Title: Adult Autoimmune Enteropathy: Mayo Clinic Rochester Experience
Abstract: Background & Aims: Autoimmune enteropathy is a rare cause of intractable diarrhea associated with circulating gut autoantibodies and a predisposition to autoimmunity. It is rarely observed in adults, with only 11 cases reported to date. Methods: Fifteen adults with autoimmune enteropathy were identified at the Mayo Clinic, Rochester, from May 2001–June 2006. The demographic, clinical, and treatment data were abstracted from their records. Results: The study population was 87% white, 47% female, with median age of 55 years (interquartile range, 42–67 years). All patients had protracted diarrhea, weight loss, and malnutrition. Celiac disease was excluded by lack of response to gluten-free diet or absence of the celiac disease susceptibility HLA genotypes. Fourteen patients were tested for gut epithelial cell antibodies, and 93% were positive for anti-enterocyte and/or anti–goblet cell antibodies. Predisposition to autoimmune diseases was noted in 80%, as indicated by a variety of circulating autoantibodies. Small intestinal histopathologic findings included subtotal villous atrophy and lymphoplasmacytic infiltration in the lamina propria with relatively few surface intraepithelial lymphocytes. T-cell receptor gene rearrangement studies were negative in all cases. Immunosuppressive therapy was required in 93% of cases. Clinical improvement was noted in 60% after 1–8 weeks of steroid therapy. Conclusions: Autoimmune enteropathy is a heterogeneous disease and should be considered in the differential diagnosis of malabsorption and small bowel villous atrophy. The presence of gut epithelial cell antibodies can help confirm the diagnosis. No single agent is unequivocally effective in inducing remission, and immunosuppressive therapy is required in most cases. Background & Aims: Autoimmune enteropathy is a rare cause of intractable diarrhea associated with circulating gut autoantibodies and a predisposition to autoimmunity. It is rarely observed in adults, with only 11 cases reported to date. Methods: Fifteen adults with autoimmune enteropathy were identified at the Mayo Clinic, Rochester, from May 2001–June 2006. The demographic, clinical, and treatment data were abstracted from their records. Results: The study population was 87% white, 47% female, with median age of 55 years (interquartile range, 42–67 years). All patients had protracted diarrhea, weight loss, and malnutrition. Celiac disease was excluded by lack of response to gluten-free diet or absence of the celiac disease susceptibility HLA genotypes. Fourteen patients were tested for gut epithelial cell antibodies, and 93% were positive for anti-enterocyte and/or anti–goblet cell antibodies. Predisposition to autoimmune diseases was noted in 80%, as indicated by a variety of circulating autoantibodies. Small intestinal histopathologic findings included subtotal villous atrophy and lymphoplasmacytic infiltration in the lamina propria with relatively few surface intraepithelial lymphocytes. T-cell receptor gene rearrangement studies were negative in all cases. Immunosuppressive therapy was required in 93% of cases. Clinical improvement was noted in 60% after 1–8 weeks of steroid therapy. Conclusions: Autoimmune enteropathy is a heterogeneous disease and should be considered in the differential diagnosis of malabsorption and small bowel villous atrophy. The presence of gut epithelial cell antibodies can help confirm the diagnosis. No single agent is unequivocally effective in inducing remission, and immunosuppressive therapy is required in most cases. See CME exam on page 1245. See CME exam on page 1245. Autoimmune enteropathy (AIE) is a rare cause of intractable diarrhea associated with circulating gut autoantibodies and a predisposition to autoimmunity. The term AIE was first coined by Unsworth and Walker-Smith, 2 pediatric gastroenterologists from St Bartholomew’s Hospital in London, in 19821Walker-Smith J.A. Unsworth D.J. Hutchins P. et al.Autoantibodies against gut epithelium in child with small-intestinal enteropathy.Lancet. 1982; 1: 566-567Abstract PubMed Google Scholar after their experience with a 15-month-old child who presented with protracted diarrhea, weight loss, and vomiting. There was evidence of villous atrophy that did not respond to dietary exclusion of gluten, cow’s milk, eggs, or to 8 weeks of complete bowel rest with intravenous alimentation. The child was also positive for IgG anti-enterocyte (AE) antibodies, which disappeared after treatment with cyclophosphamide, although the mucosal abnormalities persisted to some degree.1Walker-Smith J.A. Unsworth D.J. Hutchins P. et al.Autoantibodies against gut epithelium in child with small-intestinal enteropathy.Lancet. 1982; 1: 566-567Abstract PubMed Google Scholar The diagnostic criteria for AIE, proposed by Unsworth and Walker-Smith, include (1) severe villous atrophy not responding to any dietary restriction, (2) circulating gut autoantibodies and/or associated autoimmune conditions, and (3) lack of severe immunodeficiency.2Unsworth D.J. Walker-Smith J.A. Autoimmunity in diarrhoeal disease.J Pediatr Gastroenterol Nutr. 1985; 4: 375-380Crossref PubMed Google Scholar Although it is primarily considered to be a disease of children, adult-onset AIE has recently been described, with a total of 11 cases reported to date. The pathophysiology of AIE is not completely understood, but the available evidence suggests a hyperactive immune state caused by a defect in regulatory T-cell homeostasis.3Ruemmele F.M. Brousse N. Goulet O. Autoimmune enteropathy: molecular concepts.Curr Opin Gastroenterol. 2004; 20: 587-591Crossref PubMed Scopus (49) Google Scholar AIE must be distinguished from refractory sprue, which is a form of celiac disease (CD) no longer responsive to a gluten-free diet.4Biagi F. Corazza G.R. Defining gluten refractory enteropathy.Eur J Gastroenterol Hepatol. 2001; 13: 561-565Crossref PubMed Scopus (74) Google Scholar Because of the rarity of the disease, there are scarce data regarding the epidemiology, natural course, and therapeutic options for AIE. Thus, treatment decisions are primarily guided by anecdotal experience. Many treatments, including corticosteroids, immunosuppressive drugs like azathioprine, cyclophosphamide, tacrolimus, cyclosporine, and infliximab, have been used with varying success.5Bousvaros A. Leichtner A.M. Book L. et al.Treatment of pediatric autoimmune enteropathy with tacrolimus (FK506).Gastroenterology. 1996; 111: 237-243Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 6Daum S. Sahin E. Jansen A. et al.Adult autoimmune enteropathy treated successfully with tacrolimus.Digestion. 2003; 68: 86-90Crossref PubMed Scopus (0) Google Scholar, 7Oliva-Hemker M.M. Loeb D.M. Abraham S.C. et al.Remission of severe autoimmune enteropathy after treatment with high-dose cyclophosphamide.J Pediatr Gastroenterol Nutr. 2003; 36: 639-643Crossref PubMed Scopus (15) Google Scholar, 8Sanderson I.R. Phillips A.D. Spencer J. et al.Response to autoimmune enteropathy to cyclosporin A therapy.Gut. 1991; 32: 1421-1425Crossref PubMed Google Scholar, 9Vanderhoof J.A. Young R.J. Autoimmune enteropathy in a child: response to infliximab therapy.J Pediatr Gastroenterol Nutr. 2002; 34: 312-316Crossref PubMed Scopus (0) Google Scholar In the present study, we sought to describe the clinical features, treatment, and outcome of adult patients with AIE seen at our institution during the past 5 years. All patients seen at Mayo Clinic, Rochester from May 2001–June 2006 with a diagnosis of adult-onset AIE were identified either retrospectively through the diagnostic index and Department of Pathology database or prospectively through our outpatient clinics. AIE was defined as adult-onset protracted diarrhea not responsive to any dietary exclusion and associated with intestinal villous atrophy, circulating gut autoantibodies, and/or predisposition to autoimmunity. All pathology slides, except one, were reviewed by a single Mayo gastrointestinal pathologist (S.C.A.). Serologic testing and indirect immunofluorescence staining for the gut epithelial cell antibodies (GECAs), namely anti-enterocyte (AE) and anti–goblet cell (AG), were performed at The Children’s Hospital of Philadelphia. Demographic, clinical, and treatment data were abstracted from the medical records, and outcome data were supplemented by follow-up telephone interviews. The study was approved by Mayo Institutional Review Board. We identified 15 cases of AIE (Table 1, Table 2) during the study period, with a median age of 55 years (interquartile range, 42–67 years) at diagnosis. The majority of patients, 87%, were white, with 8 men and 7 women. All patients had chronic diarrhea, weight loss, and malnutrition. The median duration of symptoms before the diagnosis was 1.5 years (interquartile range, 1–4.5 years). Seven patients (47%) required parenteral nutritional support because of significant weight loss. CD was excluded in 13 patients (87%) by lack of any response to a gluten-free diet and absence of the CD susceptibility HLA genotypes. The other 2 patients (13%) fulfilled criteria for refractory sprue. Both the patients had CD-associated HLA genotype, positive IgA tissue transglutaminase antibodies (tTGs), and histologic picture compatible with sprue in one case and features of both AIE and sprue in the other case. Both these patients were unresponsive to strict gluten-free diet and tested positive for AE antibodies. T-cell receptor gene rearrangement studies by polymerase chain reaction amplification ruled out any clonal proliferation in both the cases. Fourteen patients were tested for GECAs (Table 3); 13 (93%) were positive for AE (Figure 1) and/or AG antibodies (Figure 2), including 2 who fulfilled criteria for refractory sprue. Abdominal computed tomography was unremarkable in all cases except prominent mesenteric lymph nodes in 6 cases (40%). The average stool output, estimated at the time of diagnosis in 9 cases (60%), was 4256 g/day, with an average fecal fat content of 60 g/day on a high fat diet (≥100 g/d). Additional laboratory abnormalities included elevated hepatic transaminases (2–5 times upper limit of normal) in 10 (67%), fat-soluble vitamin deficiencies in 9 (60%), elevated IgA tTG antibodies in 5 (33%), and mild Ig deficiencies IgG subtype, IgM, or IgA in 5 patients (33%). Another 2 patients (18%) had concurrent common variable immunodeficiency (CVID). A predisposition to autoimmunity was noted in 12 patients (80%), as indicated by a variety of circulating autoantibodies and associated autoimmune disorders (Table 3).Table 1Summary of Clinical Characteristics of Study PopulationPatient characteristicsData (N = 15)Median age at diagnosis, y (IQR)55 (42–67)Median duration of symptom before AIE diagnosis, y (IQR)1.5 (1–4.5)Male (%)8 (53)Median follow-up, y (IQR)2 (1–4.8)GECAs (%)13 (87)Other autoantibodies10 (67)tTG positive (%)5 (33)Associated autoimmune disorders (%)13 (87)IQR, interquartile range (25th–75th percentile). Open table in a new tab Table 2Clinical Characteristics of 15 Adult Patients With Autoimmune EnteropathyPatient no.Age at Dx (y)SexGut epithelial antibodiesOther autoantibodiesGluten sensitivity antibodiesAssociated disordersCD-associated HLADuration of symptoms before Dx (mo)Histologic featurestTGAnti-gliadin137MAE IgG +ANA––PI–13AIE-like275MAE IgG + and AG IgG +AchR Ab, striated muscle Ab, anti-GAD65 Ab––MG, thymoma, AIM, AGEC–8AIE-like346FAG IgG +––Psoriatic arthritis–15AIE-like442FAG IgG +–+Atopic dermatitis, AGEC–204AIE-like538FAG IgG +Parietal cell Ab–+PI, AGEC–180AIE-like676FAE IgG +ANA––+5AIE-like755MNegative––HG, ↓ IgG, ↓ IgM–4AIE-like840MAE IgM +ANA––CVID, AC–32AIE-like954MAG IgG +––CVID–120Sprue-like1067MAE IgA +++PHGG–36Sprue-like1145FAE IgG +, AG IgG +Anti-SSA, anti-phospholipid antibody++SS, RA. RP, RS, LC+10Sprue-like1259MAE IgG +ANA––AGEC–18Mixed (AIE + sprue)1375MNot checkedASCA++PHGG, AGEC–13Mixed (AIE + sprue)1461FAE IgG +pANCA, ANA+–Hypothyroidism, RS+12Mixed (AIE + sprue)1559FAE IgG +ANA++LC, hypothyroid–360Sprue-likeaPathology not reviewed by S.C.A., previously reviewed pathology report consistent with celiac sprue.AchR, acetylcholine receptor; Ab, antibodies; AC, autoimmune colopathy; AGEC, autoimmune gastroenterocolitis; AIM, autoimmune inflammatory myopathy; ASCA, anti-Saccharomyces cerevisiae antibodies; ANA, antinuclear antibody; Dx, diagnosis; GAD, glutamic acid dehydrogenase; HG, hypogammaglobulinemia; IFX, infliximab; LC, lymphocytic colitis; MG, myasthenia gravis, 6-MP, 6-mercaptopurine; PHGG, polyclonal hypergammaglobulinemia; PI, pancreatic insufficiency (documented by pancreatic function testing); pANCA, perinuclear antineutrophil cytoplasmic antibody; RA, rheumatoid arthritis; RP, Raynaud’s phenomenon; RS, refractory sprue; SS, Sjögren’s syndrome.a Pathology not reviewed by S.C.A., previously reviewed pathology report consistent with celiac sprue. Open table in a new tab Table 3Gut Epithelial Cell AntibodiesGECANo. (%)AE IgG antibodies5 (33)AE IgM antibodies1 (7)AE IgA antibodies1 (7)AG IgG antibodies4 (27)AE IgG plus AG IgG antibodies2 (13)Total13 (87) Open table in a new tab Figure 2Anti-goblet antibodies. Immunofluorescence staining in the goblet cells mucus, sparing the enterocytes (original magnification, 100×).View Large Image Figure ViewerDownload Hi-res image Download (PPT) IQR, interquartile range (25th–75th percentile). AchR, acetylcholine receptor; Ab, antibodies; AC, autoimmune colopathy; AGEC, autoimmune gastroenterocolitis; AIM, autoimmune inflammatory myopathy; ASCA, anti-Saccharomyces cerevisiae antibodies; ANA, antinuclear antibody; Dx, diagnosis; GAD, glutamic acid dehydrogenase; HG, hypogammaglobulinemia; IFX, infliximab; LC, lymphocytic colitis; MG, myasthenia gravis, 6-MP, 6-mercaptopurine; PHGG, polyclonal hypergammaglobulinemia; PI, pancreatic insufficiency (documented by pancreatic function testing); pANCA, perinuclear antineutrophil cytoplasmic antibody; RA, rheumatoid arthritis; RP, Raynaud’s phenomenon; RS, refractory sprue; SS, Sjögren’s syndrome. Initial esophagogastroduodenoscopy was grossly abnormal in 8 patients (53%), showing duodenal scalloping, fissuring, mosaic pattern, and villous atrophy. Capsule enteroscopy was performed in 7 patients (47%). Capsule failed to leave the stomach in one case, and in all others capsule enteroscopy showed abnormal small bowel. In 5 cases (71%) capsule enteroscopy changes of fissuring, scalloping, and mosaic pattern were restricted to the proximal small bowel. One case had aphthous ulceration in the mid–small bowel and edema of the distal small bowel. Small bowel biopsies were available for review (by S.C.A.) in 14 of 15 cases. In 8 patients (57%) (all but one with AE and/or AG antibodies), the biopsies demonstrated classic histopathologic features of AIE as previously described in children including increased mononuclear inflammation in the lamina propria, lymphocytic infiltration into deep crypt epithelium with a relative paucity of surface lymphocytosis (<40 lymphocytes per 100 epithelial cells), and increased numbers of crypt apoptotic bodies (Figure 3). In all patients except one, the lamina propria mononuclear infiltrates were composed of both plasma cells and lymphocytes; 1 patient with CVID lacked mucosal plasma cells but had prominent lymphocytic lamina propria infiltrates. Villous blunting was evident in all biopsies, ranging from mild (villous:crypt ratio, 1:1; n = 2) to moderate (n = 4) to severe (total or near-total villous atrophy; n = 2). In 5 of these cases, there was neutrophilic cryptitis and villitis. Goblet cells were absent from the epithelium in 6 cases and Paneth’s cells in 3 cases. Many patients had evidence for an autoimmune process involving the entire gastrointestinal tract (Figure 4). Concomitant colonic biopsies were taken in 5 of 8 patients; only one was normal, whereas the others all demonstrated histologic abnormalities identical to those seen in the small bowel. Gastric biopsies were taken in 3 patients and revealed autoimmune atrophic gastritis in 2 cases and normal histology in 1 case.Figure 4Histopathologic findings in a patient with AG antibodies and pan-gastrointestinal autoimmune disease. (A) Duodenal biopsy demonstrates moderate villous blunting and absence of goblet cells; there is no abnormal surface lymphocytosis. (B) Colonic biopsy with absent goblet cells, mild lymphocytosis in the deep crypt epithelium (arrow), and crypt apoptosis (arrowhead). (C) Gastric biopsy taken from the fundus demonstrates features of autoimmune atrophic gastritis, with complete absence of oxyntic glands and partial replacement by pseudopyloric metaplasia (arrow).View Large Image Figure ViewerDownload Hi-res image Download (PPT) In 3 patients (21%), small bowel biopsies demonstrated histopathologic features of both AIE and CD (Figure 5). All showed near-total villous atrophy with surface intraepithelial lymphocytosis, ranging from 50 to ≥100 lymphocytes per 100 epithelial cells. All had neutrophilic cryptitis, increased numbers of deep crypt apoptoses, and deep cryptal lymphocytosis. In 1 patient, there was absence of goblet cells. This group of patients included 2 with positive AE antibodies (GECAs were not tested in the other), 2 with positive gluten-sensitivity antibodies, and 1 with CD-associated HLA type (DQ2). Concomitant colon biopsies were obtained in 2 patients; one was normal, and the other demonstrated mild lymphocytic colitis (20 lymphocytes/100 epithelial cells). Gastric fundal biopsy obtained in 1 patient showed autoimmune atrophic gastritis. In 3 patients (21%) with positive GECAs (AE antibodies in 2 cases and AG antibody in the other), small bowel biopsies lacked classic features of AIE and instead revealed sprue-like changes. There was surface intraepithelial lymphocytosis ranging from 50 to ≥100 lymphocytes/100 epithelial cells. Villous blunting was mild in 1 patient and near-total in the other 2 patients. One patient had CVID and exhibited an absence of plasma cells in the lamina propria. None of the biopsies had neutrophilic inflammation or absence of goblet cells. Gluten-sensitivity antibodies were demonstrated in 2 of these 3 patients, and one also had the CD-associated HLA type DQ2. The remaining patient, whose small bowel biopsy had previously been reviewed by another Mayo gastrointestinal pathologist and was not available for review by S.C.A., exhibited total villous atrophy, crypt hyperplasia, increased intraepithelial lymphocytosis (60–80 lymphocytes per 100 epithelial cells), and chronic inflammation suggestive of celiac sprue. This patient had both positive AE antibodies (IgG) and positive gluten-sensitivity antibodies (tTG IgA, anti-gliadin IgG, and IgA). CD-associated HLA type, however, was negative. Fourteen patients (93%), including 2 with CVID that failed prior treatment with intravenous immunoglobulins, received immunosuppressive therapy (Table 4); prednisone alone was used in 4, prednisone followed by budesonide in 2, prednisone followed by azathioprine or 6-mercaptopurine in 3, prednisone followed by budesonide and azathioprine in 1, budesonide followed by prednisone in 1, budesonide followed by azathioprine in 1, and prednisone followed by either 6-mercaptopurine or azathioprine with infliximab in 2 patients. The remaining 1 patient received metronidazole 500 mg orally 3 times a day for 4 weeks and diphenoxylate without benefit.Table 4Treatment Regimens and Outcome in 15 Patients With AIEPatient noGenderAge at Dx (y)Drug in mg/day (mo received)Response to immunosuppressantsFollow-up (y)aLength of follow-up from onset of symptoms to date of last clinical contact.1M37P 30 (5), IV P 50 (2), IV P 25 (14), B 9 (2), AZA (2), 6-MP 75 (13), IFX (4)Responsive to IFX22M75P 40 taper (4), P 20 (11), AZA (2)Responsive to high dose P, AZA1.63F46P 40 taper (2), P10 (4)Responsive to high dose P24F42B 9 (3) followed by P 20 (4)Responsive to P175F38P 40 taper (12), B 9 (6), AZA (2)Responsive to P, B, AZA13.76F76IV P 40 (0.5)Unresponsive0.57M55P 40 taper (1.3)Responsive to P0.58M40P 30 taper (2), P 5 (10), AZA (3), IVIG (12)Partial response to P, AZA3.89M54P 40 taper (12), 6-MP (48)Partial response to P, 6-MP4.810M67P 10 (4), P 5 (10)Responsive to P3.511F45P 30 (13), B 9 (3)Responsive to high dose P, B112M59P 40 taper (3), P 30 (2), P 20 (2), CsA (0.5), T (2), AZA (1), IFX (1)Responsive to high dose P, AZA and IFX113M75M (1)Immunosuppressants not used1.214F61B 3 (24), AZA (1)Partial response to B3515F59P 60 taper (6), B 9 (0.5)Unresponsive2AZA, azathioprine 2–2.5 mg/kg; B, budesonide; CsA, cyclosporine 100 mg twice a day; IVIG, IV immunoglobulin; IFX, infliximab 5 mg/kg (0, 2, 6 wk and then every 8 wk); P, prednisone; IV P, methylprednisolone sodium succinate; M, metronidazole 500 mg 3 times a day; 6-MP, 6-mercaptopurine 1–1.5 mg/kg daily; T, tacrolimus 4 mg twice a day; Dx, diagnosis.a Length of follow-up from onset of symptoms to date of last clinical contact. Open table in a new tab AZA, azathioprine 2–2.5 mg/kg; B, budesonide; CsA, cyclosporine 100 mg twice a day; IVIG, IV immunoglobulin; IFX, infliximab 5 mg/kg (0, 2, 6 wk and then every 8 wk); P, prednisone; IV P, methylprednisolone sodium succinate; M, metronidazole 500 mg 3 times a day; 6-MP, 6-mercaptopurine 1–1.5 mg/kg daily; T, tacrolimus 4 mg twice a day; Dx, diagnosis. Overall, 9 patients (60%) responded clinically with complete resolution of diarrhea, 3 patients (20%) had a partial response with less than 50% reduction in bowel frequency, and 3 patients (20%) failed to respond. Follow-up small bowel endoscopic biopsies were available in 6 of the 9 responders and showed normal-appearing small bowel mucosa with preserved villous architecture and without significant inflammatory infiltrate. Persistent villous atrophy was noted in follow-up endoscopic biopsies from those with partial clinical response. Rapid clinical response to high dose steroids (defined as steroids ≥40 mg/day) was noted in 2 cases. However, 3–11 months later both these patients required additional immunomodulatory therapy to maintain clinical remission. One patient responded quickly to prednisone 10 mg/day and remained in remission on prednisone 5 mg/day during 14 months of follow-up. One patient, refractory to intravenous high dose methylprednisolone and 6-mercaptopurine for 6 months, had a dramatic response to infliximab (5 mg/kg) within 1 week of the second dose. Infliximab was given as an induction dose at 0, 2, and 6 weeks, followed by a maintenance dose every 8 weeks. The patient first experienced resolution of abdominal pain, followed by steady weight gain, then improvement of diarrhea, and finally discontinuation of parenteral nutritional support within 6 weeks of first dose. The other 5 responders achieved remission on 20–60 mg/day prednisone in 4–8 weeks. Two of these were later switched to budesonide 6–12 mg/day for maintenance. Azathioprine 2 mg/kg/day was added in 1 of these 2 cases. Three partial responders had a waxing and waning course despite immunomodulator therapy. Follow-up of more than 1 year was available in 13 patients (87%). The median length of follow-up from the onset of symptoms to the date of last clinical contact was 2 years (interquartile range, 1–4.8 years). One patient died 6 months after the onset of symptoms from overwhelming septicemia complicating unremitting underlying disease. There were 2 thromboembolic events without any known risk factors, including sagittal venous sinus thrombosis and deep venous thrombosis with pulmonary embolism 6–8 months after the onset of symptoms. AIE is defined as a condition with adult-onset chronic diarrhea, malabsorption, complete lack of response to gluten-free diet or other dietary exclusions with specific small intestinal histologic features and is usually characterized by the presence of circulating GECAs. On the basis of our experience, proposed diagnostic criteria for AIE are listed in Table 5.Table 5Proposed Diagnostic Criteria for Adult AIE1Adult-onset chronic diarrhea (>6 weeks’ duration)2Malabsorption3Specific small bowel histologyPartial/complete villous bluntingDeep crypt lymphocytosisIncreased crypt apoptotic bodiesMinimal intraepithelial lymphocytosis4Exclusion of other causes of villous atrophy including CD, refractory sprue, and intestinal lymphoma5AE and/or AG antibodiesNOTE. Criteria 1–4 are required for a definite diagnosis of AIE. Presence of AE and/or AG antibodies is an important diagnostic support, but their absence does not exclude the diagnosis of AIE. Open table in a new tab NOTE. Criteria 1–4 are required for a definite diagnosis of AIE. Presence of AE and/or AG antibodies is an important diagnostic support, but their absence does not exclude the diagnosis of AIE. The current study represents the largest series of adult patients reported to date with the diagnosis of AIE. All these cases share a constellation of clinical features that are similar to what has previously been reported in children1Walker-Smith J.A. Unsworth D.J. Hutchins P. et al.Autoantibodies against gut epithelium in child with small-intestinal enteropathy.Lancet. 1982; 1: 566-567Abstract PubMed Google Scholar, 10Sykora J. Varvarovska J. Stozicky F. et al.[Autoimmune enteropathy with onset in early infancy: clinico-morphologic and immunologic manifestations].Cas Lek Cesk. 2002; 141: 646-650PubMed Google Scholar, 11Savage M.O. Mirakian R. Wozniak E.R. et al.Specific autoantibodies to gut epithelium in two infants with severe protracted diarrhoea.J Pediatr Gastroenterol Nutr. 1985; 4: 187-195Crossref PubMed Google Scholar, 12Mirakian R. Richardson A. Milla P.J. et al.Protracted diarrhoea of infancy: evidence in support of an autoimmune variant.Br Med J (Clin Res Ed). 1986; 293: 1132-1136Crossref PubMed Google Scholar, 13Hill S.M. Milla P.J. Bottazzo G.F. et al.Autoimmune enteropathy and colitis: is there a generalised autoimmune gut disorder?.Gut. 1991; 32: 36-42Crossref PubMed Google Scholar and more recently in adults6Daum S. Sahin E. Jansen A. et al.Adult autoimmune enteropathy treated successfully with tacrolimus.Digestion. 2003; 68: 86-90Crossref PubMed Scopus (0) Google Scholar, 14Leon F. Olivencia P. Rodriguez-Pena R. et al.Clinical and immunological features of adult-onset generalized autoimmune gut disorder.Am J Gastroenterol. 2004; 99: 1563-1571Crossref PubMed Scopus (38) Google Scholar, 15Corazza G.R. Biagi F. Volta U. et al.Autoimmune enteropathy and villous atrophy in adults.Lancet. 1997; 350: 106-109Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 16McCune C.A. Hughes S. Unsworth D.J. Thymoma, autoimmunity and fatal immunodeficiency.Q J M. 2000; 93: 559-560Crossref Google Scholar, 17Casis B. Fernandez-Vazquez I. Barnardos E. et al.Autoimmune enteropathy in an adult with autoimmune multisystemic involvement.Scand J Gastroenterol. 2002; 37: 1012-1016Crossref PubMed Scopus (0) Google Scholar, 18Carroccio A. Volta U. Di Prima L. et al.Autoimmune enteropathy and colitis in an adult patient.Dig Dis Sci. 2003; 48: 1600-1606Crossref PubMed Scopus (0) Google Scholar, 19Mais D.D. Mulhall B.P. Adolphson K.R. et al.Thymoma-associated autoimmune enteropathy: a report of two cases.Am J Clin Pathol. 1999; 112: 810-815Crossref PubMed Google Scholar, 20Mitomi H. Tanabe S. Igarashi M. et al.Autoimmune enteropathy with severe atrophic gastritis and colitis in an adult: proposal of a generalized autoimmune disorder of the alimentary tract.Scand J Gastroenterol. 1998; 33: 716-720Crossref PubMed Scopus (0) Google Scholar (Table 6).Table 6Summary of 11 Adult AIE Cases Reported in the LiteratureAge/sex (reference)AE antibodiesOther autoantibodiesAssociated autoimmunityHLA typingTreatmentOutcome38/F15Corazza G.R. Biagi F. Volta U. et al.Autoimmune enteropathy and villous atrophy in adults.Lancet. 1997; 350: 106-109Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar+——DQ2+P 50 mg/dSteroid responsive47/F15Corazza G.R. Biagi F. Volta U. et al.Autoimmune enteropathy and villous atrophy in adults.Lancet. 1997; 350: 106-109Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar+Antimicrosomal Ab, AP Ab—DQ2+P 40mg/dSteroid responsive59/M20Mitomi H. Tanabe S. Igarashi M. et al.Autoimmune enteropathy with severe atrophic gastritis and colitis in an adult: proposal of a generalized autoimmune disorder of the alimentary tract.Scand J Gastroenterol. 1998; 33: 716-720Crossref PubMed Scopus (0) Google ScholarNot checkedAnti-intrinsic factor AbAtrophic gastritis, colitisNDP 40mg/dSteroid responsive52/M19Mais D.D. Mulhall B.P. Adolphson K.R. et al.Thymoma-associated autoimmune enteropathy: a report of two cases.Am J Clin Pathol. 1999; 112: 810-815Crossref PubMed Google Scholar+—Concurrent thymomaNDThymectomyImproved after thymectomy48/F19Mais D.D. Mulhall B.P. Adolphson K.R. et al.Thymoma-associated autoimmune enteropathy: a report of two cases.Am J Clin Pathol. 1999; 112: 810-815Crossref PubMed Google Scholar–—Post-thymoma resectionNDIVIG, TPNNo response to IVIG and TPN58/F17Casis B. Fernandez-Vazquez I. Barnardos E. et al.Autoimmune enteropathy in an adult with autoimmune multisystemic involvement.Scand J Gastroenterol. 2002; 37: 1012-1016Crossref PubMed Scopus (0) Google Scholar–ANA, antimicrosomal Ab, AT Ab, anti-gliadin IgG Ab, AP AbThyroi