Autoimmune enteropathy (AIE) is a rare cause of intractable diarrhea associated with villous atrophy of the small bowel, lack of response to dietary exclusion, and autoimmunity predisposition.1,2 Although the diagnosis is more frequent in children, its prevalence is increasing in adults.3 Symptoms are unspecific and can coexist with other autoimmune disorders.4 Pathophysiology is not completely understood, but evidence suggests a hyperactive immune state due to a defect in regulatory T-cell homeostasis.5 Differential diagnosis with other enteropathies with villous atrophy and negative celiac serology is challenging because they all manifest clinically with a malabsorption syndrome and have overlap histopathological features.6 These include: lymphoproliferative associated like enteropathy-associated T-cell lymphoma type 1 and type 2; iatrogenic enteropathies due to angiotensin type 2 receptor blockers or chemotherapy; infectious enteropathies secondary to giardiasis, HIV, tuberculosis, or Whipple disease; and inflammatory enteropathies such as Crohn's disease or idiopathic.
Treatment of AIE is challenging and is based on immunosuppression, including corticosteroids, calcineurin inhibitors, and antitumor necrosis factor therapy, and nutritional support.3,7 We report a case of AIE diagnosed in an adult patient presenting with chronic intractable diarrhea and significant weight loss, highlighting the diagnostic and therapeutic challenge in the management of this disorder.
A 73-year-old woman with type 2 diabetes under metformin was admitted to the emergency department with severe nonbloody diarrhea for the past 5 months and a weight loss of 18 kg (20% of body weight). Physical examination was unremarkable, except for signs of severe weight loss. She denied relevant medical history or other medication such as olmesartan. Laboratory evaluation revealed normocytic normochromic anemia, low prothrombin time (58%), hypokalemia (2.4 mEq/L), hypoalbuminemia (2.8 g/dL), and elevated C-reactive protein (2.02 mg/dL). Serology for celiac disease, HIV, and stool cultures were also negative; antinuclear antibodies were positive up to 1:2,560 dilution. Abdominal ultrasound and computed tomography were both normal. The patient was admitted and started electrolyte and albumin supplementation and gluten-free diet, without clinical improvement.
Afterward, an esophagogastroduodenoscopy revealed duodenal villous atrophy with focal erythema (Figure 1). An ileocolonoscopy was also performed with colonic biopsies to exclude microscopic colitis that revealed no abnormalities. Capsule endoscopy later unveiled villous atrophy of the duodenum and proximal jejunum (Figure 2). The anatomopathological evaluation of duodenal biopsies demonstrated villous blunting; scattered intraepithelial lymphocytes (<40/100 enterocytes); deep cryptal lymphocytosis with increased crypt epithelial cells apoptosis; and expansion of the lamina propria due to mononuclear infiltration with lymphocytes, eosinophils, and plasma cells (Figure 3). Anti-enterocyte antibodies and HLA DQ2/DQ8 were both negative.
In this regard, AIE was considered to be the most likely diagnosis. The patient started on a steroid regimen with significant clinical improvement and mild weight increase. However, after 4 months under prednisone, the patient was readmitted for recurrent diarrhea and hypokalemia. At this point, the patient started combined therapy with steroid and azathioprine with fast clinical improvement and absence of diarrhea after 5 days. The patient progressively gained weight after discharge, and after 3 months of immunosuppressive treatment, azathioprine was stopped because of hepatotoxicity, whereas prednisone was tapered to a low maintenance dose without further relapse.
AIE is a rare disorder characterized by intractable diarrhea and small intestine mucosal atrophy resulting from immune-mediated injury.2 Typically, patients are unresponsive to dietary modifications, including a gluten-free diet.1,4 Although it is primarily a pediatric disease, it is now well recognized to occur in adult patients as well.8 The disease often presents in association with other autoimmune disorders in infants.7
AIE remains a challenging diagnosis because symptoms are nonspecific, including refractory diarrhea with malabsorption and anorexia leading to severe weight loss.4,7 The diagnosis is based on the following criteria: chronic diarrhea (>6 weeks duration); malabsorption; specific small bowel histology; exclusion of other causes of villous atrophy; and the presence of anti-enterocyte and/or anti-goblet cell antibodies.1 Small bowel histology include partial/complete villous blunting, deep crypt lymphocytosis, increased crypt apoptotic bodies, and minimal intraepithelial lymphocytosis.1 Positive anti-enterocyte and/or anti-goblet cell antibodies are an important diagnosis support, but their absence does not exclude the diagnosis of AIE.2 However, sensitivity and specificity of these antibodies is unclear because they might be detected in other inflammatory diseases.1,7 Capsule endoscopy can be helpful by ascertaining inflammation diffusely involving the small bowel, revealing mucosal scalloping, fissuring, and mosaic patterns.1,9 Medication history is paramount in the evaluation of a patient with chronic diarrhea. Olmesartan-associated enteropathy should also be excluded because it can also present with chronic watery diarrhea, villous atrophy, and histological abnormalities with epithelial lymphocytosis.10 Despite its rarity, AIE remains a diagnosis of exclusion and it should be included in the differential diagnosis of malabsorption syndromes associated with small intestinal mucosal atrophy.3,7 We report the case of AIE in an adult patient presenting with chronic diarrhea and significant weight loss, whose esophagogastroduodenoscopy revealed duodenal villous atrophy extending to proximal jejunum as documented in capsule endoscopy, with negative anti-enterocyte antibodies, highlighting the need to exclude other causes of small bowel villous atrophy to confirm the diagnosis.
AIE seems to result from dysregulation of gut humoral and cellular immune function with an underlying defect in the regulatory T-cell system.4 Owing to its frequent association with other autoimmune disorders, AIE has been included in the IPEX syndromes (immunodysregulation, polyendocrinopathy, enteropathy X-linked).8 Patients with AIE may also have other autoantibodies, including antinuclear antibody, liver/kidney microsomal antibodies, and anti-smooth muscle antibodies.4 Left untreated or with inappropriate treatment, AIE can lead to major complications such as severe malabsorption and intestinal failure.8 A timely diagnosis is mandatory to start appropriate immunosuppressive treatment and nutritional support, which is the gold standard for patients with AIE.3,7 Immunosuppression often includes steroids, with reported clinical improvement in up to 60% of patients after up to 8 weeks of therapy.1,4 Other agents include antitumor necrosis factors such as infliximab, 6-mercaptopurine, azathioprine, cyclosporine, or tacrolimus.1,3,8 In a reported case, abatacept was used in a patient with complications associated with azathioprine, infliximab, and methotrexate, with few side effects and no need for monitoring therapeutic levels.11 In our case, therapeutic management was challenging and included corticosteroids at the beginning, combined with azathioprine after relapsing. Subsequently, azathioprine was discontinued because of hepatotoxicity, but the patient maintained clinical remission with prednisone alone.
Author contributions: AC Carvalho drafted the manuscript, performed a review of the literature, and is the article guarantor. J. Pinho was responsible for data acquisition and the concept and design of the study. E. Cancela and A. Silva critically revised the report.
Financial disclosure: None to report.
Informed consent was obtained for this case report.
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