Intractable Diarrhea Research Articles

Genomic analysis of an infant with intractable diarrhea and dilated cardiomyopathy

We describe a case of an infant presenting with intractable diarrhea who subsequently developed dilated cardiomyopathy, for whom a diagnosis was not initially achieved despite extensive clinical testing, including panel-based genetic testing. Research-based whole-genome sequences of the proband and both parents were analyzed by the SAVANNA pipeline, a variant prioritization strategy integrating features of variants, genes, and phenotypes, which was implemented using publicly available tools. Although the intestinal morphological abnormalities characteristic of congenital tufting enteropathy (CTE) were not observed in the initial clinical gastrointestinal tract biopsies of the proband, an intronic variant, EPCAM c.556-14A>G, previously identified as pathogenic for CTE, was found in the homozygous state. A newborn cousin of the proband also presenting with intractable diarrhea was found to carry the same homozygous EPCAM variant, and clinical testing revealed intestinal tufting and loss of EPCAM staining. This variant, however, was considered nonexplanatory for the proband's dilated cardiomyopathy, which could be a sequela of the child's condition and/or related to other genetic variants, which include de novo mutations in the genes NEDD4L and GSK3A and a maternally inherited SCN5A variant. This study illustrates three ways in which genomic sequencing can aid in the diagnosis of clinically challenging patients: differential diagnosis despite atypical clinical presentation, distinguishing the possibilities of a syndromic condition versus multiple conditions, and generating hypotheses for novel contributory genes.

Portal vein/superior mesenteric vein resection in pancreatic cancer treatment in the elderly.

There is an increased interest in extending surgical criteria for pancreatic cancer by performing pancreaticoduodenectomy (PD) combined with portal vein (PV) or superior mesenteric vein (SMV) resection and reconstruction for borderline resectable patients. However, whether this procedure suitable for elderly patients remains unclear. Here, we studied cases of pancreatic cancer treatment in our medical center to evaluate feasibility and safety of this procedure in the elderly.Eighty-three patients 65 years of age or older who underwent PD from January 2009 to March 2014 were divided into 2 groups: PD only (Group A, 52 cases), and PD combined with PV/SMV resection and reconstruction (Group B, 31 cases). Surgical outcomes and survival rates were compared between groups. Information regarding preoperative, intraoperative and postoperative conditions, and follow-up visits were provided. The outcomes of postoperative complications and survival rates were investigated.No difference in the preoperative data was detected between 2 groups with the exception that the serum albumin level was significantly lower in Group B (P = .013), indicating more deteriorating health conditions in this group. Although intraoperative time and blood loss were higher in Group B (P < .001 and P = .048, respectively), the overall postoperative complications and survival curve showed no statistical differences between 2 groups with one exception in that there was higher incidence of intractable diarrhea in Group B (P = .034). The symptoms, however, resolved later on with conservative treatment. The median survival time for patients in this study was comparable to other reported PD treatments. There was zero postoperative mortality in both groups.PD combined with PV/SMV treatment did not lead to increased morbidity and motility in elderly patients 65 years of age and above. This procedure could provide a promising opportunity for borderline resectable elderly pancreatic cancer patients.

Dramatic Elevation inParathyroid Hormone after Denosumab Administration in a Woman with Scleroderma

Denosumab (Prolia), an injectable human monoclonal antibody with affinity for nuclear factor-kappa ligand (RANKL), is approved for the treatment of osteoporosis in postmenopausal women and men at high risk for fracture, or patients who have failed or are intolerant of ther treatments. There have been case reports of denosumab leading to elevated parathyroid hormone (PTH) among patients with severe renal impairment, defined as creatinine clearances under 30 mL/min or on dialysis, which is the level at which the manufacturer suggests monitoring for hypocalcemia. We report a case of a marked increase in PTH in a woman with suspected malabsorption due to scleroderma, without severe renal impairment, whose intractable diarrhea limited her treatment options.

Living Donor Liver Transplantation for Progressive Familial Intrahepatic Cholestasis Type 1: Two Reported Cases

BackgroundProgressive familial intrahepatic cholestasis type 1 (PFIC1) is an inherited disease characterized by cholestatic features. We report two patients with PFIC1 who underwent liver retransplantation. Case ReportOne patient was a 3-year-old female who underwent liver transplantation for PFIC1. She presented with severe diarrhea and fatty liver, and went into liver failure. She therefore underwent liver retransplantation and external biliary diversion 8 years after the initial liver transplantation. The explanted liver was histologically diagnosed with chronic rejection. Her intractable diarrhea stopped after the retransplantation. She was diagnosed with a fatty liver 8 months after the retransplantation and died 4 years after retransplantation due to bleeding from an ileostomy. The other patient was a 3-year-old male. This patient underwent liver retransplantation due to liver cirrhosis caused by steatohepatitis 9 years after the initial liver transplantation. The biliary tract was not diverted. He also experienced severe diarrhea after the retransplantation and requires home parenteral nutrition due to an eating disorder. ConclusionsLiver transplantation is the only treatment to resolve life-threatening issues due to PFIC1, but requires further improvement as a therapeutic modality.

Safety analysis of regorafenib prior to selective internal radiation therapy (SIRT) using 90Y resin microspheres for the treatment (tx) of patients (pts) with refractory metastatic colorectal cancer (mCRC) with liver metastases (mets).

e15040 Background: SIRT (or radioembolization) has been successfully used in the tx of mCRC patients with liver mets who are not surgical candidates. The addition of the multi-kinase inhibitor, regorafenib to SIRT is an attractive option as anti-tumor and maintenance tx for refractory CRC. Here we present the safety analysis of the 1st of 2 cohorts of our Phase II, open-label study comparing the safety of the combination of SIRT and regorafenib where chemotherapy occurs either before or after SIRT. Methods: mCRC pts with evidence of liver mets not treatable by surgical resection or local ablation were tx with 160 mg regorafenib QD PO on days 1-21 of a 28-day cycle followed by a 1 week (wk) washout then SIRT infusion (SIR-Spheres; Sirtex, North Sydney, Australia). Liver function was evaluated 2 wks and 4 wks after SIRT, and regorafenib was re-initiated if liver function was normal. Pts were evaluated for safety, and restaged on wk 6 and 12 following SIRT. The primary objective was to evaluate the safety of this tx schema. Results: 25 pts were enrolled from 7/15 to 8/16: median age 56 yrs, 48% male; 88% colon cancer, 12%, rectal cancer; 48% KRASmt, 4% BRAFmt. 68% of pts had prior systemic therapy for metastatic disease and 80% of pts had prior CRC surgeries. Pts received a median 11 wks regorafenib. 3 pts received regorafenib, but not SIRT due to disease progression. The median activity of SIRT delivered to the liver was 38 mCi and the median lung shunt fraction was 4%. The median tumor volume treated was 76 mL. The most common tx-related adverse events (AEs) were fatigue (60% all grades [G]; 8% G3/4), decreased appetite (32% all G; 0 G 3/4), and nausea (32%, all G; G 3/4). There were 4 tx-related serious AEs (bowel perforation, intractable abdominal pain, portal hypertension, and diarrhea) and no tx-related deaths. The overall response rate was 4%. The median PFS was 4 months and the median OS was 12 months. Conclusions: The treatment of mCRC pts with liver mets with regorafenib followed by SIRT infusion was found to be tolerable in this pt population. Further efficacy analysis of this treatment schema is merited. Clinical trial information: NCT02195011.

Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa

BackgroundTrichohepatoenteric syndrome (THE-S) or phenotypic diarrhoea of infancy is a rare autosomal recessive disorder characterised by severe infantile diarrhoea, facial dysmorphism, immunodeficiency and woolly hair. It was first described in 1982 in two infants with intractable diarrhoea, liver cirrhosis and abnormal hair structure on microscopy. We report on two siblings from a consanguineous family of Somali descent who, despite extensive clinical investigation, remained undiagnosed until their demise. The index patient died of fulminant cytomegalovirus pneumonitis at 3 months of age.MethodsWhole exome sequencing (WES) was performed on a premortem DNA sample from the index case. Variants in a homozygous recessive state or compound heterozygous state were prioritized as potential candidate variants using TAPER™. Sanger sequencing was done to genotype the parents, unaffected sibling and a deceased sibling for the variant of interest.ResultsExome sequencing identified a novel homozygous mutation (c.4507C > T, rs200067423) in TTC37 which was confirmed by Sanger sequencing in the index case. The identification of this mutation led to the diagnosis of THE-S in the proband and the same homozygous variant was confirmed in a male sibling who died 4 years earlier with severe chronic diarrhoea of infancy. The unaffected parents and sister were heterozygous for the identified variant.ConclusionsWES permitted definitive genetic diagnosis despite an atypical presentation in the index case and suggests that severe infection, likely secondary to immunodeficiency, may be a presenting feature. In addition definitive molecular diagnosis allows for genetic counseling and future prenatal diagnosis, and demonstrates the value of WES for post-mortem diagnosis of disorders with a non-specific clinical presentation in which a Mendelian cause is suspected.

Congenital Glucose–Galactose Malabsorption: A Case Report

Congenital glucose–galactose malabsorption (CGGM) is a rare cause of intractable infantile diarrhea, with only a few hundred cases recognized worldwide. This life-threatening disorder must be considered in the differential diagnosis of an infant who presents with diarrhea and dehydration that fails to respond to standard therapy. The clinical and diagnostic course of an infant with recurrent episodes of watery diarrhea and hypernatremic dehydration found to be homozygous for a rare variant in the SLC5A1 gene, c.187C>T (p.R63X) is described.

Prune-Belly 症候群に併発した, いわゆる"難治性下痢"の 1 治験例

Prune-Belly 症候群に併発した, いわゆる"難治性下痢"の 1 治験例

The First World Diagnosis of Allergy

Six infants were affected with intractable diarrhea and therefore admitted to our ward. That was the birth of allergy, which revolutionized the medical world. Such as Jobs changed our way of living, we insured to sick babies and children a new way of living with allergy, when not escaping it. The figures 1-3 show a rare microscopic appearance of the immune cells involved in an oral provocation test. About 40 years ago the whole world lived in the complete ignorance of allergy. We have made the first world diagnosis of allergy and of cow’s milk allergy (CMA) in six parenterally fed babies.

The First World Diagnosis of Allergy

Six infants were affected with intractable diarrhea and therefore admitted to our ward. That was the birth of allergy, which revolutionized the medical world. Such as Jobs changed our way of living, we insured to sick babies and children a new way of living with allergy, when not escaping it. The figures 1-3 show a rare microscopic appearance of the immune cells involved in an oral provocation test. About 40 years ago the whole world lived in the complete ignorance of allergy. We have made the first world diagnosis of allergy and of cow’s milk allergy (CMA) in six parenterally fed babies.

Management of syndromic diarrhea/tricho-hepato-enteric syndrome: A review of the literature.

Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare disease linked to the loss of function of either TTC37 or SKIV2L, two components of the SKI complex. It is characterized by a combination of 9 signs (intractable diarrhea, hair abnormalities, facial dysmorphism, immune abnormalities, IUGR/SGA, liver abnormalities, skin abnormalities, congenital heart defect and platelet abnormalities). We present a comprehensive review of the management of SD/THE and tested therapeutic regimens. A review of the literature was conducted in May 2017: 29 articles and 2 abstracts were included describing a total of 80 patients, of which 40 presented with mutations of TTC37, 14 of SKIV2L. Parenteral nutrition was used in the management of 83% of the patients and weaned in 44% (mean duration of 14.97 months). Immunoglobulins were used in 33 patients, but data on efficacy was reported for 6 patients with a diminution of infection (n = 3) or diarrhea reduction (n = 2). Antibiotics (n = 11) provided no efficacy. Steroids (n = 17) and immunosuppressant drugs (n = 13) were used with little efficacy and mostly in patients with IBD-like SD/THE. Hematopoietic stem cell transplantation (HSCT) was performed in 4 patients: 2 died, for one it corrected the immune defects but not the other features and for the last one, it provided only a partial improvement. Finally, no specific diet was effective except for some contradictory reports for elemental formula. In conclusion, the management of SD/THE mainly involves parenteral nutrition and immunoglobulin supplementation. Antibiotics, steroids, immunosuppressants, and HSCT are not recommended as principle treatments since there is no evidence of efficacy.

New mutations of EpCAM gene for tufting enteropathy in Saudi Arabia

Background/Aim:Tufting enteropathy (TE) is a rare cause of congenital intractable diarrhea in children. It often results in an irreversible intestinal failure and total parenteral nutrition (TPN) dependency; eventually, intestinal transplantation may be necessary. Data on TE from the Middle East are scarce; therefore, our aim of conducting this study was to clarify the clinical, histopathologic, and molecular features of TE in Saudi children.Patients and Methods:This was a retrospective chart review of four children with TE who presented between January 2011 and December 2013 to King Fahad Specialist Hospital-Dammam (KFSH-D). The diagnosis of TE was suspected based on characteristic histopathologic intestinal biopsy findings and confirmed by EpCAM gene testing.Results:Molecular testing identified two novel mutations in the EpCAM gene in our patients. These mutations were associated with severe phenotype of the disease characterized by very early onset (median of 2 weeks of life), TPN dependency, and death during early childhood. Two patients died due to central line-related complications. Two patients were referred for intestinal transplantation due to loss of intravenous access in one and progressive liver disease in the other.Conclusion:Mutations in EpCAM gene in Saudi children are characterized by severe phenotype and poor outcome.

Nonobstructive Diffuse Dilated Bowel Loops: Prenatal Diagnosis, Fetal Characteristics and Neonatal Outcomes.

The purpose of this study was to describe the characteristics and outcomes of fetuses with a diagnosis of nonobstructive diffuse dilated bowel loops. We conducted a retrospective study of all pregnancies with fetal diagnosis of nonobstructive diffuse dilated bowel loops over 14 years in a large tertiary referral center. Fetomaternal and neonatal characteristics and outcomes were assessed. Seven fetuses had sonograms showing diffuse dilated bowel loops; none of them had intestinal obstruction after labor. The median gestational age at diagnosis was 33 weeks 1 day (range, 27 weeks-34 weeks 1 day). The median gestational age at delivery was 34 weeks 1 day (range, 32 weeks 4 days-39 weeks 1 day). Four cases had premature rupture of membranes beyond 32 weeks. Four among the 7 had gastrointestinal manifestations. Three cases presented with hematochezia, which resolved with conservative treatment. One fetus had intractable diarrhea, had a diagnosis of rare microvillus inclusion disease, and died of sepsis after 92 days. Not a single case of Hirschsprung disease was observed in our group. Nonobstructive diffuse dilated bowel loops diagnosed in the second half of pregnancy are associated with premature rupture of membranes and premature labor. As neonatal gastrointestinal complications may be anticipated, prenatal parental counseling with a neonatologist and pediatric gastroenterologist should be conducted.

Clinical and Metabolic Effects of Biliopancreatic Diversion Persist After Reduction of the Gastric Pouch and Elongation of the Common Alimentary Tract. Preliminary Report in a Series of Patients with a 10-Year Follow-Up.

Biliopancreatic diversion (BPD) is a bariatric technique burdened, in some instances, by clinical evidence of malabsorption and malnutrition, and by intractable diarrhea. The objective of this study was to assess metabolic and nutritional effects on patients undergoing BPD and BPD plus revisional surgery because of side effects. Thirty-five consecutive BPD patients underwent revisional surgery (elongation of the common limb from 50 to 200cm and reduction of the gastric pouch from 500 to 40ml) after a median 48-month period [48.3±9.17months (mean±SD)] and were observed for a total period of 116.2±6.21months; 88 patients only undergoing BPD (controls) were observed for 120months. Revisional surgery significantly improved side effects of BPD, with resolution of clinical symptoms in most instances. After revisional surgery, patients had a further decrease of body weight. The effect on disappearance of diabetes mellitus (DM) was remarkable, with no difference between revisional surgery and BPD. Triglycerides and transaminases decreased in a similar way, while cholesterol levels differed significantly. Estimated glomerular filtration rate improved. Nutritional parameters were similarly affected. This study suggests that it is possible to maintain the clinical and metabolic effects of BPD after a revisional procedure that leads to lesser malabsorption and to a greater restriction of the stomach. In particular, the positive effects on DM still persist after revisional surgery. This approach should be kept in mind in the presence of significant side effects due, inter alia, to excessive malabsorption.

Safety of Bifidobacterium breve (BBG‐01) in preterm infants

Since 1982, viable cells of Bifidobacterium breve (BBG-01) have been used in pediatric patients for clinical conditions such as intractable infantile diarrhea, preterm status, and pediatric surgery. Although the efficacy of BBG-01 has been widely reported, adverse events related to the use of BBG-01 have been reported in very few cases. In order to trace adverse events seen by 109 doctors in 88 medical institutions where BBG-01 was used, a questionnaire survey of the number of occurrences and details of each case was conducted. Eighty-six clinicians (70 institutions) responded to the questionnaire (response rate, 78.9%). Number of respondents according to department of diagnosis (no. BBG-01-treated infants) was as follows: pediatrics, 29 respondents (10 938 patients); premature and newborn medicine, 26 (10 677 patients); obstetrics and gynecology, 1 (1212 patients) and pediatric surgery, 22 (169 patients). More than 90% of the total BBG-01-treated patients (23 092 patients) were in the departments of premature and newborn medicine and pediatrics, and BBG-01 had been used mainly in preterm infants and children with intractable diarrhea. Adverse events occurred in two extremely premature infants with functional ileus due to starch aggregates as vehicle, and in two surgical neonates with bacteremia caused by B. breve genetically identical to BBG-01, and no serious adverse events with poor outcome were reported. Adverse events related to the use of BBG-01 have an extremely low incidence and are mild in severity, thus ensuring the superior safety of this preparation.

A rare cause of intractable diarrhea

A rare cause of intractable diarrhea

Intractable Diarrhea: A Diagnostic Dilemma

As per the American Gastroenterological Association, chronic diarrhea is defined as a decrease in fecal consistency lasting greater than four weeks. Co-morbidities, socio-economic status, family history, diet and immune status must be taken into account when searching for a diagnosis. A 47-year old female with past medical history of DMI with nephropathy, right BKA and hypothyroidism was admitted to the Medical ICU for DKA and septic shock due to HCAP. After a prolonged course complicated by chronic respiratory failure, she was unable to be weaned off the ventilator and underwent tracheostomy and PEG tube placement. Throughout her hospitalization, she was found to have severe, intractable diarrhea, often stooling up to 12 times per day with significant volumes. Differential diagnoses included osmotic diarrhea due to tube feeds vs malabsorption due to bowel edema/ischemia vs secretory diarrhea of unknown etiology. GI was consulted, and work-up included multiple rounds of fecal fat testing, C difficile toxin, celiac antibodies, stool studies, culture and gram stain, all which resulted as normal. Octreotide scan showed no evidence of primary or secondary neuroendocrine tumour. CT Abdomen/Pelvis showed evidence of colitis and the patient underwent colonoscopy with biopsies consistent with ischemic colitis. The patient finished a course of antibiotics, however, continued to have intractable diarrhea for >4 months inpatient duration despite aggressive medical therapy. Concomitantly, she developed a skin rash, which when biopsied, was consistent with small vessel-vasculitis. It was then postulated that this could be the underlying etiology, and she was started on high dose steroids with resolution of rash, however, diarrhea persisted. Eventually when the patient was medically stable, she underwent repeat colonoscopy with colonic biopsies showing regenerative ischemic changes. To this day, there is still no clear consensus among specialists for the cause of the patient's prolonged symptomatology. Chronic diarrhea has a wide differential whose etiology depends largely on the unique characteristics of a patient. It is a difficult entity to diagnose as clinicians are often faced with multiple medical co-morbidities that can easily confound diagnosis. Unfortunately, an ideal strategy for work-up of chronic diarrhea has yet to be established and, ultimately, a cause may never be uncovered, as was the case with our patient.

“Mast”ering the Evaluation of Chronic Diarrhea

Case: A 39-year-old Chinese female with no PMHx presented to our office with complaints of worsening diarrhea over the last 6 months. She complained of 4 - 6 watery bowel movements daily. She denied blood in the stool, abdominal pain, or weight loss. She noted no change in appetite or diet and no new medications. She has a significant allergy history for almonds, eggs, and peanuts. Stool studies were negative and the physical exam was benign. A colonoscopy revealed normal mucosa. Multiple random biopsies from the colon and rectum revealed increased mast cells in the lamina propria (>50 /HPF) consistent with mastocytic enterocolitis. Discussion: Mastocytic enterocolitis describes patients with diarrhea who have what pathologists have interpreted as an increased number of mast cells in the colon and lower duodenum. Mast cells have a role in the allergic hypersensitivity type I reaction and are rich in gastrointestinal mucosa, enabling their immune function to environmental substances. As mastocytic enterocolitis can be a manifestation of systemic mastocytosis, an attempt to establish whether this is the case through bone marrow biopsy can be justified. It has been proposed that a screening for an 816V mutational analysis on the peripheral blood can also be considered. However, mastocytes can also be increased in other GI diseases including IBS where they have been found in the cecum, TI, and jejunum. Though there is no definitive treatment for the condition, various medications such as H1/H2 antihistamines, cromolyn sodium, antileukotriene agents, and budesonide have all been tried with varying success. The fortuitous diffuse mucosal distribution of mast cells throughout the lamina propria perfectly suits the type of tissue sample obtainable on random endoscopic biopsy specimens. Physicians managing patients with chronic intractable diarrhea should be encouraged to incorporate endoscopy, random colonic or duodenal mucosal sampling, and immunostaining as part of their investigational protocol. If increased mast cells are found, physicians should consider therapeutic options that alter mast cell mediator release and function. As mast cell populations can demonstrate fluctuations, investigations are best performed during active symptoms and before treatment. Further studies in this area should elucidate clinical subclasses of disorders with distinct immunologic or central nervous system triggers for mucosal mast cell proliferation and mediator release.

Cryptosporidium in humans and animals-a one health approach to prophylaxis.

Cryptosporidium is a major cause of moderate-to-severe diarrhoea in humans worldwide, second only to rotavirus. Due to the wide host range and environmental persistence of this parasite, cryptosporidiosis can be zoonotic and associated with foodborne and waterborne outbreaks. Currently, 31 species are recognized as valid, and of these, Cryptosporidium hominis and Cryptosporidium parvum are responsible for the majority of infections in humans. The immune status of the host, both innate and adaptive immunity, has a major impact on the severity of the disease and its prognosis. Immunocompetent individuals typically experience self-limiting diarrhoea and transient gastroenteritis lasting up to 2weeks and recover without treatment, suggesting an efficient host antiparasite immune response. Immunocompromised individuals can suffer from intractable diarrhoea, which can be fatal. Effective drug treatments and vaccines are not yet available. As a result of this, the close cooperation and interaction between veterinarians, health physicians, environmental managers and public health operators is essential to properly control this disease. This review focuses on a One Health approach to prophylaxis, including the importance of understanding transmission routes for zoonotic Cryptosporidium species, improved sanitation and better risk management, improved detection, diagnosis and treatment and the prospect of an effective anticryptosporidial vaccine.

Congenital Sodium Diarrhea: A Form of Intractable Diarrhea, With a Link to Inflammatory Bowel Disease.

Congenital diarrheal disorders (CDDs) represent a group of challenging clinical conditions for pediatricians because of the severity of the presentation and the broad range of possible differential diagnoses. CDDs arise from alterations in the transport of nutrients and electrolytes across the intestinal mucosa, from enterocyte and enteroendocrine cell differentiation and/or polarization defects, and from the modulation of the intestinal immune response. Advances were made recently in deciphering the etiology and pathophysiology of one of these disorders, congenital sodium diarrhea (CSD). CSD refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. A syndromic form of CSD features choanal and intestinal atresias as well as recurrent corneal erosions. Small bowel histology frequently detects an epithelial "tufting" dysplasia. It is autosomal recessively inherited, and caused by SPINT2 mutations. The nonsyndromic form of CSD can be caused by dominant activating mutations in GUCY2C, encoding intestinal receptor guanylate cyclase C (GC-C), and by autosomal recessive SLC9A3 loss-of-function mutations. SLC9A3 encodes Na/H antiporter 3, the major intestinal brush border Na/H exchanger, and a downstream target of GC-C. A number of patients with GUCY2C and SLC9A3 mutations developed inflammatory bowel disease. Both the number of recognized CDD forms as well as the number of underlying disease genes are gradually increasing. Knowledge of these CDD genes enables noninvasive, next-generation gene panel-based testing to facilitate an early diagnosis in CDD. Primary Na/H antiporter 3 and GC-C malfunction is implicated as a predisposition for inflammatory bowel disease in subset of patients.