Predicting Efficacy of Plastic Stents for Posttransplantation Biliary Strictures.

BACKGROUND: Biliary strictures (BS) are a common complication of liver transplantation. The standard treatment is sequential insertion of increasing numbers of plastic stents by endoscopic retrograde cholangiopancreatography (ERCP). Despite high success rates, some strictures fail to resolve and require surgery as definitive treatment. GOALS: To identify predictors of response or failure of standard endoscopic treatment, allowing earlier referral to alternative modalities when needed and avoiding unnecessary procedures. STUDY: Database of Gastroenterology Department at Tel Aviv Medical Center was retrospectively reviewed, and data regarding patients who underwent liver transplantation and developed BS were analyzed. RESULTS: Thirty-one patients met the study criteria. Twenty-four (77.4%) resolved with plastic stenting and 7 ultimately required surgery. There were no significant differences between stent responders and nonresponders regarding demographics, transplant and postoperative hospitalization data, time from transplantation to presentation with stricture, total number of ERCP sessions, or maximal number of stents.A trend toward difference was noted in the time elapsed between the first and the second ERCP, whereby ERCP nonresponders required a second procedure sooner than responders. Patients presenting to their second procedure as scheduled ultimately had a 95% endoscopic success rate, whereas those presenting urgently with acute cholangitis had a 55% failure rate (P=0.02). CONCLUSIONS: Urgent repeat ERCP is a harbinger of ultimate failure of plastic stent treatment for BS after liver transplant. This finding may assist earlier triage of these patients toward alternative treatment such as metal stents or surgery, thus sparing needless procedures and complications.

The Mediterranean dietary pattern as the diet of choice for non-alcoholic fatty liver disease: Evidence and plausible mechanisms.

Non-alcoholic fatty liver disease (NAFLD) has become a major global health burden, leading to increased risk for cirrhosis, hepatocellular carcinoma, type-2 diabetes and cardiovascular disease. Lifestyle intervention aiming at weight reduction is the most established treatment. However, changing the dietary composition even without weight loss can also reduce steatosis and improve metabolic alterations as insulin resistance and lipid profile. The Mediterranean diet (MD) pattern has been proposed as appropriate for this goal, and was recommended as the diet of choice for the treatment of NAFLD by the EASL-EASD-EASO Clinical Practice Guidelines. The MD has an established superiority in long term weight reduction over low fat diet, but it improves metabolic status and steatosis even without it. However, the effect on liver inflammation and fibrosis was tested only in few observational studies with positive results. Furthermore, considering the strong association between NAFLD and diabetes and CVD, the MD has a highly established advantage in prevention of these diseases, demonstrated in randomized clinical trials. The individual components of the MD such as olive oil, fish, nuts, whole grains, fruits, and vegetables, have been shown to beneficially effect or negatively correlate with NAFLD, while consumption of components that characterize a Western dietary pattern as soft drinks, fructose, meat and saturated fatty acids have been shown to have detrimental association with NAFLD. In this review we will cover the epidemiological evidence and the plausible molecular mechanisms by which the MD as a whole and each of its components can be of benefit in NAFLD.

Management of endoscopic retrograde cholangiopancreatography-related perforations: Experience of a tertiary center.

BACKGROUND: Endoscopic retrograde cholangiopancreatography-induced perforation (EP) is a rare but severe complication. We describe the risk factors, management, and outcome of ERCP-induced perforations in a tertiary center. METHODS: This is a case-control study. All EP cases between March 2004 and February 2015 were compared to a control group without perforation. Data on patients, procedures, presentation, perforation type, radiologic findings, management, and outcome were assessed. RESULTS: Of 6,934 endoscopic retrograde cholangiopancreatographies, 37 patients (0.53%) had EP. Independent risk factors included failure of cannulation, a procedure described as "difficult," performing a precut and resection of a periampullary adenoma. Perforation was diagnosed during the procedure in 7 patients (19%). Median interval for diagnosis was 11 hours (range: 0-201 hours), with 84% diagnosed within 30 hours. The periampullary region was the most common EP site (51%). Twenty-nine patients (78%) were managed conservatively and 8 (22%) were operated. Three patients failed conservative management and required delayed operation. Failure of conservative management had a detrimental effect on morbidity and duration of stay. All patients who required operative intervention had perforation of either the duodenal free wall or the periampullary region. CONCLUSION: Clear risk factors can be used to raise suspicion of EP. Early diagnosis and management are critical for better outcome. This is especially important when operative intervention is indicated. Nonetheless, the majority of patients may be managed conservatively.

Non-alcoholic fatty liver disease is not associated with a lower health perception.

AIM: To examine the association between non-alcoholic fatty liver disease (NAFLD) and general health perception. METHODS: This cross sectional and prospective follow-up study was performed on a cohort of a sub-sample of the first Israeli national health and nutrition examination survey, with no secondary liver disease or history of alcohol abuse. On the first survey, in 2003-2004, 349 participants were included. In 2009-2010 participants from the baseline survey were invited to participate in a follow-up survey. On both baseline and follow-up surveys the data collected included: self-reported general health perception, physical activity habits, frequency of physician's visits, fatigue impact scale and abdominal ultrasound. Fatty liver was diagnosed by abdominal ultrasonography using standardized criteria and the ratio between the median brightness level of the liver and the right kidney was calculated to determine the Hepato-Renal Index. RESULTS: Out of 349 eligible participants in the first survey, 213 volunteers participated in the follow-up cohort and were included in the current analysis, NAFLD was diagnosed in 70/213 (32.9%). The prevalence of "very good" self-reported health perception was lower among participants diagnosed with NAFLD compared to those without NAFLD. However, adjustment for BMI attenuated the association (OR = 0.73, 95%CI: 0.36-1.50, P = 0.392). Similar results were observed for the hepato-renal index; it was inversely associated with "very good" health perception but adjustment for BMI attenuated the association. In a full model of multivariate analysis, that included all potential predictors for health perception, NAFLD was not associated with the self-reported general health perception (OR = 0.86, 95%CI: 0.40-1.86, P = 0.704). The odds for "very good" self-reported general health perception (compared to "else") increased among men (OR = 2.42, 95%CI: 1.26-4.66, P = 0.008) and those with higher performance of leisure time physical activity (OR = 1.01, 95%CI: 1.00-1.01, P < 0.001, per every minute/week) and decreased with increasing level of BMI (OR = 0.91, 95%CI: 0.84-0.99, P = 0.028, per every kg/m(2)) and older age (OR = 0.96, 95%CI: 0.93-0.99, P = 0.033, per one year). Current smoking was not associated with health perception (OR = 1.31, 95%CI: 0.54-3.16, P = 0.552). Newly diagnosed (naive) and previously diagnosed (at the first survey, not naive) NAFLD patients did not differ in their self-health perception. The presence of NAFLD at the first survey as compared to normal liver did not predict health perception deterioration at the 7 years follow-up. In terms of health-services utilization, subjects diagnosed with NAFLD had a similar number of physician's visits (general physicians and specialty consultants) as in the normal liver group. Parameters in the fatigue impact scale were equivalent between the NAFLD and the normal liver groups. CONCLUSION: Fatty liver without clinically significant liver disease does not have independent impact on self-health perception.

Optimising the Inflammatory Bowel Disease Unit to Improve Quality of Care: Expert Recommendations.

INTRODUCTION: The best care setting for patients with inflammatory bowel disease [IBD] may be in a dedicated unit. Whereas not all gastroenterology units have the same resources to develop dedicated IBD facilities and services, there are steps that can be taken by any unit to optimise patients' access to interdisciplinary expert care. A series of pragmatic recommendations relating to IBD unit optimisation have been developed through discussion among a large panel of international experts. METHODS: Suggested recommendations were extracted through systematic search of published evidence and structured requests for expert opinion. Physicians [n = 238] identified as IBD specialists by publications or clinical focus on IBD were invited for discussion and recommendation modification [Barcelona, Spain; 2014]. Final recommendations were voted on by the group. Participants also completed an online survey to evaluate their own experience related to IBD units. RESULTS: A total of 60% of attendees completed the survey, with 15% self-classifying their centre as a dedicated IBD unit. Only half of respondents indicated that they had a defined IBD treatment algorithm in place. Key recommendations included the need to develop a multidisciplinary team covering specifically-defined specialist expertise in IBD, to instil processes that facilitate cross-functional communication and to invest in shared care models of IBD management. CONCLUSIONS: Optimising the setup of IBD units will require progressive leadership and willingness to challenge the status quo in order to provide better quality of care for our patients. IBD units are an important step towards harmonising care for IBD across Europe and for establishing standards for disease management programmes.

Treatment of hepatocellular carcinoma: Steps forward but still a long way to go.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third cause of tumor associated deaths worldwide. HCC incidence rates are increasing in many parts of the world including developing and developed countries. Potentially curative treatments for HCC are resection and liver transplantation, but these are only suitable for patients with small tumors, meeting strict pre-defined criteria, or well-compensated liver disease. Early diagnosis of HCC can be achieved by surveillance of at-risk populations. For patients with non-resectable disease treatments modalities include loco-ablative and systemic therapies. In this review we focus on treatment options in HCC and their allocation. Although significant research is in progress, to this date, the results are unsatisfactory with limited long-term survival. In the fight against this deadly disease, there is still a long way to go.

Prognosis of primary sclerosing cholangitis in israel is independent of coexisting inflammatory bowel Disease.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a rare chronic progressive cholestatic disorder. We assessed its characteristics and natural history in Israel and compared its outcome with respect to coexisting inflammatory bowel disease (IBD). METHODS: Data on characteristics, course and outcome were retrospectively retrieved on patients diagnosed with PSC from five large Israeli medical centers between 1988 and 2012. Patients with isolated PSC were compared with those with coexisting IBD to identify predictors of outcome. RESULTS: Of 141 patients (56% males) with confirmed PSC, 98 (69.5%) had coexisting IBD. The average age at presentation was 38.8 ± 15.4 years and duration of follow-up was 7.93 ± 6.26 years. The crude estimated point prevalence was 4 cases per 105 persons. Demographics and clinical characteristics were similar among all patients except for symptoms at diagnosis (which were more prevalent among PSC­IBD patients) and utilization of multiple diagnostic modalities (which was more prevalent among isolated-PSC patients). More than one-third of the entire cohort had cirrhosis. A total of 15 patients (10.6%) died and 19 patients (13.5%) developed malignancy during follow-up. Nine patients (6.3%) underwent liver transplantation. Mean survival for the entire cohort was 26.3 ± 1.4 years and mean transplant-free survival was 23.5 ± 1.6 years. Cox proportional hazard regression for transplantation or death revealed two independent risk factors: cirrhosis and malignancy [hazard ratio 4.25 (p = 0.004) and 2.58 (p = 0.046), respectively]. CONCLUSIONS: Survival rate of PSC patients in Israel is longer than reported rates worldwide and is independent of coexisting IBD.

The incidence and predictors of lupus-like reaction in patients with IBD treated with anti-TNF therapies.

BACKGROUND: The incidence of lupus-like reactions (LLRs) in patients with inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (ATNF) has not been well defined. We aimed to characterize the features and predictors associated with LLR. METHODS: We studied a cohort of adult patients with IBD treated with ATNF by a single specialist during 2009. Patients with LLR were characterized and compared with those without LLR for possible predictors. RESULTS: Twenty of 289 patients (6.9%) had LLR (19.9 cases per 1000 patient-years). Female gender and IBD-unclassified were more prevalent in the LLR group (85% versus 54%, P = 0.009; and 15% versus 2.2%, P = 0.018, respectively), with a hazard ratio of 3.89 (95% confidence interval = 1.12-13.55; P = 0.033) and 7.38 (95% confidence interval = 1.93-28.23; P = 0.003), respectively. ATNF duration was shorter in the LLR group (median, 1 year [interquartile range, 0-3] versus 3 years [interquartile range, 1-6.5], P = 0.005). Arthropathy was universal, followed by fatigue and dermatitis (30% each). Antinuclear antibodies were universally positive, and 16 of 20 had anti-double-stranded DNA. ATNF was discontinued in all; 8 patients required corticosteroids and 1 required hydroxychloroquine followed by complete clinical resolution (mean 7.9 ± 5.9 months). Antinuclear antibodies reverted or normalized in 7 of 16 patients (44%). Fourteen patients (70%) were switched to a second ATNF, 2 with concomitant immunomodulators, and 12 as monotherapy. One patient on ATNF monotherapy developed a second LLR and was successfully switched to a third ATNF. CONCLUSION: LLRs secondary to ATNFs are more frequent than previously reported, more common in women and IBD-unclassified. It is reversible with cessation of the culprit agent and steroids. Switching to an alternative ATNF rarely results in recurrence.

False negative fecal occult blood test may be associated with increased mortality from colorectal cancer.

BACKGROUND: Fecal Occult Blood Test (FOBT) is an accepted screening test for colorectal cancer (CRC). It has been shown to decrease mortality by up to 30%. The outcome of screening failures has not been adequately studied. AIMS: The purpose of this study was to assess the outcome of patients who were diagnosed with CRC after a false negative FOBT. METHODS: We identified all consecutive CRCs from pathology reports between 2005 and 2010. Patients were divided according to their FOBT result. Those who became positive were compared to patients who remained negative. RESULTS: Altogether 401 CRCs were identified. Of those, 202 never performed a FOBT. At least one negative FOBT was performed by 133 individuals (67%). Of these, 76 remained negative (false negatives, FN) and 57 became positive (positive conversion, PC, controls). The prevalence of metastatic disease was threefold higher among the FNs as compared to the PC group (16 [22.2%] vs. 4 [7.5%], P=0.022). All-cause mortality was also significantly higher among FNs versus PCs (24 [31.6%] vs. 5 [8.8%], P=0.001); in Cox regression analysis of survival (covariates: FNs vs. PC, gender, age, medications and co-morbidities) FNs had increased mortality compared to the PC (HR 2.929, P=0.033, CI 95% 1.092-7.858). No statistically significant difference was found regarding all primary end points when comparing the FN and the "No test" group. CONCLUSION: These data disclose a particular risk of FOBT as a screening test. A subgroup of patients with "false" negative tests may have increased morbidity and mortality. Efforts should be made to recognize and characterize this high-risk group.

Effects of CYP4F2 polymorphism on response to warfarin during induction phase: a prospective, open-label, observational cohort study.

BACKGROUND: The cytochrome P450 (CYP) 4F2 isozyme has been reported to metabolize vitamin K(1) in vitro, and the V433M polymorphism in the CYP4F2 gene has been associated with reduced vitamin K(1) metabolism and the need for a higher maintenance dosage in patients receiving warfarin. OBJECTIVE: The purpose of the present study was to evaluate the effects of V433M polymorphism on warfarin response during the induction phase. METHODS: Warfarin-naive white patients in whom warfarin was scheduled to be initiated with a target INR of 2 to 3 were enrolled into the study. On enrollment, a single blood sample for the genotyping of CYP4F2, CYP2C9, and VKORC1 was drawn. The international normalized ratio (INR) was followed daily during induction and twice weekly until stable anticoagulation was reached. The relationships between several markers of warfarin response during induction and CYP4F2 polymorphism were determined. RESULTS: The cohort consisted of 241 patients (115 men; mean [SD] age, 55.2 [19.4] years; weight, 79.5 [18.3] kg). Most of the patients were carriers of the CYP4F2 CC genotype (112 patients) or the CT genotype (104 patients). In carriers of the TT genotype (25 patients), INR >3 was >4-fold lower compared with that in carriers of the CC or CT genotype, suggesting that patients with the TT genotype were less sensitive to warfarin during induction. Also in TT carriers, the extent of excessive anticoagulation was >10-fold lower than in the other carriers. Both of these findings had a nominal P value of <0.05. After adjustment for false discovery rate, none of the findings remained significant at a threshold q value of <0.05. Among CC carriers, the concurrent use of a statin was associated with a 1-mg/d reduction in warfarin maintenance dosage. No similar effect was noted in the CT or TT carriers, suggesting a possible genetic influence on warfarin-statin interaction. CONCLUSIONS: These preliminary findings suggest that among white patients treated with warfarin, CYP4F2 polymorphism had a measurable effect on warfarin responsiveness during induction; however, the observed differences failed to reach the level of statistical significance. The possibility that the effect of statins on warfarin anticoagulation varies among carriers of different CYP4F2 genotypes could not be excluded and should be evaluated further in a larger patient sample.

Factor VII R353Q genetic polymorphism is associated with altered warfarin sensitivity among CYP2C9 *1/*1 carriers.

OBJECTIVE: Warfarin responsiveness is characterized by marked interindividual variability. A major portion of this variability is attributed to CYP2C9 and VKORC1 polymorphisms, but almost 50% is still unaccounted for. This paper reports the first prospective study on the association between factor VII R353Q polymorphism and warfarin responsiveness during induction. METHODS: Genotyping for factor VII R353Q and 323D/I polymorphisms was performed in a cohort consisting of 374 patients (198 CYP2C9*1/*1) treated with warfarin who were prospectively followed from warfarin initiation. RESULTS: Compared with *1/*1-R/R and *1/*1-R/Q genotype carriers, *1/*1-Q/Q homozygotes achieved higher International Normalized Ratio (INR) values while consuming lower warfarin doses. The greater sensitivity was illustrated by 82.1% higher Warfarin Sensitivity Index During Induction (WSIDI) (0.14 ± 0.11 vs. 0.08 ± 0.50 mg⁻¹ Mann-Whitney, P = 0.043). Multiple regression analysis consisting of both genetic and nongenetic factors explained 26% of WSIDI variability, with R353Q genetic polymorphism having a modest yet significant effect and accounting for 1.7% of the overall variability. Moreover, the incidence of overanticoagulation (i.e., INR > 4) was 6.94-fold higher among *1/*1-Q/Q vs. *1/*1-R/R&R/Q carriers during warfarin induction (Pearson chi-square, P = 0.005). These findings were not accounted for by a chance difference in the distribution of VKORC1 genotypes. Analysis of these parameters among the entire cohort, including CYP2C9*2 and CYP2C9*3 variant allele carriers, did not reach statistical significance. Warfarin responsiveness during induction was unrelated to factor VII 323D/I genetic polymorphism. CONCLUSIONS: The response to warfarin during induction is influenced by factor VII R353Q polymorphism. The prospective use of this polymorphism, along with CYP2C9 and VKORC1, may enhance the accuracy of warfarin loading. However, the impact of R353Q polymorphism on overall warfarin response is subtle, and it is therefore unlikely that its use would be of clinical importance.