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Hepatorenal syndrome (HRS) is a functional renal failure that develops in patients with advanced hepatic cirrhosis with ascites and in those with fulminant hepatic failure. The prevalence of HRS varies among studies but in general it is the third most common cause of acute kidney injury (AKI) in cirrhotic patients after pre-renal azotemia and acute tubular necrosis. HRS carries a grim prognosis with a mortality rate approaching 90% three months after disease diagnosis. Fortunately, different strategies have been proven to be successful in preventing HRS. Although treatment options are available, they are not universally effective in restoring renal function but they might prolong survival long enough for liver transplantation, which is the ultimate treatment. Much has been learned in the last two decades regarding the pathophysiology and management of this disease which lead to notable evolution in the HRS definition and better understanding on how best to manage HRS patients. In the current review, we will summarize the recent advancement in epidemiology, pathophysiology, and management of HRS.

Background Cardiovascular and liver disease are main causes of death in people with human immunodeficiency virus (HIV) (PWH). In HIV-uninfected patients, nonalcoholic fatty liver disease (NAFLD) is associated with incident metabolic complications. We investigated the effect of NAFLD on development of metabolic comorbid conditions in PWH. Methods We included PWH undergoing a screening program for NAFLD using transient elastography. NAFLD was defined as a controlled attenuation parameter ≥248 dB/m with exclusion of other liver diseases. Incident diabetes, hypertension, dyslipidemia, and chronic kidney disease were investigated using survival analysis and Cox proportional hazards. Results The study included 485 HIV-monoinfected patients. During a median follow-up of 40.1 months (interquartile range, 26.5–50.7 months), patients with NAFLD had higher incidences of diabetes (4.74 [95% confidence interval, 3.09–7.27] vs 0.87 [.42–1.83] per 100 person-years) and dyslipidemia (8.16 [5.42–12.27] vs 3.99 [2.67–5.95] per 100 person-years) than those without NAFLD. With multivariable analysis, NAFLD was an independent predictor of diabetes (adjusted hazard ratio, 5.13; 95% confidence interval, 2.14–12.31) and dyslipidemia (2.35; 1.34–4.14) development. Conclusions HIV-monoinfected patients with NAFLD are at higher risk of incident diabetes and dyslipidemia. Early referral strategies and timely management of metabolic risk may improve outcomes.

HIV-infected patients are at increased risk of nonalcoholic steatohepatitis (NASH). Vitamin E is recommended for treatment of NASH in the general population. However, its safety and efficacy among HIV-infected patients remain unknown.Single-centre, phase IV, open-label, single arm clinical trial.HIV mono-infected patients without significant alcohol intake or viral hepatitis coinfection were included. The diagnosis of NASH was based on the co-existence of fatty liver, diagnosed by controlled attenuation parameter (CAP) at least 248 dB/m and significant hepatocyte apoptosis, defined by the serum biomarker cytokeratin 18 (CK-18) greater than 130.5 U/L. Participants were treated with 800 IU daily of oral vitamin E (alpha-tocopherol) for 24 weeks, and followed for an additional 24 weeks postdiscontinuation. Generalized linear mixed effects models were used to evaluate changes in alanine aminotransferase (ALT), CAP and CK-18 at the completion of treatment and end of follow-up, controlling for pretreatment trends.A total of 27 patients were included. Four (15%) had a pretreatment liver biopsy, which confirmed the diagnosis of NASH in all cases. Compared with baseline, 24 weeks of vitamin E treatment improved ALT [-27 units/l; 95% confidence interval (CI) -37 to -17], CAP scores (-22 dB/m; 95% CI -42 to -1) and CK-18 (-123 units/l; 95% CI -201 to -46). Conversely, there was no change in BMI. No serious adverse event was reported and no patient was lost to follow-up.In this first clinical trial, we showed that vitamin E is an effective and well tolerated treatment for NASH in HIV-infected patients.

Background Human immunodeficiency virus (HIV)–infected patients are at increased risk of liver-related mortality. The effect of occult cirrhosis (OcC), defined as preclinical compensated cirrhosis without any clinical findings, on liver-related events is unknown. Methods HIV-infected patients from 2 Canadian cohorts underwent transient elastography (TE) examination and were classified as (1) OcC (TE ≥13 kPa with no sign of cirrhosis, including absence of thrombocytopenia and signs of advanced liver disease on ultrasound or gastroscopy); (2) overt cirrhosis (OvC) (TE ≥13 kPa with signs of cirrhosis); or (3) noncirrhotic patients (TE Results A total of 1092 HIV-infected patients (51% coinfected with hepatitis C virus) were included. Prevalence of OcC and OvC at baseline was 2.7% and 10.7%, respectively. During a median follow-up of 1.8 (interquartile range, 1.5–2.8) years, the incidence of liver-related events in noncirrhosis, OcC, and OvC was 3.4 (95% confidence interval [CI], 1.2–7.3), 34.0 (95% CI, 6.0–104.0), and 37.0 (95% CI, 17.0–69.1) per 1000 person-years, respectively. Baseline OcC (adjusted hazard ratio [aHR], 7.1 [95% CI, 1.3–38.0]) and OvC (aHR, 8.5 [95% CI, 2.8–26.0]) were independently associated with liver-related events. Monitoring rates for HCC were lower in patients with OcC (24%) compared to those with OvC (40%). Conclusions HIV-infected patients with OcC have a high incidence of liver-related events. Greater surveillance and earlier recognition with appropriate screening strategies are necessary for improved outcomes.

Background & Aims: Polycystic ovary disease (PCOS) may be a risk factor for nonalcoholic fatty liver disease (NAFLD) due to common pathogenetic pathways, including insulin resistance and obesity. Both PCOS and NAFLD are more severe in South Asian women. Data on NAFLD in South Asian women with PCOS are lacking.Methods: We investigated prevalence and predictors of NAFLD and liver fibrosis by transient elastography (TE) with associated controlled attenuation parameter (CAP) in PCOS patients from South Asia, through a routine screening program. NAFLD was defined as CAP >288 dB/m. Significant liver fibrosis (stage 2 and higher out of 4) was defined as TE measurement >8.0 kPa. Elevated ALT was defined as ALT >24 IU/L, as per upper limit of normal reported in South Asian women. Hyperandrogenism was defined as free androgen index >5. Predictors of NAFLD were determined by logistic regression analysis.Results: 101 PCOS patients (mean age 36.3 years) with no significant alcohol intake or viral hepatitis were included. Prevalence of NAFLD and significant liver fibrosis was 39.6% and 6.9%, respectively. Elevated ALT was observed in 40.0% and 11.5% of patients with and without NAFLD, respectively. After adjusting for duration of PCOS and insulin resistance measured by HOMA-IR, independent predictors of NAFLD were higher BMI (adjusted odds ratio [aOR] 1.30, 95% CI 1.13-1.52), hyperandrogenism (aOR 5.32, 95% CI 1.56-18.17) and elevated ALT (aOR 3.54, 95% CI 1.10-11.47). Lifetime cardiovascular risk was higher in patients with NAFLD compared to those without NAFLD (0.31+0.11 vs. 0.26+0.13).Conclusions: Despite their young age, NAFLD diagnosed by TE with CAP is a frequent comorbidity in South Asian women with PCOS and is strongly associated with higher BMI and hyperandrogenism. Non-invasive screening strategies could help early diagnosis and initiation of interventions, including counselling on weight loss, cardiovascular risk stratification and linkage to hepatology care where appropriate.

Objectives: Current guidelines recommend use of a diagnostic algorithm to assess disease severity in cases of suspected nonalcoholic fatty liver disease (NAFLD). We applied this algorithm to HIV-monoinfected patients. Methods: We analysed three prospective screening programmes for NAFLD carried out in the following cohorts: the Liver Disease in HIV (LIVEHIV) cohort in Montreal, the Modena HIV Metabolic Clinic (MHMC) cohort and the Liver Pathologies in HIV in Palermo (LHivPa) cohort. In the LIVEHIV and LHivPa cohorts, NAFLD was diagnosed if the controlled attenuation parameter (CAP) was ≥248dB/m; in the MHMC cohort, it was diagnosed if the liver/spleen Hounsfield unit (HU) ratio on abdominal computerized tomography scan was

Background Inflammatory bowel disease (IBD) patients may be at risk for nonalcoholic fatty liver disease (NAFLD) due to chronic inflammation, hepatotoxic drugs, and alteration of the gut microbiota. Prospective data using accurate diagnostic methods are lacking. Methods We prospectively investigated prevalence and predictors of NAFLD and liver fibrosis by transient elastography (TE) with associated controlled attenuation parameter (CAP) in IBD patients as part of a routine screening program. NAFLD was defined as CAP ≥248 dB/m. Significant liver fibrosis (stage 2 or higher out of 4) was defined as TE measurement ≥7.0 kPa. Predictors of NAFLD and significant liver fibrosis were determined by logistic regression analysis. Results A total of 384 patients (mean age 42.4 years, 45.0% male, 64.6% with Crohn's disease) with no significant alcohol intake were included. Prevalence of NAFLD and significant liver fibrosis was 32.8% and 12.2%, respectively. Independent predictors of NAFLD were older age (adjusted odds ratio [aOR], 1.45; 95% confidence interval [CI], 1.15-1.82), higher body mass index (BMI; aOR, 1.31; 95% CI, 1.20-1.42) and higher triglycerides (aOR, 1.45; 95% CI, 1.01-2.09). Significant liver fibrosis was independently predicted by older age (aOR, 1.38; 95% CI, 1.12-1.64) and higher BMI (aOR, 1.14; 95% CI, 1.07-1.23). Extrahepatic diseases were more common in IBD patients with NAFLD compared with those without, namely chronic kidney disease (10.3 vs 2.3%; P < 0.001) and cardiovascular diseases (11.3 vs 4.7%; P = 0.02). Conclusions NAFLD diagnosed by TE with CAP is a frequent comorbidity in IBD patients and is associated with extrahepatic diseases. Noninvasive screening strategies could help early diagnosis and initiation of interventions, including weight loss, correction of dyslipidemia, and linkage to care. 10.1093/ibd/izy200_video1izy200.video15794817619001.

Author(s): Tam, Edward; Luetkemeyer, Anne F; Mantry, Parvez S; Satapathy, Sanjaya K; Ghali, Peter; Kang, Minhee; Haubrich, Richard; Shen, Xianlin; Ni, Liyun; Camus, Gregory; Copans, Amanda; Rossaro, Lorenzo; Guyer, Bill; Brown, Robert S; RESCUE and ACTG A5348 study investigators | Abstract: Background a aimsWe report data from two similarly designed studies that evaluated the efficacy, safety, and optimal duration of ledipasvir/sofosbuvir (LDV/SOF)n±nribavirin (RBV) for retreatment of chronic hepatitis C virus (HCV) in individuals who failed to achieve sustained virological response (SVR) with prior SOF-based, non-NS5A inhibitor-containing regimens.MethodsThe RESCUE study enrolled HCV mono-infected adults with genotype (GT) 1 or 4. Non-cirrhotic participants were randomized to 12nweeks of LDV/SOF or LDV/SOFn+nRBV. Compensated cirrhotic participants were randomized to LDV/SOFn+nRBV (12nweeks) or LDV/SOF (24nweeks). The AIDS Clinical Trials Group A5348 study randomized genotype 1 adults with HCV/HIV co-infection to LDV/SOFn+nRBV (12nweeks) or LDV/SOF (24nweeks). Both studies used SVR at 12nweeks post-treatment (SVR12) as the primary endpoint.ResultsIn the RESCUE study, 82 participants were randomized and treated, and all completed treatment. Overall, SVR12 was 88% (72/82); 81-100% in non-cirrhotic participants treated with LDV/SOF or LDV/SOFn+nRBV for 12nweeks and 80-92% in cirrhotic participants treated with LDV/SOFn+nRBV for 12nweeks or LDV/SOF for 24nweeks. Adverse events (AEs), mostly mild-to-moderate in severity, were experienced by 78% of participants, with headache and fatigue most frequently reported. One serious AE, not related to treatment, was observed. No premature discontinuations of study drug, or deaths occurred. In the A5348 study, seven participants were randomized (cirrhotic nn=n1; GT1a nn=n5) and all attained SVR12, with no serious AEs or premature discontinuations.ConclusionsIn this SOF-experienced, NS5A inhibitor-naive population, which included participants with cirrhosis or HCV/HIV co-infection, high SVR12 rates were achieved.

Antiretroviral therapy (ART) has led to dramatic improvements in the lives of HIV-infected persons. However, residual immune activation, which persists despite ART, is associated with increased risk of non-AIDS morbidities. Accumulating evidence shows that disruption of the gut mucosal epithelium during SIV/HIV infections allows translocation of microbial products into the circulation, triggering immune activation. This disruption is due to immune, structural and microbial alterations. In this review, we highlighted the key findings of gut mucosa studies of SIV-infected macaques and HIV-infected humans that have revealed virus-induced changes of intestinal CD4, CD8 T cells, innate lymphoid cells, myeloid cells, and of the local cytokine/chemokine network in addition to epithelial injuries. We review the interplay between the host immune response and the intestinal microbiota, which also impacts disease progression. Collectively, these studies have instructed clinical research on early ART initiation, modifiers of microbiota composition, and recombinant cytokines for restoring gut barrier integrity., Highlights • SIV/HIV-induced multiple gut damage contributes to impaired containment of gut luminal microbiota. • Early antiretroviral therapy (ART) does not fully restore HIV-induced gut damage. • Novel therapies that restore gut barrier integrity are needed to reduce microbial translocation and inflammation.

Background & Aims Diagnosis of preclinical compensated cirrhosis (occult cirrhosis, OC) is challenging due to lack of clinical findings. We evaluated prevalence and outcomes of OC by transient elastography (TE, Fibroscan®). Methods Eight hundred and seventy-one patients with compensated chronic liver disease (CLD) and TE examination were divided into: (i) OC (TE ≥ 13 kPa and no sign of cirrhosis, including absence of thrombocytopenia and signs of advanced liver disease on ultrasound or gastroscopy); (ii) clinically evident cirrhosis (TE ≥ 13 kPa with signs of cirrhosis); (iii) non-cirrhotic CLD (TE

Background and aim HIV-infected individuals are at high risk of developing nonalcoholic steatohepatitis (NASH), a leading cause of end-stage liver disease in Western countries. Nonetheless, due to the invasiveness of liver biopsy, NASH remains poorly understood in HIV mono-infection. We aimed to characterize the prevalence and predictors of NASH in unselected HIV mono-infected patients by means of non-invasive diagnostic tools. Methods HIV-infected adults without significant alcohol intake or co-infection with hepatitis B or C underwent a routine screening program employing transient elastography (TE) with controlled attenuation parameter (CAP) and the serum biomarker cytokeratin-18 (CK-18). NASH was diagnosed non-invasively as the coexistence of fatty liver (CAP ≥248 dB/m) and CK-18 >246 U/L. Identified cases of NASH were offered a diagnostic liver biopsy. Predictors of NASH were determined by multivariate logistic regression analysis. Results 202 consecutive HIV mono-infected patients were included. NASH was non-invasively diagnosed in 23 cases (11.4%). Among them, 17 underwent a liver biopsy, and histology confirmed NASH in all cases. The prevalence of NASH was higher in patients with hypertriglyceridemia (17.1%), insulin resistance defined by homeostasis model for assessment of insulin resistance (HOMA-IR) (25%), those with detectable HIV viral load (42.9%) and those with elevated ALT (53.6%). After adjustment, higher HOMA-IR (adjusted odds ratio [aOR] = 1.20, 95% CI 1.01–1.43; p = 0.03) and ALT (aOR = 2.39, 95% CI 1.50–3.79; p

Background and Aims. Serum fibrosis biomarkers have shown good accuracy in the liver transplant (LT) population. We employed a simple serum biomarker to elucidate incidence and predictors of advanced fibrosis after LT over a long follow-up period.Methods. We included 440 consecutive patients who underwent LT between 1991 and 2013. Advanced liver fibrosis was defined as FIB-4 > 3.25 beyond 12 months after LT.Results. Over 2030.5 person-years (PY) of follow-up, 189 (43%) developed FIB-4 > 3.25, accounting for an incidence of 9.3/100 PY (95% confidence interval [CI], 8.1–10.7). Advanced fibrosis was predicted by chronic HCV infection (adjusted hazard ratio (aHR) = 3.96, 95% CI 2.92–5.36,p< 0.001), hypoalbuminemia (aHR = 2.31, 95% CI 1.72–3.09;p< 0.001), and hyponatremia (aHR = 1.48, 95% CI 1.09–2.01;p= 0.01). LT recipients with more than 1 predictor had a higher incidence of advanced fibrosis, the highest being when all 3 predictors coexisted (log-rank:p< 0.001).Conclusions. Chronic HCV infection, hypoalbuminemia, and hyponatremia predict progression to advanced liver fibrosis following LT. Patients with these risk factors should be serially monitored using noninvasive fibrosis biomarkers and prioritized for interventions.

Hepatic steatosis (HS) seems common in patients infected with human immunodeficiency virus (HIV). However, the relative effect of HIV, as well as hepatitis C virus (HCV) in those co-infected, and the influence of HS on liver fibrosis progression are unclear.The LIVEr disease in HIV (LIVEHIV) is a Canadian prospective cohort study using transient elastography and associated controlled attenuation parameter (CAP) to screen for HS and liver fibrosis, in unselected HIV-infected adults. HS progression was defined as development of any grade HS (CAP ⩾248dB/m), or transition to severe HS (CAP292dB/m), for those with any grade HS at baseline. Fibrosis progression was defined as development of significant liver fibrosis (liver stiffness measurement [LSM]7.1kPa), or transition to cirrhosis (LSM12.5kPa) for those with significant liver fibrosis at baseline. Cox regression analysis was used to assess predictors of HS and fibrosis progression.A prospective cohort study was conducted, which included 726 HIV-infected patients (22.7% HCV co-infected). Prevalence of any grade HS did not differ between HIV mono-infected and HIV/HCV co-infected patients (36.1% vs. 38.6%, respectively). 313 patients were followed for a median of 15.4 (interquartile range 8.5-23.0) months. The rate of HS progression was 37.8 (95% confidence interval [CI] 29.2-49.0) and 21.9 (95% CI 15.6-30.7) per 100 person-years in HIV mono-infection and HIV/HCV co-infection, respectively. HCV co-infection was an independent negative predictor of HS progression (adjusted hazard ratio [aHR] 0.50, 95% CI 0.28-0.89). HS predicted liver fibrosis progression in HIV mono-infection (aHR 4.18, 95% CI 1.21-14.5), but not in HIV/HCV co-infection.HS progresses faster and is associated with liver fibrosis progression in HIV mono-infection but not in HIV/HCV co-infection. Lay summary: Fatty liver is the most frequent liver disease in Western countries. People living with HIV seem at high risk of fatty liver due to frequent metabolic disorders and the long-term effects of antiretroviral therapy. However, due to the invasiveness of liver biopsy, the traditional method of diagnosing fatty liver, there are few data regarding its frequency in people living with HIV. In this study, we used a non-invasive diagnostic tool to analyze the epidemiology of fatty liver in 726 HIV+ patients. We found that fatty liver affects over one-third of people living with HIV. When followed over time, we found that HIV+ patients without HCV co-infection develop fatty liver more frequently than those co-infected with HCV.

OBJECTIVE: To provide an approach to the care of liver transplant (LT) patients, a growing patient population with unique needs.METHODS: A literature search of PubMed for guidelines and review articles using the keywords “liver transplantation”, “long term complications” and “medical management” was conducted, resulting in 77 articles.RESULTS: As a result of being on immunosuppression, LT recipients are at increased risk of infections and must be screened regularly for metabolic complications and malignancies.DISCUSSION: Although immunosuppression is key to maintaining allograft health after transplantation, it comes with its own set of medical issues to follow. Physicians following LT recipients must be aware of the greater risk for hypertension, diabetes, dyslipidemia, renal failure, metabolic bone disease and malignancies in these patients, all of whom require regular monitoring and screening. Vaccination, quality of life, sexual function and pregnancy must be specifically addressed in transplant patients.

BackgroundThe preparation for colonoscopy is elaborate and complex. In the context of colorectal cancer screening, up to 11% of patients do not keep their colonoscopy appointments and up to 33% of those attending their appointments have inadequately cleansed bowels that can delay cancer diagnosis and treatment. A smartphone app may be an acceptable and wide-reaching tool to improve patient adherence to colonoscopy. ObjectiveThe aim of this qualitative study was to employ a user-centered approach to design the content and features of a smartphone app called colonAPPscopy to support individuals preparing for their colonoscopy appointments. MethodsWe conducted 2 focus group discussions (FGDs) with gastroenterology patients treated at the McGill University Health Centre in Montreal, Canada. Patients were aged 50 to 75 years, were English- or French-speaking, and had undergone outpatient colonoscopy in the previous 3 months; they did not have inflammatory bowel disease or colorectal cancer. FGDs were 75 to 90 min, conducted by a trained facilitator, and audiotaped. Participants discussed the electronic health support tools they might use to help them prepare for the colonoscopy, the content needed for colonoscopy preparation, and the features that would make the smartphone app useful. Recordings of FGDs were transcribed and analyzed using thematic analysis to identify key user-defined content and features to inform the design of colonAPPscopy. ResultsA total of 9 patients (7 male and 2 female) participated in one of 2 FGDs. Main content areas focused on bowel preparation instructions, medication restrictions, appointment logistics, communication, and postcolonoscopy expectations. Design features to make the app useful and engaging included minimization of data input, reminders and alerts for up to 7 days precolonoscopy, and visual aids. Participants wanted a smartphone app that comes from a trusted source, sends timely and tailored messages, provides reassurance, provides clear instructions, and is simple to use. ConclusionsParticipants identified the need for postcolonoscopy information as well as reminders and alerts in the week before colonoscopy, novel content, and features that had not been included in previous smartphone-based strategies for colonoscopy preparation. The ability to tailor instructions made the smartphone app preferable to other modes of delivery. Study findings recognize the importance of including potential users in the development phase of building a smartphone app.

Smoking is a common behavior among transplant candidates. The aim of this study was to evaluate the effects of smoking on a range of complications after liver transplantation. We reviewed data about patient demographics and various complications after liver transplantation that were recorded in the McGill University Health Centre liver transplant database over a 14-year period. χ2 and multivariate analyses were performed. Four hundred forty-four liver transplants were performed from 1990 to 2004, and 63 were repeat transplants. Only primary liver transplant recipients were included in our analysis. Smokers (ie, active or former smokers) were more likely to be male (77.9% versus 62.7%, P = 0.009) and Caucasian (88.4% versus 78.0%, P = 0.03). The median survival time was 13.23 years for smokers and was not estimable for nonsmokers because of censoring. The median recurrent viral hepatitis–free survival time was 0.87 years for smokers and 4.10 years for nonsmokers (P = 0.03). The following variables were not found to be associated with the smoking status: patient survival (P = 0.78), time to biliary complications after liver transplantation (P = 0.67), time to the first rejection episode after liver transplantation (P = 0.61), and time to depression after liver transplantation (P = 0.67). A Cox proportional hazards regression showed that recurrent viral hepatitis–free survival was still strongly associated with smoking [HR = 2.04, 95% confidence interval (CI) = 1.13-3.68, P = 0.018] and was marginally associated with East Asian race (HR = 0.26, 95% CI = 0.06-1.06, P = 0.06) and male sex (HR = 0.59, 95% CI = 0.34-1.02, P = 0.06). In conclusion, recurrent viral hepatitis–free survival was decreased for smokers after liver transplantation, likely because of the adverse effects of tobacco on immunological host defenses. Overall, the biliary complication–free, depression-free, and rejection-free survival rates were similar for smokers and nonsmokers. These findings suggest that smoking cessation should be encouraged, particularly in recipients undergoing transplantation for viral hepatitis. Liver Transpl, 2012. © 2012 AASLD.

Public safety and the right of the health care worker to practise without prejudice based on underlying illness may be at odds for those affected by the hepatitis B virus (HBV). Nevertheless, HBV does not preclude entry into a health care profession, and the risk of transmission from health care worker to patient is not uniform across the spectrum of health care fields. In the present article, the authors present an overview of the literature regarding transmission of HBV from the health care worker to the patient, and the current recommendations that vary from province to province within Canada. The establishment of national guidelines to standardize monitoring of HBV infection among health care workers would improve health care work-place safety and patient care.

BACKGROUND: Alcoholic liver disease (ALD) is associated with a high risk of morbidity and mortality. Malnutrition accompanies this condition and may be both a consequence of and contributor to the pathology. Many trials have investigated the benefits of providing supplemental nutrition in the management of patients with ALD. The present study is a meta-analysis of the available evidence.METHOD: A meta-analysis of randomized controlled studies comparing nutritional supplementation plus a normal hospital diet versus diet alone.RESULTS: Seven randomized controlled studies including 262 patients with ALD were identified. Pooled analysis revealed no statistical difference in mortality between groups given special nutritional therapy versus a normal balanced diet (OR 0.80 [95% CI 0.42 to 1.52]). In addition, nutrition did not significantly improve ascites (OR 1.29 [95% CI 0.52 to 3.20]) or any biochemical parameters. However, encephalopathy showed a significant improvement or resolution (OR 0.24 [95% CI 0.06 to 0.93]).CONCLUSION: Nutritional supplementation provided no mortality benefit in patients with ALD, and neither ascites nor biochemical parameters significantly improved. However, encephalopathy was significantly ameliorated and, therefore, nutritional supplementation should be encouraged in that setting.

Background/Aims VCH-759 is a non-nucleoside inhibitor of HCV RNA-dependent polymerase with sub-micromolar IC 50 values versus genotype 1a/1b replicons. Methods The antiviral activity, pharmacokinetics and tolerability of VCH-759 administered as monotherapy for 10 days with a 14 day follow-up period were evaluated in 31 treatment-nai¨ve genotype 1 participants. Three cohorts received: 400mg thrice (t.i.d.), 800mg twice (b.i.d.), 800mg t.i.d or placebo. Results VCH-759 was well tolerated with the most frequent adverse event being gastrointestinal upset in both the active and placebo groups attributable, in part, to the dosing vehicle. VCH-759 was rapidly absorbed and trough plasma levels were at or above the IC 90 (non protein-adjusted) for all dosing regimens. The mean maximal decrease in HCV RNA log 10 (IU/mL) was 1.97, 2.30 and 2.46 for 400mg t.i.d., 800mg b.i.d. and 800mg t.i.d. doses. Viral polymerase genotypic sequencing revealed emergence of HCV variants in a majority of participants that coincided with on-treatment viral rebound. Conclusions VCH-759 was well tolerated and achieved a⩾2 log 10 decline in HCV RNA with 800mg b.i.d. and t.i.d doses. In a subset of participants, viral rebound was observed and associated with resistant variants. This data supports further evaluation of VCH-759 in combination with interferon–ribavirin treatment.

The present article describes three difficult cases of recurrent bleeding from obscure causes, followed by a review of the pitfalls and pharmacological management of obscure gastrointestinal bleeding. All three patients underwent multiple investigations. An intervening complicating diagnosis or antiplatelet drugs may have compounded long-term bleeding in two of the cases. A bleeding angiodysplasia was confirmed in one case but was aggravated by the need for anticoagulation. After multiple transfusions and several attempts at endoscopic management in some cases, long-acting octreotide was associated with decreased transfusion requirements and increased hemoglobin levels in all three cases, although other factors may have contributed in some. In the third case, however, the addition of low-dose thalidomide stopped bleeding for a period of at least 23 months.

BACKGROUND: Patients with cirrhosis are known to experience sleep disturbance, which negatively impacts health-related quality of life.OBJECTIVE: To assess the prevalence and predictors of sleep disturbance before and after liver transplantation (LT).METHODS: Both pre- and post-LT patients were administered the Basic Nordic Sleep Questionnaire. The primary outcome was overall sleep satisfaction; the secondary outcomes were sleep latency and sleep duration.RESULTS: Eighty-three patients participated pre-LT and 273 post-LT. Overall, participants having completed both pre- and post-LT questionnaires reported satisfactory sleep 61% of the time before LT and 65% of the time after LT. However, on review of all questionnaires, patients with alcoholic liver disease (ETOH) experienced dramatically less sleep disturbance (OR 0.13 [95% CI 0.03 to 0.60]) post-LT, whereas those with hepatitis C remained without improvement (OR 0.90 [95% CI [0.38 to 2.15]). On logistic regression, patients with ETOH had statistically less sleep satisfaction pre-LT (OR 5.8 [95% CI 1.0 to 40.5]) and significantly better sleep satisfaction post-LT (OR 0.50 [95% CI 0.20 to 1.00]) compared with those with hepatitis C. In addition, both ETOH and other conditions had significantly better sleep latency than hepatitis C patients.CONCLUSIONS: Sleep parameters for patients who undergo LT for hepatitis C do not improve following LT as much as they do in patients transplanted for ETOH. Following LT, patients transplanted for ETOH are significantly more satisfied with their sleep than those transplanted for hepatitis C. Physicians should address and manage sleep quality after LT, so as to ultimately improve quality of life.

Noninvasive serum fibrosis biomarkers predict clinical outcomes in pretransplant patients with chronic liver disease. We investigated the role of serum fibrosis biomarkers and of changes in biomarkers in predicting death and graft loss after liver transplantation (LT). We included 547 patients who underwent LT between 1991 and 2012 and who met the following criteria: patient and graft survival12 months; serum fibrosis biomarkers aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis score 4 (FIB-4), and nonalcoholic fatty liver disease (NAFLD) fibrosis score available at 1 year after LT; and a minimum follow-up of 1 year. Delta of fibrosis biomarkers was defined as (end of follow-up score--baseline score)/follow-up duration. Baseline and delta fibrosis biomarkers were associated with death: APRI1.5 (adjusted hazard ratio [aHR], 2.2; 95% confidence interval [CI], 1.4-3.3; P0.001) and delta APRI0.5 (aHR, 5.3; 95% CI, 3.4-8.2; P0.001); FIB-43.3 (aHR, 1.9; 95% CI, 1.3-2.8; P = 0.002) and delta FIB-41.4 (aHR, 2.4; 95% CI, 1.4-4.1; P = 0.001); and NAFLD fibrosis score0.7 (aHR, 1.9; 95% CI, 1.3-2.9; P = 0.002) and delta NAFLD fibrosis score (aHR, 3.7; 95% CI, 2.6-5.4; P0.001). Baseline and delta fibrosis biomarkers were associated also with graft loss. In conclusion, serum fibrosis biomarkers 1 year after LT and changes in serum fibrosis biomarkers predict death and graft loss in LT recipients. They may help in risk stratification of LT recipients and identify patients requiring closer monitoring.

Background & Aims Non-invasive diagnostic methods for liver fibrosis predict clinical outcomes in viral hepatitis and nonalcoholic fatty liver disease (NAFLD). We specifically evaluated prognostic value of non-invasive fibrosis methods in nonalcoholic steatohepatitis (NASH) against hepatic venous pressure gradient (HVPG) and liver histology. Methods This was a retrospective cohort study of 148 consecutive patients who met the following criteria: transjugular liver biopsy with HVPG measurement; biopsy-proven NASH; absence of decompensation; AST-to-Platelets Ratio Index (APRI), fibrosis-4 (FIB-4), NAFLD fibrosis score, ultrasound, hepatic steatosis index and Xenon-133 scan available within 6 months from biopsy; a minimum follow-up of 1 year. Outcomes were defined by death, liver transplantation, cirrhosis complications. Kaplan–Meier and Cox regression analyses were employed to estimate incidence and predictors of outcomes, respectively. Prognostic value was expressed as area under the curve (AUC). Results During a median follow-up of 5 years (interquartile range 3-8), 16.2% developed outcomes, including 7.4% who died or underwent liver transplantation. After adjustment for age, sex, diabetes, the following fibrosis tools predicted outcomes: HVPG >10mmHg (HR=9.60; 95% confidence interval [CI] 3.07-30.12), histologic fibrosis F3-F4 (HR=3.14; 1.41-6.95), APRI >1.5 (HR=5.02; 1.6-15.7), FIB-4 >3.25 (HR=6.33; 1.98-20.2), NAFLD fibrosis score >0.676 (HR=11.9; 3.79-37.4). Prognostic value was as follows: histologic fibrosis stage, AUC=0.85 (95% CI 0.76-0.93); HVPG, AUC=0.81 (0.70-0.91); APRI, AUC=0.89 (0.82-0.96); FIB-4, AUC=0.89 (0.83-0.95); NAFLD fibrosis score, AUC=0.79 (0.69-0.91). Neither histologic steatosis nor non-invasive steatosis methods predicted outcomes (AUC

Patients with ileal pouches and ostomies present with management issues that are challenging to the clinician. Endoscopy plays a significant role in diagnosing and guiding therapy in such patients. Unfortunately, there are very few prospective studies that evaluates endoscopy in these situations. Nevertheless, it is clear that endoscopy remains a powerful tool that is important for diagnosis and therapy of complications unique to these surgical procedures. It seems prudent to advocate endoscopic cancer surveillance for patients with pouches and ostomies; however, it remains to be seen whether these efforts will ultimately have an impact on long-term patient morbidity and mortality.

OBJECTIVE: To determine practices among physicians in Canada for the assessment of liver fibrosis in patients with chronic liver diseases.METHODS: Hepatologists, gastroenterologists, infectious diseases specialists, members of the Canadian Gastroenterology Association and/or the Canadian HIV Trials Network who manage patients with liver diseases were invited to participate in a web-based, national survey.RESULTS: Of the 237 physicians invited, 104 (43.9%) completed the survey. Routine assessment of liver fibrosis was requested by the surveyed physicians mostly for chronic hepatitis C (76.5%), followed by autoimmune/cholestatic liver disease (59.6%) and chronic hepatitis B (52.9%). Liver biopsy was the main diagnostic tool for 46.2% of the respondents, Fibroscan (Echosens, France) for 39.4% and Fibrotest (LabCorp, USA) for 7.7%. Etiology-specific differences were observed: noninvasive methods were mostly used for hepatitis C (63% versus 37% liver biopsy) and hepatitis B (62.9% versus 37.1% liver biopsy). For 42.7% of respondents, the use of noninvasive methods reduced the need for liver biopsy by >50%. Physicians’ characteristics associated with higher use of noninvasive methods were older age and being based at a university hospital or in private practice versus community hospital. Physicians’ main concerns regarding noninvasive fibrosis assessment methods were access/availability (42.3%), lack of guidelines for clinical use (26.9%) and cost/lack of reimbursement (14.4%).CONCLUSIONS: Physicians who manage patients with chronic liver diseases in Canada require routine assessment of liver fibrosis stage. Although biopsy remains the primary diagnostic tool for almost one-half of respondents, noninvasive methods, particularly Fibroscan, have significantly reduced the need for liver biopsy in Canada. Limitations in access to and availability of the noninvasive methods represent a significant barrier. Finally, there is a need for clinical guidelines and a better reimbursement policy to implement noninvasive tools to assess liver fibrosis.

Gastrointestinal (GI) symptoms are conditions that are frequently observed in clinical practice. A post-hoc analysis has been undertaken to evaluate the effect of bile salt hydrolase-active L. reuteri NCIMB 30242 on GI health status based on Rome III questionnaire response in otherwise healthy hypercholesterolemic subjects.A total of 127 subjects received either L. reuteri NCIMB 30242 or placebo capsules over a 9-week intervention in a randomized, double-blind, placebo-controlled, parallel-arm, multicenter study. Subjects were asked to complete the Rome III diagnostic GI questionnaire prior to the baseline and end point visits of the clinical study.GI health status was evaluated, per questionnaire, by assessing all questions with 5- or 7-point response scales for symptoms of the stomach and intestines.Subjects receiving L. reuteri NCIMB 30242 reported significant improvements in general GI health status (p = 0.029) and in symptoms related to diarrhea (p = 0.018) as compared to placebo over the intervention period. Further, a greater proportion of L. reuteri-treated subjects showed improved general GI health status (p = 0.042) and improved diarrhea symptoms (p = 0.03).L. reuteri NCIMB 30242 capsules appear to be well tolerated and potentially beneficial for GI health status. Further clinical investigation is warranted for the treatment of functional GI disorders.

BACKGROUND Chronic kidney disease (CKD) is a frequent complication after liver transplantation (LT) and is associated with increased mortality. Strategies to reduce calcineurin inhibitor (CNI) dose or conversion to either mycophenolate mofetil and/or rapamycin resulted in variable results and side-effect profiles. METHODS We evaluated the effectiveness of CNI conversion to long-term anti-CD25 monoclonal antibody (mAb)-based immunosuppression in 15 adult LT patients with CKD at 7.6±4 years posttransplant (intervention group). Three patients had been previously switched to rapamycin, and 12 patients were on CNI. The control group included 15 LT patients on CNI with stable renal function over a similar posttransplant follow-up period. RESULTS Anti-CD25 mAb were given over a period of 26±15 months (range, 2-51 months) and were well tolerated. The slope of calculated creatinine clearance was -0.66 mL/min/month over 6 months before conversion and -0.05 mL/min/month after conversion to anti-CD25 mAb (P=0.16 and P=0.86 vs. controls). Three acute rejection episodes occurred in the intervention group. Acute rejection was reversible in two patients. However, one patient died of chronic rejection 1 year after having been switched to tacrolimus. Anti-CD25 mAb were replaced with either CNI or rapamycin in six patients (acute rejection [n=2], progression to end-stage renal disease [n=2], poor venous status [n=1], increased liver enzymes [n=1]). CONCLUSION The use of long-term anti-CD25 mAb therapy as a replacement to CNI and rapamycin-based immunosuppression may be feasible. It is crucial that rejection surveillance is intensified. A randomized controlled trial is required to confirm the benefits of this strategy.

Background & Aims Hepatitis B virus (HBV) genotype and quantitative hepatitis B surface antigen (qHBsAg) have been related to clinical outcome. In this nationwide cross-sectional study, we aimed to investigate the epidemiology and clinical significance of HBV genotype and qHBsAg in patients with chronic hepatitis B (CHB). Methods Six hundred and thirty patients with CHB were seen in four urban tertiary referral centres in Canada. HBV genotype was determined by line probe assay (INNO-LIPA) and HBV DNA quantified by commercial PCR (Roche TaqMan, sensitivity

Background Clostridium difficile-associated diarrhea (CDAD) is an increasingly important diagnosis in solid organ transplant recipients, with rising incidence and mortality. We describe the incidence, risk factors, and outcomes of colectomy for CDAD after solid organ transplantation. Methods Patients with CDAD were identified from a prospective transplant database. Complicated Clostridium difficile colitis (CCDC) was defined as CDAD associated with graft loss, total colectomy, or death. Results From 1999 to 2010, we performed solid organ transplants for 1331 recipients at our institution. The incidence of CDAD was 12.4% (165 patients); it increased from 4.5% (1999) to 21.1% (2005) and finally 9.5% (2010). The peak frequency of CDAD was between 6 and 10 days posttransplantation. Age more than 55 years (hazard ratio [HR]: 1.47, 95% confidence interval [CI]=1.16-1.81), induction with antithymocyte globulin (HR: 1.43, 95% CI=1.075-1.94), and transplant other than kidney alone (liver, heart, pancreas, or combined kidney organ) (HR: 1.41, 95% CI=1.05-1.92) were significant independent risk factors for CDAD. CCDC occurred in 15.8% of CDAD cases. Independent predictors of CCDC were white blood cell count more than 25,000/μL (HR: 1.08, 95% CI=1.025-1.15) and evidence of pancolitis on computed tomography scan (HR: 2.52, 95% CI=1.195-5.35). Six patients with CCDC underwent colectomy with 83% patient survival and 20% graft loss. Of the medically treated patients with CCDC (n=20), the patient survival was 35% with 100% graft loss. Conclusions We have identified significant risk factors for CDAD and predictors of progression to CCDC. Furthermore, we found that colectomy can be performed with excellent survival in selected patients.

Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver damage and is the most common cause of chronic liver diseases in Western countries. Although a relatively common condition affecting approximately 20% of the general population, NAFLD is especially prevalent in obese individuals, a figure likely to rise as obesity rates in Western countries continue to increase. Liver biopsy remains the gold standard diagnostic method; however, its invasive nature, among other factors, has prompted the need to develop less invasive, alternative methods to quantify hepatic fat and determine disease severity. Xenon-133 liver scanning is one such method that has been in use for more than 10 years in the evaluation of patients with suspected NAFLD. This study compared Xenon-133 liver scan with other currently used, invasive and noninvasive methods of liver assessment.BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is an important and common condition affecting approximately 20% of the general population. Given the limitation of radiological investigations, diagnosis often requires a liver biopsy.OBJECTIVE: To compare Xenon-133 (Xe-133) liver scanning with ultrasonography in the diagnosis of NAFLD.METHODS: From January 2003 to February 2007, 258 consecutive patients with suspected NAFLD underwent Xe-133 liver scanning at Royal Victoria Hospital (Montreal, Quebec). Of these, 43 patients underwent ultrasonography and liver biopsy for the evaluation of NAFLD. Patients with other liver diseases and significant alcohol consumption were excluded. Two nuclear medicine physicians assessed liver Xe-133 uptake and measured the grade of steatosis using a standardized protocol. The degree of steatosis was determined from biopsy specimens assessed by two hepatopathologists.RESULTS: NAFLD was identified by liver biopsy in 35 of 43 patients (81.4%). Xe-133 scan demonstrated 94.3% sensitivity (95% CI 81.4% to 98.4%) and 87.5% specificity (95% CI 52.9% to 99.4%) for the presence of NAFLD. The positive and negative predictive values for detection of steatosis by Xe-133 scan were 97.1% (95% CI 85.1% to 99.8%) and 77.8% (95% CI 45.3% to 93.7%), respectively. The positive and negative likelihood ratios were 7.54 (95% CI 1.20 to 47.26) and 0.07 (95% CI 0.02 to 0.26), respectively. Two patients with NAFLD (5.7%) who had a negative Xe-133 scan result had histologically mild steatosis (CONCLUSION: Xe-133 liver scan proved to be a safe, reliable, non-invasive method for diagnosing and quantifying hepatic steatosis, and was superior to ultrasound.

BACKGROUND Chronic kidney disease (CKD) is a well-known complication after liver transplantation (LT) and is associated with increased mortality. The purpose of this study was to determine risk factors of advanced CKD and mortality after LT. METHODS Four hundred forty-five adult patients underwent LT between June 1990 and September 2007 and survived more than 1 month. Multivariate Cox regression analyses were performed for time to CKD stage 4 (glomerular filtration rate [GFR] ≤30 mL/min), time to chronic dialysis, and all-cause mortality. Several patient and disease characteristics were used as independent pre- and posttransplant variables. We specifically analyzed a drop more than or equal to 30% in the estimated GFR (eGFR) during the first year posttransplant. RESULTS Diabetes mellitus pretransplant and a drop more than or equal to 30% in the eGFR between 3 and 12 months predicted CKD stage 4 (odds ratio [OR] 4.1, 95% confidence interval [CI] 1.9-5.4, P

The Model for End-Stage Liver Disease (MELD) score is now used for allocation in liver transplantation waiting lists, replacing the Child–Turcotte–Pugh (CTP) score. The MELD score is primarily a “justice” system (i.e., organs from deceased donors are allocated to the sickest patients first).1 However, implementation of the MELD score has raised the issue of utility of the donated liver grafts.2 According to the “utility” concept (i.e., organs are allocated preferentially to the lowest-risk candidates), an ideal liver allocation model should not only identify the patient with the highest probability of dying on the waiting list, but also predict early postoperative mortality and long-term survival. Early postoperative mortality usually is associated with technical failures, high-risk recipients and poor-quality grafts. On the other hand, long-term survival is compromised by recurrence of primary disease, opportunistic infections and development of cancer.3 Because of this difference in causative factors, prediction of early and late mortality after liver transplantation might be associated with different preoperative parameters. Most of the scores assessing the severity of cirrhosis, including CTP and MELD scores, have also been used to predict early mortality after liver transplantation,4 but usually without success. For example, the MELD score was unable to predict early (90-d) postoperative mortality in almost all of the relevant studies.5–7 To increase their accuracy, the most recent models for the prediction of early postoperative mortality have included the MELD score and many other variables, such as serum sodium,8 donor quality9 or serum cholinesterase.10 Prediction of long-term survival alone after liver transplantation is less well studied. Most of the relevant studies either utilize the MELD score or derive from a hepatitis C virus (HCV) patient population. Some of the former studies suggest that the MELD score can accurately predict late posttransplant mortality,11 whereas some others do not.12 On the other hand, analyses based on HCV population incorporate many other variables, such as donor’s sex and recipient’s age, in the predictive model.13 This study aims to identify preoperative parameters that might be associated with early postoperative mortality and long-term survival after liver transplantation.

Cholangiocarcinoma is a biliary tumor, which not infrequently complicates primary sclerosing cholangitis. It carries a poor prognosis and, with the exception of carefully selected individuals in research protocols, contraindicates orthotopic liver transplantation. There has been some suggestion that cholangiocarcinomas incidentally discovered at the time of transplantation carry a better prognosis. The goal of this retrospective study was to perform a national review of outcomes after liver transplantation in Canadian recipients found to have incidental cholangiocarcinoma in their explanted native liver. Six of the seven liver transplant centers in Canada provided clinical and follow-up information on all liver transplant recipients found to have incidental cholangiocarcinoma in their explants. The diagnosis or suspicion of cholangiocarcinoma prior to transplantation were exclusion criteria for this study. Ten individuals with cholangiocarcinoma were transplanted between 1996 and 2003. The median duration of follow-up was 28 months. Eight of the 10 had PSC. All of the tumors were stage I or II. The 3-year survival for these patients was 30%. The median time to recurrence was 26 months (95% confidence interval 13-37), and the median time to death was 30 months (95% confidence interval 28-53). In conclusion, although early survival of patients transplanted for incidental cholangiocarcinoma appears good, intermediate- and long-term survival rates are not better than for individuals historically transplanted with known cholangiocarcinoma. Aggressive investigation for cholangiocarcinoma is mandated. Incidentally found tumours remain a difficult treatment problem, and prospective adjuvant chemo-, radio-, and immunotherapies should be investigated.

Obesity is an increasingly prevalent problem with many associated health risks. Obese patients may present with liver diseases directly attributable to their obesity, such as nonalcoholic steatohepatitis (NASH). However, many such individuals are prescribed various potentially hepatotoxic medications for obesity itself, as well as for the complications of obesity. Clinically, it may be difficult to distinguish the two. Furthermore, many of these medications are in common use, and some are not commonly recognized as potentially injurious to the liver. While some medications have predictable hepatotoxicity, many more have associated idiosyncratic reactions. We review the literature and case-reports of hepatotoxicity associated with four categories of medications: those used primarily in the treatment of obesity, those used in the treatment of diabetes mellitus, those used in the treatment of hyperlipidemia, and those used in the treatment of hypertension. For each class, we present the described epidemiology, clinical presentation, pathology, and prognosis.