsequently identified as GH, in 78% of 9 patients with isolated ACTH deficiency [55]. The same autoantibodies were also found in 73% of patients with LH, of whom 88% had a GH deficiency [55]. GH-secreting cell autoantibodies have been detected in some patients with Turner's syndrome, partial GH deficiency or idiopathic GH deficiency [56], but their role is still controversial. A controversial topic is the diagnostic value of pituitary autoantibodies in empty sella syndrome. Empty sella syndrome is certainly heterogeneous and the link between this condition and LH is still unclear, especially in those cases with normal pituitary function. In a Swedish study of 30 patients with empty sella syndrome (15 of whom with type 2 diabetes or impaired glucose tolerance and central obesity) [57] high-titer pituitary autoantibodies were not detected. However, it must be noted that in that study only 13% of patients had pituitary dysfunction, which indicates that patients with empty sella syndrome and normal pituitary function are unlikely to have had prior hypophysitis. Insufficient information is available to derive any conclusive estimate of the proportion of patients with empty sella syndrome and pituitary dysfunction who have had autoimmune hypophysitis. Using immunoblotting, autoantibodies to a 45 kDa pituitary-specific membrane protein were detected in 1/19 patients with idiopathic GH deficiency and empty sella syndrome [58]. In addition, another patient had autoantibodies to a 43 kDa membrane protein. Pituitary-specific autoantibodies to 43 kDa, 49 kDa and 68 kDa membrane proteins were also detected by Nishiki et al. [59] in 5/13 patients with LH, 1/12 with LINH, but in none of 4 patients with isolated ACTH deficiency.
Please cite this article as: Falorni A, et al, Diagnosis and classification of autoimmune hypophysitis, Autoimmun Rev (2014), http://dx.doi.org/ 10.1016/j.autrev.2014.01.021
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A. Falorni et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
In subsequent studies, the 49 kDa protein was purified, sequenced and identified as α-enolase, the first pituitary autoantigen recognized by human autoantibodies [60]. However, α-enolase is widely expressed in several human tissues and α-enolase autoantibodies have a very low diagnostic specificity for lymphocytic hypophysitis. Anti-enolase antibodies have been found in several patients with non-organ-specific autoimmunity, but also in 20% of patients with pituitary adenoma and 5–10% healthy control subjects [18]. More recently, also gamma-enolase has been recognized as a target of pituitary autoantibodies [61]. Interestingly, gamma-enolase is expressed in both the pituitary and the placenta, thus providing a theoretical basis for the strong association between pituitary autoimmunity and pregnancy. The use of radioligand binding assays [62] has led to several studies in organ-specific autoimmune diseases. This technique has shown the presence of autoantibodies against pituitary gland specific factor 1a (PGSF1a) in 33% patients with biopsy-proven LH and in 20% patients with isolated ACTH deficiency [63]. PGSF2 autoantibodies were detected in 14% patients with suspected LH or LINH. Anti-GH antibodies were present in 25% patients with LH and in 6% patients with other autoimmune diseases. No patients with pituitary adenomata showed reactivity to either PGSF1a or PGSF2, but PGSF1a autoantibodies were found in 77% patients with rheumatoid arthritis [64]. However, no information is available on pituitary hormone function in these latter patients and it is not possible to understand at present whether these results are due to a lack of specificity of this autoantibody marker or to a high diagnostic sensitivity for a subtle pituitary dysfunction. Immunoscreening of a pituitary cDNA expression library, followed by retesting using a radioligand binding assay with in vitro translated radiolabelled autoantigen, confirmed PGSF1a, PGSF2 and neuronspecific enolase (NSE) as autoantigen target of autoantibodies in LH. In the same study, autoantibodies to corticotroph-specific transcription factor (TPIT) were detected in 9/86 (10%) LH patients and in 1/90 healthy control sera [65]. Recently, the Italian Autoimmune Hypophysitis Network Group has studied 95 patients with anti-pituitary autoantibodies (APA) and autoimmune hypophysitis for the presence of anti-hypothalamus antibodies (AHA) [66]. AHA were detected by immunofluorescence and positive samples were retested by double immunofluorescence to identify the hypothalamic cells targeted by the immune reaction. AHA were positive in 20/95 (21%) patients. They immunostained arginine vasopressin (AVP)-secreting cells in 13 of the 20 positive cases. Clinical or subclinical diabetes insipidus was demonstrated in all AVP cell antibody-positive patients. These results, though from a limited number of patients, may be interpreted to indicate that AVP antibodies may help in the identification of patients with clinical or subclinical diabetes insipidus. The detection of AHA targeting CRH-secreting cells in patients with GH/ACTH deficiency, but with APA specifically directed to GH-secreting cells, suggest a combined autoimmune aggression to both the pituitary and the hypothalamus in a proportion of patients with a clinical diagnosis of LH. Although the research on pituitary autoantibodies is constantly growing, at present the clinical applicability of these immune markers in the routine diagnosis and management of patients with lymphocytic hypophysitis is limited by a very low diagnostic sensitivity and specificity and by conflicting results generated by different methods. 7. 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. It is rarely effective in resolving endocrine dysfunctions,
with the exception of hyperprolactinemia-related hypogonadism [8]. So far, post-surgical follow-up reports have been short-term and have shown both recovery and recurrences [67,68], with significant incidence of iatrogenic hypopituitarism, especially diabetes insipidus [1,9,67]. For these reasons, most authors suggest to limit its indications, favouring a more conservative treatment [8,67]. Among pharmacologic therapies, high dose glucocorticoids are reported both as a first line (e.g. 20–60 mg/d prednisone [68,69], 120 mg/d methylprednisolone [43]) or as second instance after neurosurgery, effective in reducing pituitary size in 75% of cases [8] and in improving endocrine dysfunction [43]. Other reported pharmacologic treatments include azatioprine, used in a patient with a recurring, inoperable mass [70] and methotrexate [67,69]. Efficacy of radiotherapy is controversial [1]. Conservative management is advocated in most subacute forms of the disease, and could consist of steroidal treatment, monitoring for endocrinological status (with possible hormonal replacement and dopaminergic treatment of hyperprolactinemia) and MRI, leaving surgery in the case of lack of response and worsening of symptoms. Finally, we note a recent mouse model of autoimmune hypophysitis [71].
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