Microvillus Inclusion Disease Research Articles

P0778 LONG TERM GROWTH CATCH-UP AFTER SMALL BOWEL TRANSPLANTATION FOR CONGENITAL MICROVILLUS INCLUSION DISEASE

Introduction: Congenital microvillus inclusion disease (CMID) causes serious watery diarrhea with nonspecific loss of ionic electrolytes, and the small bowel transplantation (SBTx) is indicated for this disease as an organic therapy. Here we report the long term follow-up of the growth of a case of CMID who had received the growth hormone (GH) therapy and underwent living-related SBTx. Methods: The patient is a 19-year-old boy. On the first day of birth he presented life-threatening dehydration and acidosis caused by severe watery diarrhea. At the age of two months, total parenteral nutrition (TPN) was introduced. Daily stool volume exceeded 2500 ml and extra-supply of NaCl, K+, and HCO3- was necessary. Almost totally depending on TPN, his growth had kept within normal range (height S.D. score: −2.0), but his growth rate after the age of 10 years declined. At the age of 11, he had a pathological bone fracture caused by phosphopenic rickets, and extra phosphorus was added to the TPN. Protein loss from intestine and hypoproteinemia were not seen. Results: At the age of 13, based on the diagnosis as GH deficiency, GH therapy was started, and initial pubertal signs appeared since 14 years old, but his growth rate was not improved (11 cm/2.7 yrs). At the age of 16 he received transplantation of an ileal graft (150 cm in length) from his grandmother. His histologically affected ileo-cecal valve and colon were reserved. At the time of transplantation his height S.D. score was -4.5. Postoperative immunosuppressive therapy consisted of a combination of tacrolimus, daclizumab, cyclophosphamide, and low-dose steroid. Thirteen months after the SBTx, free from TPN, he fed himself totally perorally, and GH therapy was restarted. After that his growth rate dramatically improved (19 cm/2.1 yrs, final height S.D. score: −2.2). Conclusion: The dramatic response of the growth to GH therapy after SBTx and establishment of peroral nutrition found in the case of CMID leads the following hypotheses: i) in CMID some growth-related factors may be lost from the affected small intestinal mucosa, ii) establishment of peroral feeding and the digestive and absorptive process from normal small intestinal mucosa may generate some growth-related factors which cannot be supplied by current TPN prescription.

P0776 ASSOCIATION OF ADENOVIRUS INFECTION AND ACUTE INTESTINAL GRAFT REJECTION IN ONE CHILD.

Introduction: Infection and acute graft rejection are the two main complications of intestinal transplantation. Clinical symptoms could be similar but their therapies are different. Their association has been described notably with CMV infection. We report a case of adenovirus infection associated with acute graft rejection in a child. Methods: Clinical case Results: A. is a 4 years old boy who had an intestinal graft (small intestin + colon) in July 2002 for microvillous atrophy intestinal disease. He has been weaned of parenteral nutrition 4 months later. A first diarrhea due to rotavirus with dehydratation occurs 6 months later. 8 months later he was rehospitalized for an acute diarrhea with fever and severe dehydratation. Blood and stools examinations were negative (bacterial and virus). The diagnosis was done by endoscopy which show ileal ulcerations and at biopsies acute rejection characterised by peri-glandular lymphocyte infiltration and glandular apoptosis associated with adenovirus infection characterized by epithelial intranuclear inclusions confirmed by immunohistochemiatry. Cidofovir treatment and increase immunosuppression was done. Clinical improvement was obtained confirmed by endoscopy. On biopsies adenovirus were no more present as well as by PCR and rejection strongly improved. Conclusion: Association of adenovirus infections and acute intestinal graft rejection has not been yet described. Negative stool examination in case of persistant diarrhea is an indication for endoscopy and biopsies which could be the only examination which allows to confirm the diagnosis of viral infection and/or rejection and to do an appropriate treatment.

New perspectives for children with microvillous inclusion disease: early small bowel transplantation.

Microvillous inclusion disease (MVID) is a congenital intestinal epithelial cell disorder leading to lifelong intestinal failure. Despite long-term total parenteral nutrition, life expectancy is extremely reduced because of metabolic or septic complications or liver failure. Twelve patients with early-onset MVID were evaluated between 1995 and 2002 for the possibility of small bowel transplantation (SbTx). Three patients died before they could be placed on the waiting list for SbTx, and one patient is still awaiting SbTx. SbTx was contraindicated in one patient. Seven of 12 patients (six boys and one girl) underwent transplantation (three SbTxs and four combined liver-SbTxs). Actuarial survival rates were 100% and 75% in the SbTx and combined liver-SbTx groups, respectively, with a mean follow-up of 3 years (1.1-8.5 years). In contrast, the survival rate was only 40% in the subgroup of five patients who did not undergo transplantation. After transplantation, all patients were weaned from parenteral nutrition: the five patients with an additional colon graft were weaned within 36 days as opposed to the others without colonic transplant who obtained full intestinal autonomy several months after transplantation. The only two surviving patients who did not undergo SbTx remain highly dependent on total parenteral nutrition, which is complicated by repeated episodes of metabolic decompensation. SbTx alone or in combination with the liver is highly successful in children with MVID, offering them a long-term perspective for the first time. Associated colon grafting markedly improves the outcome and quality of life after SbTx in patients with MVID.

Irreversible Intestinal Failure

ABSTRACTIntestinal failure (IF) can be defined as the reduction of functional gut mass below the minimal amount necessary for digestion and absorption adequate to satisfy the nutrient and fluid requirements for maintenance in adults or growth in children. In developed countries, IF mainly includes individuals with the congenital or early onset of conditions requiring protracted or indefinite parenteral nutrition (PN). Short bowel syndrome was the first commonly recognized cause of protracted IF. The normal physiologic process of intestinal adaptation after extensive resection usually allows for recovery of sufficient intestinal function within weeks to months. During this time, patients can be sustained on parenteral nutrition. Only a few children have permanent intestinal insufficiency and life‐long dependency on PN. Non‐transplant surgery including small bowel tapering and lengthening may allow weaning from PN in some cases. Hormonal therapy with recombinant human growth hormone has produced poor results while therapy with glucagon‐like peptide‐2 holds promise. Congenital diseases of enterocyte development such as microvillus inclusion disease or intestinal epithelial dysplasia cause permanent IF for which no curative medical treatment is currently available. Severe and extensive motility disorders such as total or subtotal intestinal aganglionosis (long segment Hirschsprung disease) or chronic intestinal pseudo‐obstruction syndrome may also cause permanent IF. PN and home‐PN remain are the mainstays of therapy regardless of the cause of IF. Some patients develop complications while receiving long‐term PN for IF especially catheter related complications (thrombosis, sepsis) and liver disease. These patients may be candidates for intestinal transplantation. This review discusses the causes of irreversible IF and emphasizes the specific medico‐surgical strategies for prevention and treatment of these conditions at several stages of IF.

Irreversible intestinal failure.

Intestinal failure (IF) can be defined as the reduction of functional gut mass below the minimal amount necessary for digestion and absorption adequate to satisfy the nutrient and fluid requirements for maintenance in adults or growth in children. In developed countries, IF mainly includes individuals with the congenital or early onset of conditions requiring protracted or indefinite parenteral nutrition (PN). Short bowel syndrome was the first commonly recognized cause of protracted IF. The normal physiologic process of intestinal adaptation after extensive resection usually allows for recovery of sufficient intestinal function within weeks to months. During this time, patients can be sustained on parenteral nutrition. Only a few children have permanent intestinal insufficiency and life-long dependency on PN. Non-transplant surgery including small bowel tapering and lengthening may allow weaning from PN in some cases. Hormonal therapy with recombinant human growth hormone has produced poor results while therapy with glucagon-like peptide-2 holds promise. Congenital diseases of enterocyte development such as microvillus inclusion disease or intestinal epithelial dysplasia cause permanent IF for which no curative medical treatment is currently available. Severe and extensive motility disorders such as total or subtotal intestinal aganglionosis (long segment Hirschsprung disease) or chronic intestinal pseudo-obstruction syndrome may also cause permanent IF. PN and home-PN remain are the mainstays of therapy regardless of the cause of IF. Some patients develop complications while receiving long-term PN for IF especially catheter related complications (thrombosis, sepsis) and liver disease. These patients may be candidates for intestinal transplantation. This review discusses the causes of irreversible IF and emphasizes the specific medico-surgical strategies for prevention and treatment of these conditions at several stages of IF.

Neonatal enteropathies: defining the causes of protracted diarrhea of infancy.

The underlying causes of chronic diarrhea beginning early in life are increasingly well defined. Infectious and post-infectious enteropathies and food sensitive/allergic enteropathy account for the majority of cases. Recent attention has focused on characterizing defined entities, which cause protracted diarrhea in infants and young children. Disorders of intestinal ion transport usually present at birth following a pregnancy complicated by polyhydramnios. Intestinal mucosal biopsies show normal architect with intact villus-crypt axis. Neonatal enteropathies, by contrast, are characterized by blunting of the villi. These include microvillus inclusion disease, tufting enteropathy, autoimmune enteropathy and IPEX syndrome - and it is these conditions that are the subject of the current review.

Neonatal Enteropathies: Defining the Causes of Protracted Diarrhea of Infancy

ABSTRACTThe underlying causes of chronic diarrhea beginning early in life are increasingly well defined. Infectious and post‐infectious enteropathies and food sensitive/allergic enteropathy account for the majority of cases. Recent attention has focused on characterizing defined entities, which cause protracted diarrhea in infants and young children. Disorders of intestinal ion transport usually present at birth following a pregnancy complicated by polyhydramnios. Intestinal mucosal biopsies show normal architect with intact villus‐crypt axis. Neonatal enteropathies, by contrast, are characterized by blunting of the villi. These include microvillus inclusion disease, tufting enteropathy, autoimmune enteropathy and IPEX syndrome ‐ and it is these conditions that are the subject of the current review.

Intractable diarrhea of infancy with congenital intestinal mucosa abnormalities: outcome of four cases

Microvillous inclusion disease (MID) and epithelial dysplasia (ED) or tufting enteropathy are the most frequent causes of intractable diarrhea with persistent villous atrophy and indefinite dependence on total parenteral nutrition (PN) from early infancy. Since these are intractable diseases, they have been proposed to be elective indication for early bowel transplantation in order to avoid complications, such as PN-related liver disease, that would require a combined small bowel-liver transplant. We describe four cases of intractable diarrhea, two with MID and two with ED, seeking to discover whether these diseases are really elective, early indications for bowel transplant. Among our four patients, only one with ED underwent transplantation. The prognosis of small bowel transplant is still poor and worse than that of prolonged HPN. Further study is necessary to achieve a safe HPN program. Referral for transplant (small bowel only or combined with liver) should be considered when there is a venous access reduction and/or severe and irreversible liver disease.

Microvillous Inclusion Disease with Abundant Vermiform, Electron-Lucent Vesicles

A 3-month-old girl with congenital secretory diarrhea underwent a duodenal biopsy. Histologic study showed villous atrophy and large amounts of PAS-positive material within enterocyte cytoplasm. Despite a clinical suspicion of microvillous inclusion disease, 2 sessions of electron microscopy were unsuccessful in detecting the diagnostic inclusions. Instead, large aggregates of electron-lucent, vermiform membranous vesicles were observed in enterocyte cytoplasm, corresponding to the PAS-positive material. A third attempt at electron microscopy was successful in detecting small numbers of microvillous inclusions. These and other recently reported cases document an expanding spectrum of ultrastructural findings in this disease, including examples where the classic microvillous inclusions are overshadowed by other features.

P352 Microvillous atrophy disease associated with coeliac disease: a case report

P352 Microvillous atrophy disease associated with coeliac disease: a case report

Intestinal transplantation for gut failure

In recent years, we have witnessed increasing clinical experience with intestinal transplantation at selected centers. Although early results with this therapy were poor, several important advances have led to improved outcomes. These improvements prompted the Centers for Medicare and Medicaid Services to issue a memorandum on October 4, 2000, according federal reimbursement for intestinal transplantation at selected centers and for selected indications.1 The Centers for Medicare and Medicaid Services stipulated that, to qualify for transplantation, patients must meet a specific definition of intestinal failure and have experienced failure of parenteral nutrition (Table 1). In addition, the Centers for Medicare and Medicaid Services set forth centerspecific criteria for reimbursement, including 1-year patient survival rates of at least 65% and minimum center volume of at least 10 transplants performed per year. Only 4 centers in the United States currently meet these criteria (Mount Sinai Medical Center, University of Pittsburgh Medical Center, University of Miami, and University of Nebraska Medical Center). Thus, intestinal transplantation is currently at a crossroads, transitioning from its historical status as an experimental therapy to standard care for patients with appropriate indications. Presently, appropriate indications, timing of referral, and outcomes of intestinal transplantation are not well recognized among physicians caring for patients who may be candidates for this therapy. Definitions of terms such as “intestinal failure” and “failure of parenteral nutrition” are not standard, and there is no accepted algorithm for integrating parenteral nutrition, intestinal rehabilitation, and transplantation for patients with intestinal failure. Herein we review (1) the applicability of intestinal transplantation for patients with intestinal failure, (2) the current state of medical practice in intestinal transplantation with an emphasis on recent improvements, and (3) current results of this therapy. We also offer for the general gastroenterologist or gastrointestinal surgeon a rational approach to managing intestinal failure and integrating intestinal rehabilitation, parenteral nutrition, and transplantation.2 Brief History

Microvillous Inclusion Disease with Abundant Vermiform, Electron-Lucent Vesicles

A 3-month-old girl with congenital secretory diarrhea underwent a duodenal biopsy. Histologic study showed villous atrophy and large amounts of PAS-positive material within enterocyte cytoplasm. Despite a clinical suspicion of microvillous inclusion disease, 2 sessions of electron microscopy were unsuccessful in detecting the diagnostic inclusions. Instead, large aggregates of electron-lucent, vermiform membranous vesicles were observed in enterocyte cytoplasm, corresponding to the PAS-positive material. A third attempt at electron microscopy was successful in detecting small numbers of microvillous inclusions. These and other recently reported cases document an expanding spectrum of ultrastructural findings in this disease, including examples where the classic microvillous inclusions are overshadowed by other features.

Research agenda for pediatric gastroenterology, hepatology and nutrition: molecular basis of gastrointestinal diseases. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation.

Research agenda for pediatric gastroenterology, hepatology and nutrition: molecular basis of gastrointestinal diseases. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation.

Research agenda for pediatric gastroenterology, hepatology and nutrition: secretion and diarrhea. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation.

Research agenda for pediatric gastroenterology, hepatology and nutrition: secretion and diarrhea. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation.

CD10: a valuable tool for the light microscopic diagnosis of microvillous inclusion disease (familial microvillous atrophy).

Microvillous inclusion disease (MID) is a specific disorder of the intestinal brush border that leads to intractable secretory diarrhea in infants. At present, electron microscopic analysis is required for its definitive diagnosis. However, this technique is not always available or feasible, and the diagnostic microvillous inclusions may not be evident in all specimens. Accordingly, the availability of a panel of histochemical and immunohistochemical stains displaying a specific staining pattern for MID will allow pathologists to reach a definitive diagnosis of this disorder without recourse to electron microscopy. CD10 is a membrane-associated neutral peptidase, shown to have a linear brush-border staining pattern in normal small intestine. We studied the staining pattern of CD10 in small intestinal biopsies from six patients with MID and in 24 control cases (10 normal small intestine, 10 celiac disease, two autoimmune enteropathy, and two allergic enteropathy). All MID cases revealed prominent cytoplasmic CD10 immunoreactivity in surface enterocytes. In contrast, all control cases showed linear brush-border staining. Similar results were obtained with periodic acid-Schiff, polyclonal carcinoembryonic antigen, and alkaline phosphatase, three stains known to show cytoplasmic staining of surface enterocytes in MID. In conclusion, CD10 is a valuable tool for the diagnosis of MID. It may be used as part of a panel that includes other stains with a distinctive staining pattern in MID such as periodic acid-Schiff, polyclonal carcinoembryonic antigen, and alkaline phosphatase. We suggest that the definitive diagnosis of MID can be reached when small bowel biopsies from infants with intractable diarrhea display cytoplasmic staining of surface enterocytes with the above-mentioned stains.

Intestinal Microvillous Atrophy in a Patient with Down Syndrome and Aganglionic Megacolon

Intestinal microvillous disorders are an uncommon cause of severe diarrhea, with very poor prognosis. The authors report the case of a female infant with Down syndrome, aganglionic megacolon, severe diarrhea, and jejunal biopsy with ultrastructural changes consistent with microvillous atrophy. The patient condition improved after a colostomy performed in the setting of the treatment of Hirschprung disease.

Immunoreactive epidermal growth factor receptors are present in gastrointestinal epithelial cells of preterm infants with necrotising enterocolitis.

Epidermal growth factor (EGF) affects epithelial cell proliferation, differentiation and migration in the gastrointestinal tract of experimental animals, and increases proliferation when given intravenously to children with congenital microvillous atrophy or necrotising enteritis. The aim of the present study is to determine whether EGF receptors (EGFR) are present in the gut epithelium of preterm infants, and to discover whether neonatal necrotising enterocolitis (NEC) is associated with the absence of EGFR from mucosal cells. Tissues were taken from involved colon and small intestine of four preterm infants with NEC, and control tissues were taken from four other neonates who had laparatomies for congenital malformations. Sections of the tissues were examined histopathologically after treatment with a monoclonal antibody against the external domain of the EGFR (Zymed Laboratories, San Francisco, CA, USA). Histopathological examination confirmed diagnosis of NEC in the involved bowel and controls showed appearance within normal limit. Immunoreactive EGFR were present on the epithelial cells of both the colon and small intestine, localised on the basolateral membrane of the cells of both subject and the controls. There was no apparent reduction in expression compared with controls. NEC in preterm infants is not associated with absence of EGFR. The presence of EGFR in gut epithelial cells raises the possibility of using EGF for prophylaxis or treatment of NEC.

Microvillous Inclusion Disease: Report of a Case with Atypical Features

Microvillous inclusion disease is a rare lethal disorder characterized by intractable, severe, watery diarrhea beginning in early infancy. The underlying defect is thought to be an autosomal recessive genetic abnormality resulting in defective brush-border assembly and differentiation. Normally, this diagnosis is easily established through the electron microscopic demonstration of characteristic microvilli-lined inclusions lying within the apical cytoplasm of surface enterocytes. In a small number of patients appearing to have microvillous inclusion disease it has not proven possible to demonstrate the typical inclusions. The existence of another entity, termed intestinal microvillous dystrophy, has been proposed to account for such occurrences. This assertion was founded in large part upon the observation that the few subjects studied all displayed a slightly atypical clinical presentation. The case now being presented exhibited the morphologic features ascribed to intestinal microvillous dystrophy but had a clinical presentation that was entirely typical of microvillous inclusion disease. It serves thus to conceptually unite intestinal microvillous dystrophy with microvillous inclusion disease.

Microvillous Inclusion Disease: Report of a Case with Atypical Features

Microvillous inclusion disease is a rare lethal disorder characterized by intractable, severe, watery diarrhea beginning in early infancy. The underlying defect is thought to be an autosomal recessive genetic abnormality resulting in defective brush-border assembly and differentiation. Normally, this diagnosis is easily established through the electron microscopic demonstration of characteristic microvilli-lined inclusions lying within the apical cytoplasm of surface enterocytes. In a small number of patients appearing to have microvillous inclusion disease it has not proven possible to demonstrate the typical inclusions. The existence of another entity, termed intestinal microvillous dystrophy, has been proposed to account for such occurrences. This assertion was founded in large part upon the observation that the few subjects studied all displayed a slightly atypical clinical presentation. The case now being presented exhibited the morphologic features ascribed to intestinal microvillous dystrophy but had a clinical presentation that was entirely typical of microvillous inclusion disease. It serves thus to conceptually unite intestinal microvillous dystrophy with microvillous inclusion disease.

Microvillous Inclusion Disease: Report of a Case with Atypical Features

Microvillous inclusion disease is a rare lethal disorder characterized by intractable, severe, watery diarrhea beginning in early infancy. The underlying defect is thought to be an autosomal recessive genetic abnormality resulting in defective brush-border assembly and differentiation. Normally, this diagnosis is easily established through the electron microscopic demonstration of characteristic microvilli-lined inclusions lying within the apical cytoplasm of surface enterocytes. In a small number of patients appearing to have microvillous inclusion disease it has not proven possible to demonstrate the typical inclusions. The existence of another entity, termed intestinal microvillous dystrophy, has been proposed to account for such occurrences. This assertion was founded in large part upon the observation that the few subjects studied all displayed a slightly atypical clinical presentation. The case now being presented exhibited the morphologic features ascribed to intestinal microvillous dystrophy but had a clinical presentation that was entirely typical of microvillous inclusion disease. It serves thus to conceptually unite intestinal microvillous dystrophy with microvillous inclusion disease.