Persistent Villous Atrophy Research Articles

Letter: coeliac disease and ischaemic heart disease ‐ a true additional risk factor? Authors' reply

We appreciate the constructive criticism of Drs Valitutti and colleagues and fully agree that the limited number of patients in our study (41 of 74 patients with a second biopsy performed has persistent villous atrophy) precludes any firm conclusions with regard to the impact of chronic inflammation on ischaemic heart disease (IHD) risk.1, 2 However, our findings support the hypothesis that chronic inflammation may contribute to an elevated IHD risk in coeliac disease, and we plan to explore this area in future research. Concerning other additional risk factors for IHD, the lack of dietary data did not enable us to examine the potential association between gluten-free products and glycaemic index. Neither did we have data on mean glycated haemoglobin levels. However, in a post-hoc analysis, spurred by the letter from Valinutti et al., we found that coeliac patients with diabetes had a lower body mass index (BMI) than reference individuals [coeliac disease; median BMI = 26.1, range 17.8–38.4 vs. reference individuals; median BMI = 28.0, range 19.6–49.4; P = 0.007 (unianova adjusted for age and sex)]. The values are both significantly increased compared with the total population in the original article (Table 3)1, but the median BMI elevation does not vary with coeliac disease status. Concerning the question raised by Valitutti et al. about the importance of depression and quality of life for IHD risk and outcome, we have recently submitted another manuscript about follow-up after MI in coeliac disease that partly addresses this question through EQ-5D questionnaire results. In conclusion, IHD risk in coeliac disease is an intriguing subject that needs further studies to elucidate the underlying causes, and we welcome further communications about our paper. The authors' declarations of personal and financial interests are unchanged from those in the original article.2

Su1019 Mucosal Healing and Risk of Lymphoproliferative Malignancy in Celiac Disease

Background: Celiac disease (CD) is associated with an increased risk of lymphoproliferative malignancy (LPM). It is unknown whether this risk is affected by the results of the followup intestinal biopsy, performed to document mucosal healing. We aimed to quantify the risk of LPM in those patients with CD who had persistent villous atrophy and those patients who had mucosal healing on follow-up biopsy. Methods: Using a population-based database that included all pathology departments in Sweden (n=28), we identified all patients with CD (equal to villous atrophy, Marsh histopathology stage 3) who had a follow-up biopsy between six months and five years after initial diagnosis, and compared the risk of LPM to that of the general population using expected rates based on age, gender, and calendar year. We used Cox regression to compare the rate of LPM in those with persistent villous atrophy to those with mucosal healing. Results: Among 7,625 patients with CD and a follow-up biopsy, persistent villous atrophy was present in 3,308 (43%). LPM developed in 53 (0.7%) patients, with a median time to LPM of 4.9 years after follow-up biopsy. The overall risk of LPM was increased compared to the general population (Standardized incidence ratio, SIR 2.81; 95% CI 2.10-3.67), but this increase was limited to those with persistent villous atrophy (SIR 3.78; 95% CI 2.71-5.12) with no significant increased risk among those with mucosal healing (SIR 1.50; 95% CI 0.77-2.62). Persistent villous atrophy compared to mucosal healing was associated with an increased risk of LPM (Hazard ratio, HR 2.26; 95% CI 1.18-4.34). This risk was primarily observed for T cell lymphoma (HR 3.51; 95% CI 0.75-16.34), with no association for B cell lymphoma (HR 0.97; 95% CI 0.21-4.49). Patients with subtotal or total villous atrophy on follow-up biopsy had a greater increase in LPM risk (HR 3.96; 95% 1.65-9.50) compared to those with partial villous atrophy (HR 1.90; 95% CI 0.70-5.19). Conclusions: The increased risk of LPM in CD is markedly influenced by the results of the follow-up biopsy; those with mucosal healing have an LPM risk similar to that of the general population. The increased risk of LPM among those with persistent villous atrophy is mainly for T cell lymphoma. Follow-up biopsy can effectively stratify CD patients regarding subsequent LPM risk.

Letter: mucosal healing and mortality in coeliac disease

We read the interesting paper by Lebwohl et al.1 The authors concluded that there was no association between persistence of villous atrophy and mortality in coeliac disease (CD). However, the study design and the interpretation of results raise some concerns. In spite of the impressive number of patients evaluated, it is of note that only 26% of the CD-diagnosed patients during the study period had a follow-up biopsy, with the reason why these biopsies were taken unknown and therefore, as the authors mention in their discussion, ascertainment bias cannot be excluded. It has recently been emphasised that small bowel biopsy remains the gold standard for monitoring mucosal healing in CD.2, 3 Persistent villous atrophy was associated with a more than threefold increased risk of osteoporosis, refractory CD and malignancies irrespective of symptom resolution on a gluten-free diet (GFD).4 Thus, the question that emerges is whether the CD patients in this study cohort were adequately followed up. A recent paper showed that medical follow-up evaluation in patients with CD is highly variable and often inadequate. In fact, follow-up consistent with current American Gastroenterology Association recommendations was observed in only 35% of patients.5 Currently, clear guidelines on when to repeat small-bowel biopsy are lacking. However, a systematic review of studies reporting the long-term management of CD suggested that follow-up biopsy at 1–2 years after commencement of the GFD is recommended, and that if histological improvement is incomplete, biopsies probably should be performed again in 1–2 years.6 Thus, the evaluated cohort of patients would not be useful to assess how persistent villous atrophy influenced mortality in CD, as the rate of follow-up small-bowel biopsy was quite low, the reason why these biopsies were taken was unknown, and there were no additional follow-up biopsies performed when histological improvement was incomplete. Likewise, follow-up biopsy in the study by Lebwohl et al.1 demonstrated that there was persistent villous atrophy in 43% of the cohort. It is reasonable to think that in these patients, dietary measures to improve GFD adherence were taken, as lack of dietary adherence is considered the main reason for persistence of villous atrophy. Improvement in dietary adherence would have influenced survival, and decreased mortality to the level of patients who have mucosal healing. In this sense, the problem in the long-term management of CD is the nondiagnosed persistent villous atrophy. Only once it is detected, can the opportune dietary measures be established. Declaration of personal and funding interests: None.

Letter: complications of coeliac disease despite a gluten‐free diet

In their recent paper, Lebwohl and colleagues report an interesting finding: persistent villous atrophy (VA) does not seem to be associated with increased mortality in coeliac disease (CD).1 This conclusive statement is quite surprising. As already stated by the authors, CD patients are at risk of earlier death,2, 3 and failure in mucosal healing has been thought to be the main factor.4, 5 This study seems to call into question this consolidate hypothesis, and it deserves some comments from a clinical practice's point of view. We know that histological recovery takes different times, according to the age when gluten-free diet (GFD) has started. In our experience, subdividing the patients according to age, only the younger patients (5–30 years) showed significant improvement of histology within 12 months (P < 0.034); older patients (>30 years) showed histological improvement, but this was not statistically significant, even after 24 months on a GFD.6 Gluten-free diet is generally advised to CD patients for three main reasons: treating symptoms related to the disease; preventing immunological gluten-related disorders; and preventing neoplastic complications. GFD and adherence to diet are considered the key factors in obtaining mucosal healing and in preventing occurrence of complications.7, 8 In our experience, the time to the occurrence of complications with GFD seems to be related to type of disease rather than to the severity of the histological lesion at the time of the diagnosis. In fact, considering the time of appearance of complications after GFD had started, complications occurred after a mean/median time with GFD of 6.5/5 years [standard deviation (s.d.) ± 5.08] in classical CD, and after a mean/median time of 3.5/4 years (s.d. ± 1) in subclinical CD. However, looking at the compliance to GFD in patients developing complications, we found that 6/14 (42.9%) patients with classical CD were not fully compliant with GFD, whilst 2/4 (50%) of subclinical CD were not fully compliant (P = n.s.).9 In light of our and Lebwohl's experience, should a GFD still be advised to prevent complications? Despite the retrospective design, Lebwohl's study calls into question whether and why an increased complication rate (increased mortality rate included) occurs in CD. Furthermore, confirmative and prospective studies are, therefore, welcomed. Declaration of personal and funding interests: None.

Trace gluten contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-responsive celiac disease patients

BackgroundPatients with persistent symptoms and/or villous atrophy despite strict adherence to a gluten-free diet (GFD) have non-responsive celiac disease (NRCD). A subset of these patients has refractory celiac disease (RCD), yet some NRCD patients may simply be reacting to gluten cross-contamination. Here we describe the effects of a 3-6 month diet of whole, unprocessed foods, termed the Gluten Contamination Elimination Diet (GCED), on NRCD. We aim to demonstrate that this diet reclassifies the majority of patients thought to have RCD type 1 (RCD1).MethodsWe reviewed the records of all GFD-adherent NRCD patients cared for in our celiac center from 2005-2011 who were documented to have started the GCED. Response to the GCED was defined as being asymptomatic after the diet, with normal villous architecture on repeat biopsy, if performed.ResultsPrior to the GCED, all patients were interviewed by an experienced dietitian and no sources of hidden gluten ingestion were identified. 17 patients completed the GCED; 15 were female (88%). Median age at start of the GCED was 42 years (range 6-73). Fourteen patients (82%) responded to the GCED. Six patients met criteria for RCD prior to the GCED; 5 (83%) were asymptomatic after the GCED and no longer meet RCD criteria. Of the 14 patients who responded to the GCED, 11 (79%) successfully returned to a traditional GFD without resurgence of symptoms.ConclusionsThe GCED may be an effective therapeutic option for GFD-adherent NRCD patients. Response to this diet identifies a subgroup of patients, previously classified as RCD1, that is not truly refractory to dietary treatment. Preventing an inaccurate diagnosis of RCD1 avoids immunotherapy. Most patients are able to return to a traditional GFD without return of symptoms.

Differential IL-13 Production by Small Intestinal Leukocytes in Active Coeliac Disease versus Refractory Coeliac Disease

A small fraction of coeliac disease (CD) patients have persistent villous atrophy despite strict adherence to a gluten-free diet. Some of these refractory CD (RCD) patients develop a clonal expansion of lymphocytes with an aberrant phenotype, referred to as RCD type II (RCDII). Pathogenesis of active CD (ACD) has been shown to be related to gluten-specific immunity whereas the disease is no longer gluten driven in RCD. We therefore hypothesized that the immune response is differentially regulated by cytokines in ACD versus RCDII and investigated mucosal cytokine release after polyclonal stimulation of isolated mucosal lymphocytes. Secretion of the TH2 cytokine IL-13 was significantly higher in lamina propria leukocytes (LPLs) isolated from RCDII patients as compared to LPL from ACD patients (P = 0.05). In patients successfully treated with a gluten-free diet LPL-derived IL-13 production was also higher as compared to ACD patients (P = 0.02). IL-13 secretion correlated with other TH2 as well as TH1 cytokines but not with IL-10 secretion. Overall, the cytokine production pattern of LPL in RCDII showed more similarities with LPL isolated from GFD patients than from ACD patients. Our data suggest that different immunological processes are involved in RCDII and ACD with a potential role for IL-13.

Mucosal healing and mortality in coeliac disease

Coeliac disease (CD), characterised by the presence of villous atrophy (VA) in the small intestine, is associated with increased mortality, but it is unknown if mortality is influenced by mucosal recovery. To determine whether persistent VA is associated with mortality in CD. Through biopsy reports from all pathology departments (n=28) in Sweden, we identified 7648 individuals with CD (defined as VA) who had undergone a follow-up biopsy within 5years following diagnosis. We used Cox regression to examine mortality according to follow-up biopsy. The mean age of CD diagnosis was 28.4; 63% were female; and the median follow-up after diagnosis was 11.5years. The overall mortality rate of patients who underwent follow-up biopsy was lower than that of those who did not undergo follow-up biopsy (Hazard Ratio 0.88, 95% CI: 0.80-0.96). Of the 7648 patients who underwent follow-up biopsy, persistent VA was present in 3317 (43%). There were 606 (8%) deaths. Patients with persistent VA were not at increased risk of death compared with those with mucosal healing (HR: 1.01; 95% CI: 0.86-1.19). Mortality was not increased in children with persistent VA (HR: 1.09 95% CI: 0.37-3.16) or adults (HR 1.00 95% CI: 0.85-1.18), including adults older than age 50years (HR: 0.96 95% CI: 0.80-1.14). Persistent villous atrophy is not associated with increased mortality in coeliac disease. While a follow-up biopsy will allow detection of refractory disease in symptomatic patients, in the select population of patients who undergo repeat biopsy, persistent villous atrophy is not useful in predicting future mortality.

PWE-117 Responses to dietary intervention guided by follow-up duodenal biopsy in coeliac disease

IntroductionBritish Society of Gastroenterology guidance on repeating the intestinal biopsy in coeliac patients on diet is ambiguous and suggests that dietary advice is the same irrespective of the follow-up biopsy...

A Child With Refractory Coeliac Disease

A Child With Refractory Coeliac Disease

Intestinal transglutaminase 2 specific antibody deposits in non-responsive coeliac disease

Background and aims The diagnosis of coeliac disease is problematic in individuals not responding to a gluten-free diet. Small-bowel villous atrophy occurs in other enteropathies and non-responsive patients are often seronegative. We investigated whether small-bowel mucosal transglutaminase-2 specific autoantibody deposits distinguish non-responsive coeliac disease from other enteropathies. Methods Small-bowel mucosal autoantibody deposits were determined in 27 non-responsive, 28 responsive coeliac patients and 10 controls with other enteropathies. Of the non-responsive coeliac patients six were adhering poorly and 21 strictly to the diet; six of the 21 had enteropathy-associated lymphoma, five refractory coeliac disease and 10 otherwise persistent villous atrophy. The presence of mucosal autoantibody deposits was compared to serology, villous morphology, densities of intraepithelial lymphocytes (IELs) and markers of refractory coeliac disease. Results Twenty out of 21 well-adhering, all six poorly adhering non-responsive and all 28 untreated responsive coeliac patients had small-bowel mucosal autoantibody deposits present, while controls with other enteropathies were negative. Small-bowel mucosal autoantibody deposits were more accurate in detecting coeliac disease than serology or IEL densities. Refractory coeliac markers revealed only cases with the most severe condition. Conclusions Small-bowel mucosal autoantibody deposits differentiate coeliac disease from other enteropathies, enabling the design of appropriate therapeutic strategies.

Classification and management of refractory coeliac disease

Refractory coeliac disease (RCD) is defined by persistent or recurrent malabsorptive symptoms and villous atrophy despite strict adherence to a gluten-free diet (GFD) for at least 6–12 months in the...

Clinical symptoms in celiac patients on a gluten-free diet

Objective. Persistent villous atrophy in patients with celiac disease (CD) on a gluten-free diet (GFD) is reported with increasing frequency. The aim of this study was to evaluate a possible association between persistent damage of the villi and “atypical” gastrointestinal symptoms in CD patients on a GFD. Material and methods. Sixty-nine CD patients on a GFD were divided into two groups: Group A included 42 patients (6 M, 36 F, age range 17–62 years) undergoing esophagogastroduodenoscopies (EGDs) due to the presence of symptoms; Group B included 27 control patients (6 M, 21 F, age range 24–71 years) who were asymptomatic at the time of the study. Both groups underwent EGDs and a duodenal histologic study. Results. Persistent endoscopic lesions were more frequent in Group A (30/42) than in Group B (12/27; p=0.01). Villous atrophy was significantly more frequent in Group A than in Group B: 85% versus 33% (p<0.0001; odds ratio (OR)=12; 95% CI 3.7–38.9). Gastrointestinal symptoms in the Group A patients were different from those present at CD diagnosis: anemia/diarrhea/weight loss in 6 cases; gastroesophageal reflux disease (GERD)-like symptoms in 12 cases; abdominal pain/constipation in 24 cases. In Group A there was no difference in gender distribution, age and duration of GFD between subjects with normal villi and those with persistent partial villous atrophy. Patients with persistent symptoms showed a higher intraepithelial eosinophil count (p=0.005) than the asymptomatic patients (p=0.01). Conclusions. Persistent intestinal villous atrophy in CD patients on a GFD is associated with gastrointestinal symptoms considered “atypical” for CD and not present at CD diagnosis.

Homocysteine and related B-vitamin status in coeliac disease: Effects of gluten exclusion and histological recovery

Objective. Hyperhomocysteinaemia is considered to be a risk factor for cardiovascular disease (particularly stroke) and has been implicated in recurrent miscarriage and osteoporotic fracture, recognized manifestations of coeliac disease (CD). The objective of this study was to compare plasma homocysteine levels and biomarker status of metabolically related B vitamins (folate, vitamin B12, B6 and riboflavin) in treated and untreated CD patients and healthy controls. Material and methods. CD patients attending a clinic for either initial or follow-up biopsy (at least 12 months after commencing a gluten-free diet) were categorized into three groups: 1) newly diagnosed (untreated; n=35); 2) persistent villous atrophy (VA) at follow-up (n=24) or 3) recovered VA at follow-up (n=41). Blood samples were analysed for plasma homocysteine, serum and red cell folate and serum vitamin B12 levels, and for plasma pyridoxal 5-phosphate (PLP, vitamin B6) and riboflavin (vitamin B2) status. Results. Homocysteine concentrations were significantly higher (p=0.05) and red cell and serum folate significantly lower (p<0.001) in untreated patients compared with controls, while all three reached normal levels in recovered VA patients. Although untreated and persistent VA patients tended to have lower B12 levels, these did not reach significance. There was no evidence of compromised B6 or riboflavin status, even in untreated CD patients. Homocysteine concentrations were inversely associated with both serum (r=−0.421; p<0.001) and red cell (r=−0.459; p<0.001) folate and with serum vitamin B12 (r=−0.353; p=0.001). Conclusions. Gluten exclusion in CD improves folate status and normalizes homocysteine concentrations. Reducing the risk of homocysteine-related disease may be another reason for aggressive diagnosis and treatment of CD.

IgA anti-actin antibodies ELISA in coeliac disease: A multicentre study

Background Previous studies have demonstrated that serum anti-actin antibodies are a reliable marker of intestinal damage severity in coeliac disease. Aims To validate in a multicentre study the clinical usefulness of serum IgA anti-actin antibody ELISA and its possible use in monitoring intestinal mucosa lesions during gluten-free diet. Patients and methods Four centres recruited 205 newly diagnosed coeliac disease patients with villous atrophy, 80 healthy controls and 81 “disease” controls. Twelve coeliac disease patients on gluten-free diet but with persistent symptoms underwent serum IgA anti-actin antibody assay and intestinal histology evaluation. IgA anti-actin antibody ELISA was performed with a commercial kit. All coeliac disease patients underwent intestinal histology study. Results IgA anti-actin antibodies showed a sensitivity of 80% and a specificity of 85% in the diagnosis of coeliac disease patients with villous atrophy. The area under the receiving operator curve for anti-actin antibodies was 0.873 [95% C.I. 0.805–0.899]. Serum anti-actin antibodies values were significantly higher in coeliac disease patients than in healthy or “disease” controls ( P < 0.0001). Serum anti-actin antibodies were positive in 41 of the 60 coeliac disease patients with mild intestinal histology lesions (69%) and in 123 of the 145 with severe lesions (85.3%) ( P < 0.05). There was a significant inverse correlation between anti-actin antibody values and the villi/crypts ratio ( r = −0.423; P < 0.0001). In the 12 coeliac disease patients on gluten-free diet who underwent re-evaluation as they were persistently symptomatic, intestinal histology showed three cases with persistent villous atrophy: all of these were positive for serum anti-actin antibodies ELISA, whereas both serum anti-tTG and EmAs were negative. The other nine patients showed normal intestinal villi and were negative for serum anti-actin antibodies. Conclusions Anti-actin antibodies are a reliable marker of severe intestinal mucosa damage in coeliac disease patients and a simple ELISA technique offers an accurate method for their determination. These antibodies seem to be a very reliable marker of persistent intestinal damage in coeliac disease patients.

Persistent small bowel mucosal villous atrophy without symptoms in coeliac disease

Refractory sprue with malabsorption carries a risk of lymphoma. To examine whether a good clinical but poor histological response during a strict gluten-free diet predicts a poor outcome. The study involved all coeliac patients who showed no histological recovery within 2 years on a strict gluten-free diet. Small intestinal biopsy and bone mineral density were investigated in 2001 and clinical features were followed up until 2005. The results were compared to those in 18 coeliac patients with a good histological recovery. Thirteen coeliac patients had persistent small intestinal villous atrophy despite maintaining gluten-free diet. All had demonstrated a good clinical response. Osteoporosis was found in 58% and 22% of the non-responders and responders, respectively (P = 0.04). In 2005, two of the non-responders had developed symptomatic refractory sprue, one died of lymphoma and one of carcinoid tumour, and one gastric adenocarcinoma was operated. None of the 18 controls had developed refractory sprue or malignancy. The frequency of histological non-responsive disease was 1.9%. Persistent villous atrophy in adult coeliac disease, even in the absence of symptoms, carries a risk of subsequent severe complications. The follow-up biopsy is important in detecting these individuals.

Resurrection of gliadin antibodies in coeliac disease. Deamidated gliadin peptide antibody test provides additional diagnostic benefit

Objective. Circulating antibodies against naïve, whole gliadin have been replaced by more accurate endomysial and tissue transglutaminase antibody tests in the diagnosis of coeliac disease. The purpose of this study was to compare these serological tests with a new test recognizing antibodies against deamidated and defined gliadin peptides. Material and methods. The study population comprised selected coeliac disease patients in a tertiary clinic: newly detected patients before and after a gluten-free diet, patients with persistent small-bowel mucosal villous atrophy despite a strict gluten-free diet and non-coeliac controls reporting abdominal symptoms after ingestion of cereals. Comparisons were made between serum IgA-class gliadin peptide, endomysial, tissue transglutaminase and conventional gliadin antibodies. Results. The deamidated gliadin peptide antibody test showed a sensitivity of 91% and a specificity of 98% in coeliac disease. The tissue transglutaminase antibody test performed equally well. The specificity of endomysial antibody was just as high, but its sensitivity was lower, 80%. The conventional gliadin antibody test showed poor sensitivity and specificity. Combination of the deamidated gliadin peptide and tissue transglutaminase tests offered the best sensitivity without loss of specificity in the diagnosis of coeliac disease. All antibody levels declined in line with mucosal recovery. The deamidated gliadin peptide antibody test showed six of the nine cases with small-bowel mucosal damage persisting on a gluten-free diet, whereas tissue transglutaminase detected only two cases and endomysial antibody none. Conclusions. The new gliadin peptide antibody test proved highly accurate in the diagnostic work-up and follow-up of coeliac disease and can be endorsed in combination with the tissue transglutaminase test.

Long-Term Parenteral Nutrition in Pediatric Autoimmune Enteropathies

Severe and protracted or persistent diarrhea (SPD) is the most severe form of diarrhea in infancy and has also been defined as intractable diarrhea when it leads to dependence on total parenteral nutrition (TPN). One of the rare causes of SPD is represented by autoimmune enteropathy that is characterized by life-threatening diarrhea mainly occurring within the first years of life, persistent villous atrophy in consecutive biopsies, resistance to bowel rest, and evidence of antigut autoantibodies. We evaluated 10 patients (seven boys, mean age at diagnosis 18 months; range: 0 to 160 months) fulfilling criteria of autoimmune enteropathy to assess dependence on TPN. TPN was first required in all patients to avoid dehydration and electrolytic imbalance. All patients were dependent on immunosuppressive therapy (steroid, azothioprine, cyclosporine, tacrolimus). Three patients died of sepsis: two during TPN while in the hospital, and one at home after he was weaned off TPN. Five patients are weaned off TPN after a mean period of 18 months; they are actually on oral alimentation with a cow milk-free diet after a period of enteral nutrition with elemental formula. One underwent total colectomy and bone marrow transplantation and one developed an IPEX syndrome. One patient is still dependent on TPN for 24 months. She is on home parenteral nutrition. Patients with diagnosis of IPEX syndrome require parenteral support with three or four infusion per week. TPN represents a fixed step in the management of autoimmune enteropathy, but it may be considered as an interim treatment while waiting for intestinal adaptation, at least in some selectioned case of autoimmune enteropathy. Bone marrow transplantation should be considered and reserved for those patients with severe complications due to home parenteral nutrition, or in those that are really dependent on parenteral nutrition.

Clinical presentation of celiac disease in the pediatric population

Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten-containing grains (including wheat, rye, and barley) in genetically susceptible individuals. CD is associated with HLA molecules DQ2 (90%-95%) and DQ8 (5%-10%), and in the continued presence of gluten the disease is self-perpetuating. CD is one of the most common lifelong disorders worldwide and is characterized by a variety of clinical presentations. These include the typical malabsorption syndrome (classic symptoms) and a spectrum of symptoms potentially affecting any organ or body system (nonclassic symptoms). Because CD often is atypical or even clinically silent, many cases go undiagnosed and are exposed to the risk of long-term complications. There is growing interest in the social aspects of CD because the burden of illness related to this condition is doubtless higher than previously thought.

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.

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