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• W2014605430 abstract "Autoimmune enteropathy is a condition of intractable diarrhea, often accompanied by extraintestinal manifestations (1). Most cases have been reported in boys with diarrhea usually beginning around 2 to 4 weeks of age. The secretory component of the diarrhea is often delayed a few months. The pathogenesis of autoimmune enteropathy is not known. Enterocyte antibodies develop in only 50% of patients, and it is not clear whether the enterocyte antibodies precede or follow intestinal inflammation (2,3). Activation of mucosal T cells accounts for injury to the epithelium. Enteric inflammation affects the small intestine and the colonic mucosa. Small bowel biopsy specimens show villus destruction and intense acute and chronic inflammation. Findings similar to celiac disease with crypt hyperplasia and increased mitosis also are identified. Electron microscopy shows shortened, disrupted microvilli; swollen mitochondria; and lysosomal antibodies. Colonic biopsy specimens show varying degrees of inflammation in the lamina propria, goblet-cell depletion, and crypt distortion. Colonic inflammation may cause inflammatory polyps and be severe enough to cause bleeding similar to that in inflammatory bowel disease. Serum immunoglobulin assays of a patient with autoimmune enteropathy often show normal immunoglobulin Ig A and IgM with decreased IgG caused by protein-losing enteropathy. Anti–smooth muscle antibodies, antinuclear antibodies, and antithyroid microsomal antibodies have also been identified. Tests of T- and B-cell function are often normal. Other laboratory findings often indicate malnutrition. During the course of the disease, other autoimmune disorders may develop, such as diabetes mellitus, glomerulonephritis, hypothyroidism, thrombocytopenia, and polyarthritis (1). Intravenous nutritional support combined with immunosuppressive therapy is often required to control symptoms and facilitate growth. CASE REPORT We describe a patient who was maintained on a combination of parenteral nutrition and immunosuppressive therapy for several years. The patient was born in May 1981 at term. After birth, diarrhea became progressively severe and more secretory and resulted in hospitalization at 7 months of age because of dehydration and malnutrition. Initially, biopsy specimens showed chronic inflammation with villus atrophy, thought to be characteristic of severe milk protein enteropathy. Failure to tolerate continuous enteral feeding of the elemental formula Tolerex prompted further evaluations. At age 29 months, tests for antienterocyte antibodies were positive, and at that point, immunosuppressive therapy was begun. Home total parenteral nutrition was used during his infancy and childhood with minimal complications. Cholelithiasis in 1986 and superior vena cavae thrombosis in 1995 were primary complications from parenteral nutrition. During his childhood, total parenteral nutrition with additional intravenous fluid replacement was required to promote growth and maintain hydration. Various doses of corticosteroids and oral azathioprine, at times up to 2 mg/kg concurrently, were used to control diarrhea. Aggressive feeding with numerous types of hypoallergenic and whole protein formulas exacerbated diarrhea. Oral and intravenous cyclosporine therapy (with targeted serum concentrations of 200 ng/mL) in addition to azathioprine therapy resulted in no greater tolerance of enteral feeding. At age 9, tacrolimus therapy was substituted for cyclosporine therapy, allowing discontinuation of fluid replacement and azathioprine. Attempts to increase tacrolimus from initial serum concentrations of 4 or 5 to 10 ng/mL did not cause enhanced enteral tolerance. Despite all therapies, small bowel biopsy specimens consistently showed total villus destruction with severe acute and chronic inflammation (Fig. 1 and 2). Comparable inflammation was observed in the colon (Fig. 3).FIG. 1.: Severe villous atrophy in the duodenum.FIG. 2.: Increased chronic inflammation in surface epithelium and lamina propria in the duodenum.FIG. 3.: Severe chronic active colitis with branched glands, cryptitis, and crypt abscess formation.In a potentially devastating complication, the patient was admitted to the hospital in 1998 with severe thrombocytopenia (platelet count was 10,000 with positive antiplatelet antibodies). At this admission, the patient was receiving tacrolimus (6.5 mg twice daily) and intravenous nutrition (approximately 2,000 calories/night over 10 hours). The patient taking food by mouth and was supplemented with enteral nutrition, 2 to 3 cans of Jevity (Ross Laboratories, Columbus, OH, U.S.A.) per day. The autoimmune thrombocytopenia reversed with high-dose intravenous steroids and has not recurred. Because the patient showed significant improvement in stools during the hospital stay, at discharge, the patient received tacrolimus and 32 mg of intravenous methylprednisolone daily, and the preadmission total parenteral nutrition calories were reduced to 1,000 calories nightly. After discharge, the patient continued to gain weight with little or no diarrhea and parenteral nutrition was weaned. Intravenous nutrition was discontinued 4 months after discharge, with continued IV steroid therapy required to maintain a normal platelet count. Attempts to wean steroid therapy over the next few months caused no relapse of thrombocytopenia; however, gastrointestinal symptoms returned and weight loss ensued. The unfortunate episode of severe autoimmune thrombocytopenia in our patient and associated aggressive use of corticosteroids to control bleeding fortuitously improved his intestinal inflammatory disease sufficient to discontinue parenteral nutrition for the first time. Therefore, we concluded that perhaps even more aggressive immunosuppression might control the patient's bowel disease and allow him to survive without parenteral nutrition. Our patient was already receiving tacrolimus therapy, and the combination of tacrolimus and high-dose methylprednisolone (32 mg daily) therapy improved his absorptive function to a degree that he could maintain his weight without parenteral nutrition. Unfortunately, attempts to wean him from high-dose corticosteroid therapy resulted in immediate exacerbation of his diarrhea. Despite apparent clinical improvement, the patient's small intestinal biopsy specimens continued to show almost total villus destruction in the proximal jejunum with severe mixed inflammatory infiltrate. Colon biopsy specimens likewise demonstrated severe inflammatory changes, even when the patient was not receiving parenteral nutrition. Ultimately, the complications associated with high-dose corticosteroid therapy encouraged us to look for alternative means of controlling the patient's disease. Higher dose tacrolimus therapy was again tried without benefit. Attempts to wean the patient from corticosteroid therapy after high-dose 6-mercaptopurine (100 mg daily) administration, given intravenously, likewise were unsuccessful. We then gave him 3 doses of infliximab, 5 mg/kg (300 mg), 8 to 10 weeks apart. The number of stools decreased from approximately 8 each day to 4, with increased stool form. He also showed significant weight gain, approximately 8 kg during this time. These infusions permitted us to reduce the corticosteroid dose to 10 mg intravenous methylprednisolone every other day, from his previous requirements of 30 to 40 mg daily. Just before each infliximab dose, he typically developed increased frequency with loosening of the stool, suggesting the need for more medication. After the third infusion, inguinal adenopathy was detected. Mesenteric adenopathy was noted on computed tomography, causing concern about intestinal lymphoma. Consultation with and evaluation by the hematology and oncology service showed that these nodes probably were a manifestation of colonic inflammation caused by autoimmune enteropathy, as previously reported in the literature (4). The family subsequently refused a fourth dose of infliximab, and high-dose corticosteroid therapy again induced sufficient remission to permit resumption of enteral feeding. DISCUSSION Autoimmune enteropathy is one cause of intractable diarrhea in infancy. Formerly a wastebasket diagnosis for children with chronic diarrhea and malnutrition during the first year of life, intractable diarrhea of infancy has now been subdivided into several different categories (5). Most of these are allergic enteropathies with mucosal injury that respond to protein hydrolysate or amino acid formulas. These patients may have a variety of histologic abnormalities, but usually by 1 year of age have had sufficient mucosal regeneration to be free of parenteral nutrition and diarrhea (6). Certain brush border membrane abnormalities cause diarrhea, including microvillus inclusion disease or congenital microvillus atrophy, and more recently tufting enteropathy (7,8). Children with these abnormalities have severe diarrhea from birth, respond poorly to therapy, and, at least in the case of microvillus inclusion disease, have severe electrolyte abnormalities that frequently result in early intestinal transplantation (9). Poorly described congenital syndromatic enteropathies also occur in children with dysmorphic features and abnormal hair configuration (10). These patients likewise respond poorly to therapy. Finally, autoimmune enteropathy is characterized by a somewhat later onset of diarrhea, often at 4 to 6 months of age, with rather severe inflammatory changes in the small intestine and frequently in the colon. These patients often have other evidence of autoimmune disease, including thyroid, renal, and hepatic diseases; pancreatic insufficiency and pancreatitis; and hematopoietic effects including platelet abnormalities (1,11). Glomerulonephritis may also occur. These differ from other causes of intractable diarrhea in that they frequently respond to immunosuppressive therapy, but the response is variable and often incomplete. Standard immunosuppressive therapies for autoimmune enteropathy include corticosteroids, 6-mercaptopurine or azathioprine, and cyclosporine (12,13). Some patients have recently received tacrolimus as a substitute for cyclosporine with encouraging results (14,15). Unfortunately, most patients with autoimmune enteropathy rarely are free of parenteral nutrition, and many do not survive beyond 16 years of age. Because of inflammatory changes in the colon, intestinal transplantation is probably not an ideal therapy. The inflammatory diseases and the therapies used theoretically may increase the risk of bowel malignancies, including small intestinal lymphoma. Autoimmune enteropathy itself has not been specifically linked to the development of intestinal malignancy. However, malignancy may appear with aggressive immunosuppression and the increasing longevity of these patients. The combination of infliximab and tacrolimus seems to control the inflammation in severe autoimmune enteropathy enough to reduce corticosteroid doses. The synergistic effect of these two medications probably is based on different mechanisms of action. Tacrolimus is similar to cyclosporine, in that both block gene activation for cytokine production by inhibiting the antigenic response of helper T lymphocytes, suppressing interleukin-2 and interferon γ. Tacrolimus absorption is bile independent with some gastric absorption, whereas cyclosporine absorption is inefficient and affected more by gut transit. Infliximab is an antibody that inhibits tumor necrosis factor-α, a proinflammatory protein (16,17). Infliximab was developed as a biologic treatment for severe Crohn disease and rheumatoid arthritis. The aggressive use of multiple antiinflammatory agents acting on different aspects of the immune system, as in many other autoimmune conditions, may have value in the treatment of autoimmune enteropathy. Despite a difficult life, our 19-year-old patient with autoimmune enteropathy has survived for many years, recently without parenteral nutrition. He has a high risk of complications from his medications that includes malignancy. His disease carries great risk itself. The long-term advisability of repeated infliximab therapy in patients with this disorder who are already receiving high doses of other immunosuppressants is unclear, although this agent positively affected the patient's quality of life and may have significant potential in treating autoimmune enteropathy." @default.
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• W2014605430 title "Autoimmune Enteropathy in a Child: Response to Infliximab Therapy" @default.
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