Udayakumar Navaneethan

Hepatitis E and pregnancy: understanding the pathogenesis.

Hepatitis E virus (HEV) is a single‐stranded RNA virus that causes large‐scale epidemics of acute viral hepatitis, particularly in developing countries. In men and non‐pregnant women, the disease is usually self‐limited and has a case‐fatality rate of less than <0.1%. However, in pregnant women, particularly from certain geographical areas in India, HEV infection is more severe, often leading to fulminant hepatic failure and death in a significant proportion of patients. In contrast, reports from Egypt, Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in non‐pregnant women. The reasons for this geographical difference are not clear. The high mortality rate in pregnancy has been thought to be secondary to the associated hormonal (oestrogen and progesterone) changes during pregnancy and consequent immunological changes. These immunological changes include downregulation of the p65 component of nuclear factor (NF‐κB) with a predominant T‐helper type 2 (Th2) bias in the T‐cell response along with host susceptibility factors, mediated by human leucocyte antigen expression. Thus far, researchers were unable to explain the high HEV morbidity in pregnancy, why it is different from other hepatitis viruses such as hepatitis A with similar epidemiological features and the reason behind the difference in HEV morbidity in pregnant women in different geographical regions. The recent developments in understanding the immune response to HEV have encouraged us to review the possible mechanisms for these differences. Further research in the immunology of HEV and pregnancy is required to conquer this disease in the near future.

Hypertriglyceridemic Pancreatitis : Presentation and Management

Hypertriglyceridemia (HTG) is reported to cause 1–4% of acute pancreatitis (AP) episodes. HTG is also implicated in more than half of gestational pancreatitis cases. Disorders of lipoprotein metabolism are conventionally divided into primary (genetic) and secondary causes, including diabetes, hypothyroidism, and obesity. Serum triglyceride (TG) levels above 1,000 mg/dl are usually considered necessary to ascribe causation for AP. The mechanism for hypertriglyceridemic pancreatitis (HTGP) is postulated to involve hydrolysis of TG by pancreatic lipase and release of free fatty acids that induce free radical damage. Multiple small studies on HTGP management have evaluated the use of insulin, heparin, or both. Many series have also reported use of apheresis to reduce TG levels. Subsequent control of HTG with dietary restrictions, antihyperlipidemic agents, and even regular apheresis has been shown anecdotally in case series to prevent future episodes of AP. However, large multicenter studies are needed to optimize future management guidelines for patients with HTGP.

Hepatopancreatobiliary manifestations and complications associated with inflammatory bowel disease.

Abstract: Diseases involving the hepatopancreatobiliary (HPB) system are frequently encountered in patients with inflammatory bowel disease (IBD). Hepatobiliary manifestations constitute some of the most common extraintestinal manifestations of IBD. They appear to occur with similar frequency in patients with Crohns disease or ulcerative colitis. HPB manifestations may occur in following settings: 1) disease possibly associated with a shared pathogenetic mechanism with IBD including primary sclerosing cholangitis (PSC), small‐duct PSC/pericholangitis and PSC/autoimmune hepatitis overlap, acute and chronic pancreatitis related to IBD; 2) diseases which parallel structural and physiological changes seen with IBD, including cholelithiasis, portal vein thrombosis, and hepatic abscess; and 3) diseases related to adverse effects associated with treatment of IBD, including drug‐induced hepatitis, pancreatitis (purine‐based agents), or liver cirrhosis (methotrexate), and reactivation of hepatitis B, and biologic agent‐associated hepatosplenic lymphoma. Less common HPB manifestations that have been described in association with IBD include autoimmune pancreatitis (AIP), IgG4‐associated cholangitis (IAC), primary biliary cirrhosis (PBC), fatty liver, granulomatous hepatitis, and amyloidosis. PSC is the most significant hepatobiliary manifestation associated with IBD and poses substantial challenges in management requiring a multidisciplinary approach. The natural disease course of PSC may progress to cirrhosis and ultimately require liver transplantation in spite of total proctocolectomy with ileal‐pouch anal anastomosis. The association between AIP, IAC, and elevated serum IgG4 in patients with PSC is intriguing. The recently reported association between IAC and IBD may open the door to investigate these complex disorders. Further studies are warranted to help understand the pathogenesis of HPB manifestations associated with IBD, which would help clinicians better manage these patients. An interdisciplinary approach, involving gastroenterologists, hepatologists, and, in advanced cases, general, colorectal, and transplant surgeons is advocated. (Inflamm Bowel Dis 2010)

Diagnostic yield of bile duct brushings for cholangiocarcinoma in primary sclerosing cholangitis: A systematic review and meta-analysis

BACKGROUND The most ominous adverse event of primary sclerosing cholangitis (PSC) is development of cholangiocarcinoma (CCA). There is a wide variation in the reported diagnostic yield of bile duct brush cytology in PSC strictures. OBJECTIVE To determine the diagnostic utility of biliary brush cytology for CCA detection in patients with PSC. DESIGN Meta-analysis. Systematic search of PubMed, EMBASE, Web of Science, and the Cochrane Library for relevant studies published up to December 2012. SETTING Meta-analysis of diagnostic parameters. PATIENTS A total of 747 patients in studies (both retrospective and prospective) in which histopathologic correlation of CCA was available. INTERVENTION Meta-analysis. Construction of 2 × 2 contingency data. MAIN OUTCOME MEASUREMENTS Sensitivity, specificity, likelihood ratio, and pooled diagnostic odds ratio. RESULTS The search yielded 54 studies of which 11, involving 747 patients, were included in our meta-analysis. The pooled sensitivity and specificity of bile duct brushings for a diagnosis of CCA in patients with PSC were 43% (95% confidence interval [CI], 35%-52%) and 97% (95% CI, 95%-98%), respectively. The pooled diagnostic odds ratio to detect CCA was 20.23 (95% CI, 8.75-46.79). The heterogeneity indices of χ(2) statistics, I(2) measure of inconsistency, and the Cochran Q test were 0.156, 14.4, and 30.5%, respectively. Visual inspection of the funnel plot showed low potential for publication bias. LIMITATIONS Inclusion of low-quality studies, study heterogeneity. CONCLUSION Our study suggests that bile duct brushing is a simple and highly specific technique for detection of CCA in patients with PSC. However, the modest sensitivity from bile duct brushing precludes its utility as a diagnostic tool for early detection of CCA in patients with PSC.

Minimally invasive techniques in pancreatic necrosis.

Traditional open surgical necrosectomy for treatment of infected pancreatic necrosis is associated with high morbidity and mortality, leading to a shift toward minimally invasive endoscopic, radiologic, and laparoscopic approaches. Percutaneous drainage is useful as a temporizing method to control sepsis and as an adjunctive treatment to surgical intervention. It is limited because of the requirement for frequent catheter care and the need for repeated procedures. Endoscopic transgastric or transduodenal therapies with endoscopic debridement/necrosectomy have recently been described and are highly successful in carefully selected patients. It avoids the need for open necrosectomy and can be used in poor operative candidates. Laparoscopic necrosectomy is also promising for treatment of pancreatic necrosis. However, the need for inducing a pneumoperitoneum and the potential risk of infection limit its usefulness in patients with critical illness. Retroperitoneal access with a nephroscope is used to directly approach the necrosis with complete removal of a sequestrum. Retroperitoneal drainage using the delay-until-liquefaction strategy also appears to be successful to treat pancreatic necrosis. The anatomic location of the necrosis, clinical comorbidities, and operator experience determine the best approach for a particular patient. Tertiary care centers with sufficient expertise are increasingly using minimally invasive procedures to manage pancreatic necrosis.Abbreviations: CT - computed tomography, EUS - endoscopic ultrasound, PANTER - pancreatitis necrosectomy versus step-up approach, PCD - percutaneous drainage, PEG - percutaneous endoscopic gastrostomy, RCT - randomized controlled trials, SAP - severe acute pancreatitis, WOPN - walled-off pancreatic necrosis

Lumen-apposing metal stents (LAMS) for pancreatic fluid collection (PFC) drainage: may not be business as usual

Lumen-apposing metal stents (LAMS) have been recently developed to improve treatment outcomes in the endoscopic management of pancreatic fluid collections (PFC), particularly in walled-off necrosis (WON), to facilitate better drainage of necrotic contents and minimise the risk of perforation and peritoneal leakage. In an ongoing randomised trial, we observed serious adverse events that included delayed bleeding, buried stent syndrome and biliary stricture that necessitated a change in the management protocol for patients with PFC treated with LAMS. Randomised trials comparing endoscopic and surgical techniques for the management of PFCs have favoured the endoscopic approach.1 ,2 Endoscopy is less expensive, associated with shorter hospital stay and the clinical outcomes are comparable. To compare the clinical outcomes of patients undergoing endoscopic drainage of WON using LAMS or plastic stents, a randomised trial (NCT02685865) was initiated at our institution. Included in the study were patients with symptomatic WON measuring >6 cm in size and located adjacent to the gastric or duodenal lumen. Excluded were patients with pseudocysts, WON inaccessible for endoscopic ultrasound-guided drainage and irreversible coagulopathy. The LAMS (Hot AXIOS, Boston Scientific) used in this trial had a single-step cautery-tipped delivery system with dimensions of 15 mm (diameter) by 10 mm (length). In the plastic stent cohort, two 7 Fr by 4 cm double pigtail stents were deployed after dilation of the transmural tract to 12 mm. Per study protocol, a follow-up CT was obtained at 4–6 weeks after the index intervention to assess treatment response with treatment success defined as resolution of WON to <3 cm in conjunction with symptom relief. The main outcome measure was to compare the median number of interventions required to achieve treatment success. The secondary outcome measures were to compare the rates of treatment success and clinical and stent-related adverse events. The total sample size was estimated at 62 patients. In this ongoing …

Progressive Primary Sclerosing Cholangitis Requiring Liver Transplantation Is Associated With Reduced Need for Colectomy in Patients With Ulcerative Colitis

BACKGROUND & AIMS We investigated the association between the severity of primary sclerosing cholangitis (PSC) and clinical outcomes of patients with ulcerative colitis (UC) on the basis of need for colectomy. METHODS We analyzed data from 167 patients with PSC and UC who were followed from 1985 to 2011. Patients with PSC and UC were divided into groups that received orthotopic liver transplantation (OLT) (n = 86) or did not (non-OLT, n = 81). Clinical and demographic variables were obtained, and patients were followed until they received OLT or the date of their last clinical visit. RESULTS The OLT group had significantly more subjects with less severe symptoms of UC (59, 68.6%) than the non-OLT group (12, 14.8%; P < .001). The subjects in the OLT group had a median of 0 UC flares compared with 3 in the non-OLT group (P < .001); fewer subjects in the OLT group required use of azathioprine or mercaptopurine (1, 1.2%), compared with the non-OLT group (14, 17.3%; P = .006). More subjects in the non-OLT group required colectomies (61, 75.3%) than in the OLT group (23, 26.7%; P < .001). On the basis of Cox regression analysis, OLT for PSC independently reduces the need for colectomy (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.25-0.75; P = .003), as does a high Mayo risk score at diagnosis (HR, 0.52; 95% CI, 0.37-0.72; P < .001). Development of colon neoplasia increased the risk for colectomy (HR, 2.47; 95% CI, 1.63-3.75; P < .001). CONCLUSIONS Severe progressive PSC that requires liver transplantation appears to reduce the disease activity of UC and the need for colectomy.

Clostridium difficile infection is associated with worse long term outcome in patients with ulcerative colitis

BACKGROUND Clostridium difficile infection (CDI) is becoming prevalent in general population as well as in patients with inflammatory bowel disease (IBD). AIM The aim of the study was to investigate the long-term impact of CDI in patients with ulcerative colitis (UC). METHODS UC inpatients or outpatients who had positive results for stool C. difficile toxins A and B between 2002 and 2007 were identified (N=45). The 45 patients were matched for age and gender to UC patients who were negative for C. difficile and had never been diagnosed with CDI (N=101). The primary Colectomy within 12 months of C. difficile testing was the primary outcome patients with CDI and no-CDI. RESULTS Forty-five patients were CDI positive and 101 were negative. Patients who were CDI positive had significantly more UC-related emergency room visits in the year following initial infection (37.8% vs. 4%, p<0.001) than those without CDI. One year following the index infection admission, CDI patients also had a significantly higher rate of colectomy than controls (35.6% vs. 9.9%, p<0.001). Among patients with CDI, 55.8% of patients had an escalation in medical treatment in the year after CDI as compared to the prior year of 12.9%, p<0.0001. CDI (odds ratio (OR) 10.0, 95% confidence interval CI: 2.7, 36.3, p<0.001) and severe disease on endoscopy (OR 16.7, 95% (CI): 4.1, 67.9, p<0.001) were found to be independently associated with colectomy within 1 year on logistic regression analyses. CONCLUSIONS CDI appears to be associated with escalation of medical therapy in the year following infection. CDI and severe disease on endoscopy appear to be associated with an increased risk for subsequent colectomy on long-term follow up.

Prevalence and risk factors for colonic perforation during colonoscopy in hospitalized inflammatory bowel disease patients

BACKGROUND Colonic perforation is a rare complication associated with colonoscopy. There are no population-based studies on the risk of colonic perforation in IBD inpatients. AIM We sought to determine the prevalence of colonic perforation during colonoscopy among IBD inpatients, and to assess its risk factors. MATERIALS AND METHODS We obtained patient data from the Nationwide Inpatient Sample and used the International Classification of Diseases, the 9th revision, clinical modification codes, to identify IBD patients who had undergone colonoscopy in 2006. The control group consisted of inpatients who had colonoscopy without IBD. RESULTS Colonic perforation occurred in 344/33,732 (1%) IBD hospitalizations and in 3658/578,458 (0.6%) controls without IBD (P=0.0001). The risk of colonic perforation in the IBD group was significantly higher than the control group even after adjusting for age, gender, comorbidities and endoscopic interventions including endoscopic dilations and colonoscopic polypectomy, with adjusted odds ratio (aOR) of 1.83 (95% confidence interval [CI]: 1.40, 2.38). In addition, older age (aOR=1.01, 95% CI: 1.006-1.015), female gender (aOR=1.20; 95% CI: 1.04, 1.38), and therapeutic endoscopic dilation (aOR=6.63; 95% CI: 3.95, 11.11) were independent risk factors for perforation. Colonoscopic biopsy, polypectomy and the presence of comorbidities did not increase the risk of perforation. CONCLUSIONS There appears to be a higher risk of colonoscopy-associated perforation in IBD inpatients than non-IBD controls. In addition, older age, female patients and endoscopic dilations appeared to be associated with an increased risk for perforation.

Impact of Clostridium difficile infection in patients with ulcerative colitis

BACKGROUND Clostridium difficile infection (CDI) is becoming prevalent in general population as well as in patients with inflammatory bowel disease (IBD). AIM The aim of the study was to identify risk factors for CDI in patients with ulcerative colitis (UC) and to assess outcome of UC in patients following CDI. METHODS UC inpatients or outpatients who had positive results for C. difficile toxins A and B between 2000 and 2006 were identified (N=39) and matched for age and gender to UC patients who were negative C. difficile toxins and had never been diagnosed with CDI (N=39). Records were reviewed for adverse clinical outcome, defined as colectomy within 3 months of C. difficile testing. Conditional logistic regression was used to analyze multivariable association to identify risk factors for CDI and for adverse clinical outcome. RESULTS A total of 78 subjects were analyzed, 60% were males. Median age was 39. Among 39 patients with CDI, 20 (47.2%) were diagnosed as outpatients, 50% failed treatment with the first antibiotic monotherapy, and 21.2% had recurrent infection. Antibiotic exposure within 30 days prior to C. difficile testing was found to be associated with an increased risk for CDI with an odds ratio of 12.0 (95% CI 1.2, 124.2) Subsequent colectomy within 3 months after CDI diagnosis, was not associated with CDI in both univariable and multivariable analyses. After adjusting for CDI, lack of 5-aminosalicylic acid (ASA) in the treatment regimen was significantly associated with colectomy with an odds ratio of 3.3 (95% CI: 1.2, 9.4). There was no UC- or CDI-associated mortality in this case series. CONCLUSIONS Recent antibiotic exposure was a risk factor for CDI in UC patients. Interestingly, CDI does not seem to adversely affect short-term adverse clinical outcome (colectomy).