Frailty is associated with increased risk of cirrhosis disease progression and death.

BACKGROUND AND AIMS: The Liver Frailty Index (LFI) is a well-studied tool that evaluates frailty in patients with cirrhosis. Consisting of grip strength, chair stands, and balance testing, the LFI has been associated with increased mortality in patients awaiting liver transplant. We aimed to extend our understanding of frailty in cirrhosis by exploring the relationship between the LFI and the risk of (1) cirrhosis progression, (2) mortality, and (3) unplanned hospitalizations, in both compensated and decompensated disease. APPROACH AND RESULTS: Adult patients with cirrhosis from four centers in North America and one in India were included. Frailty was measured at baseline using the LFI and categorized as robust (LFI < 3.2), prefrail (LFI 3.2-4.5), and frail (LFI > 4.5). Progression of cirrhosis was defined by an increase in clinical stage, ranging from 1 to 5, from baseline using the D'Amico classification. Factors associated with progression, mortality, and hospitalizations were evaluated using multivariate regression models, with transplant as a competing risk. In total, 822 patients with cirrhosis were included. Average Model for End-Stage Liver Disease (MELD) score was 15.5 ± 6.0. In patients with compensated cirrhosis, being frail versus robust was associated with increased risk of progression to the next cirrhosis stage or to death (HR, 2.45; 95% CI, 1.14-5.29) and with an increased risk of unplanned hospitalizations (2.32; 95% CI, 1.13-4.79), after adjusting for age, sex, and MELD score. Similar HRs were observed in patients with decompensated cirrhosis. CONCLUSIONS: Frailty was an independent predictor of cirrhosis progression or death and unplanned hospitalization across patients with compensated and decompensated cirrhosis. Future studies are needed to evaluate the possibility of slowing cirrhosis disease progression by reversing or preventing frailty.

Assessing Patient Proficiency with Internet-Connected Technology and Their Preferences for E-Health in Cirrhosis.

There is a rapidly evolving need for e-health to support chronic disease self-management and connect patients with their healthcare teams. Patients with cirrhosis have a high symptom burden, significant comorbidities, and a range of psychological and cognitive issues. Patients with cirrhosis were assessed for their readiness and interest in e-health. Adults attending one of two outpatient cirrhosis clinics in Alberta were recruited. Eligible participants were not required to own or have experience with digital technologies or the Internet. Medical history, socioeconomic status, and attitudes regarding e-health, the Computer Proficiency Questionnaire, and the Mobile Device Proficiency Questionnaire were used to describe participants' knowledge and skills. Of the 117 recruited patients, 68.4% owned a computer and 84.6% owned a mobile device. Patients had mean proficiency scores of 72.8% (SD 25.9%) and 69.3% (SD 26.4%) for these devices, respectively. In multiple regression analyses, significant predictors of device proficiency were age, education, and household income. Most patients (78.7%) were confident they could participate in videoconferencing after training and most (61.5%) were interested in an online personalized health management program. This diverse group of patients with cirrhosis had technology ownership, proficiency, and online behaviours similar to the general population. Moreover, the patients were very receptive to e-health if training was provided. This promising data is timely given the unique demands of COVID-19 and its influence on self-management and healthcare delivery to a vulnerable population.

Predicting Hepatic Encephalopathy-Related Hospitalizations Using a Composite Assessment of Cognitive Impairment and Frailty in 355 Patients With Cirrhosis.

INTRODUCTION: Hepatic encephalopathy (HE) is the most common potentially modifiable reason for admission in patients with cirrhosis. Cognitive and physical components of frailty have pathophysiologic rationale as risk factors for HE. We aimed to assess the utility of a composite score (MoCA-CFS) developed using the Montreal Cognitive Assessment (MoCA) and the Clinical Frailty Scale (CFS) for predicting HE admissions within 6 months. METHODS: Consecutive adult patients with cirrhosis were followed for 6 months or until death/transplant. Patients with overt HE and dementia were excluded. Primary outcome was the prediction of HE-related admissions at 6 months. RESULTS: A total of 355 patients were included; mean age 55.9 ± 9.6; 62.5% male; Hepatitis C and alcohol etiology in 64%. Thirty-six percent of patients had cognitive impairment according to the MoCA (≤24) and 14% were frail on the CFS (>4). The MoCA-CFS independently predicted HE hospitalization within 6 months, a MoCA-CFS score of 1 and 2 respectively increasing the odds of hospitalization by 3.3 (95% CI:1.5-7.7) and 5.7 (95% CI:1.9-17.3). HRQoL decreased with increasing MoCA-CFS. Depression and older age were independent predictors of a low MoCA. CONCLUSIONS: Cognitive and physical frailty are common in patients with cirrhosis. In addition to being an independent predictor of HE admissions within 6 months, the MoCA-CFS composite score predicts impaired HRQoL and all-cause admissions within 6 months. These data support the predictive value of a "multidimensional" frailty tool for the prediction of adverse clinical outcomes and highlight the potential for a multi-faceted approach to therapy targeting cognitive impairment, physical frailty and depression.

A Rapid Bedside Screen to Predict Unplanned Hospitalization and Death in Outpatients With Cirrhosis: A Prospective Evaluation of the Clinical Frailty Scale.

OBJECTIVES: Screening tools to determine which outpatients with cirrhosis are at highest risk for unplanned hospitalization are lacking. Frailty is a novel prognostic factor but conventional screening for frailty is time consuming. We evaluated the ability of a 1 min bedside screen (Clinical Frailty Scale (CFS)) to predict unplanned hospitalization or death in outpatients with cirrhosis and compared the CFS with two conventional frailty measures (Fried Frailty Criteria (FFC) and Short Physical Performance Battery (SPPB)). METHODS: We prospectively enrolled consecutive outpatients from three tertiary care liver clinics. Frailty was defined by CFS >4. The primary outcome was the composite of unplanned hospitalization or death within 6 months of study entry. RESULTS: A total of 300 outpatients were enrolled (mean age 57 years, 35% female, 81% white, 66% hepatitis C or alcohol-related liver disease, mean Model for End-Stage Liver Disease (MELD) score 12, 28% with ascites). Overall, 54 (18%) outpatients were frail and 91 (30%) patients had an unplanned hospitalization or death within 6 months. CFS >4 was independently associated with increased rates of unplanned hospitalization or death (57% frail vs. 24% not frail, adjusted odds ratio 3.6; 95% confidence interval (CI): 1.7-7.5; P=0.0008) and there was a dose response (adjusted odds ratio 1.9 per 1-unit increase in CFS, 95% CI: 1.4-2.6; P<0.0001). Models including MELD, ascites, and CFS >4 had a greater discrimination (c-statistic=0.84) than models using FFC or SPPB. CONCLUSIONS: Frailty is strongly and independently associated with an increased risk of unplanned hospitalization or death in outpatients with cirrhosis. The CFS is a rapid screen that could be easily adopted in liver clinics to identify those at highest risk of adverse events.

The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn's disease.

BACKGROUND & AIMS: Probiotic formulations of single species of bacteria have not been effective in preventing the recurrence of Crohn's disease after surgery. We investigated the ability of VSL#3, a mixture of 8 different bacterial probiotic species, to prevent Crohn's disease recurrence after surgery in a multicenter, randomized, double-blind, placebo-controlled trial. METHODS: Within 30 days of ileocolonic resection and re-anastomosis, patients with Crohn's disease were randomly assigned to groups given 1 sachet of VSL#3 (900 billion viable bacteria, comprising 4 strains of Lactobacillus, 3 strains of Bifidobacterium, and 1 strain of Streptococcus salivarius subspecies thermophilus) (n = 59) or matching placebo (n = 60). Colonoscopy was performed at days 90 and 365 to evaluate the neoterminal ileum for disease recurrence and obtain mucosal biopsies for cytokine analysis. Patients from both groups with either no or mild endoscopic recurrence at day 90 received VSL#3 until day 365. The primary outcome was the proportion of patients with severe endoscopic recurrence at day 90. RESULTS: At day 90, the proportion of patients with severe endoscopic lesions did not differ significantly between VSL#3 (9.3%) and placebo (15.7%, P = .19). The proportions of patients with non-severe lesions at day 90 who had severe endoscopic recurrence at day 365 were 10.0% in the early VSL#3 group (given VSL#3 for the entire 365 days) and 26.7% in the late VSL#3 group (given VSL#3 from days 90 through 365) (P = .09). Aggregate rates of severe recurrence (on days 90 and 365) were not statistically different, 20.5% of subjects in the early VSL#3 group and 42.1% in the late VSL#3 group. Patients receiving VSL#3 had reduced mucosal inflammatory cytokine levels compared with placebo at day 90 (P < .05). Crohn's disease activity index and inflammatory bowel disease quality of life scores were similar in the 2 groups. CONCLUSIONS: There were no statistical differences in endoscopic recurrence rates at day 90 between patients who received VSL#3 and patients who received placebo. Lower mucosal levels of inflammatory cytokines and a lower rate of recurrence among patients who received early VSL#3 (for the entire 365 days) indicate that this probiotic should be further investigated for prevention of Crohn's disease recurrence. Clinical trials.gov number: NCT00175292.

VSL#3 ® probiotic therapy does not reduce portal pressures in patients with decompensated cirrhosis.

BACKGROUND & AIMS: In patients with decompensated cirrhosis, bacterial translocation can contribute to splanchnic vasodilatation, decreased effective circulating volume, and portal hypertension. The primary objective of this randomized, double blind placebo controlled trial was to evaluate the effect of the probiotic VSL#3(®) on the hepatic venous pressure gradient (HVPG). METHODS: Seventeen patients with decompensated cirrhosis and an HVPG of ≥ 10 mmHg were randomized to receive 2 months of VSL#3(®) or an identical placebo. HVPG, endotoxin, interleukin (IL)-6, IL-8, IL-10, renin, aldosterone, nitric oxide and stool microbiota were measured at baseline and study end. RESULTS: Two of the 17 patients were taken off the trial before completion (one for alcohol abuse and the second for SBP - both in placebo arm). Data were analysed on the remaining 15 patients. The median model for end-stage liver disease score was 12, and 80% of patients had Child Pugh B disease. The treatment arm had a greater decrease in HVPG from baseline to study end than the placebo arm (median change from baseline -11.6% vs +2.8%), although this reduction was not statistically significant in either group. There was a significant reduction in the plasma aldosterone level in the VSL#3(®) group, but no significant changes in the other measured parameters, including the stool microflora analysis. CONCLUSIONS: Within the limitations of our sample size, VSL#3(®) therapy does not appear to have a significant impact on portal pressure reduction in patients with decompensated cirrhosis.

A chair-stand time of greater than 15 seconds is associated with an increased risk of death and hospitalization in cirrhosis.

Background: Frailty is a clinical state of increased vulnerability and is common in patients with cirrhosis. The liver frailty index (LFI) is a validated tool to evaluate frailty in cirrhosis, comprising of grip strength, chair stands, and balance tests. The chair-stand test is an easy to conduct frailty subcomponent that does not require specialized equipment and may be valuable to predict adverse clinical outcomes in cirrhosis. The objective of this study was to determine if the chair-stand test is an independent predictor of mortality and hospitalization in cirrhosis. Methods: A retrospective review of 787 patients with cirrhosis was conducted. Chair-stand times were collected at baseline in person and divided into three groups: <10 seconds (n = 276), 10-15 seconds (n = 290), and >15 seconds (n = 221). Fine-Gray proportional hazards regression models were used to evaluate the association between chair-stand times and the outcomes of mortality and non-elective hospitalization. Results: The hazard of mortality (HR 3.21, 95% CI 2.16%-4.78%, p <0.001) and non-elective hospitalization (HR 2.24, 95% CI 1.73%-2.91%, p <0.001) was increased in group 3 in comparison to group 1. A chair-stand test time >15 seconds had increased all-cause mortality (HR 2.78, 95% CI 2.01%-3.83%, p <0.001) and non-elective hospitalizations (HR 1.84, 95% CI 1.48%-2.29%, p <0.001) compared to <15 seconds. Conclusions: A chair-stand test time of >15 seconds is independently associated with mortality and non-elective hospitalizations. This test holds promise as a rapid prognostication tool in cirrhosis. Future work will include external validation and virtual assessment in this population.

Anxiety in cirrhosis: a prospective study on prevalence and development of a practical screening nomogram.

OBJECTIVES: The prevalence and effects of anxiety on health-related quality of life and clinical outcomes in cirrhosis are not well understood. This is increasingly relevant during COVID-19. Our aim was to use the Mini-International Neuropsychiatric Interview (MINI) to determine the prevalence of anxiety, its association with clinical outcomes in cirrhosis and to develop a rapid cirrhosis-specific anxiety screening nomogram. METHODS: Adults with a diagnosis of cirrhosis were prospectively recruited as outpatients at three tertiary care hospitals across Alberta and followed for up to 6 months to determine the association with unplanned hospitalization/death. The Hospital Anxiety and Depression scale (HADS) was used as a screening tool as it is free of influence from somatic symptoms. Anxiety was diagnosed using the MINI. RESULTS: Of 304 patients, 17% of patients had anxiety by the MINI and 32% by the HADS. Anxious patients had lower health-related quality of life as assessed by the chronic liver disease questionnaire (P < 0.001) and EuroQol Visual Analogue Scale (P < 0.001), and also had higher levels of frailty using the Clinical Frailty score (P = 0.004). Multivariable analysis revealed smoking and three HADS subcomponents as independent predictors of anxiety. These were used to develop a rapid screening nomogram. CONCLUSION: A formal diagnosis of anxiety was made in approximately one in five patients with cirrhosis, and it was associated with worse HrQoL and frailty. The use of a 4-question nonsomatic symptom-based nomogram requires validation but is promising as a rapid screen for anxiety in cirrhosis.

Serum IgG4 cut-off of 70 mg/dL is associated with a shorter time to cirrhosis decompensation and liver transplantation in primary sclerosing cholangitis patients.

BACKGROUND: Primary sclerosing cholangitis (PSC) is an immune-mediated biliary disorder of unknown etiology with no effective treatment. The purpose of this study was to better prognosticate the development of cirrhosis, decompensation, and requirement for liver transplantation (LT) in PSC patients based on serum immunoglobulin G4 (IgG4) levels. METHODS: A retrospective chart review was conducted on PSC patients seen at the University of Alberta Hospital between 2002 and 2017. PSC patients were categorized as high IgG4 group (≥70 mg/dL) or normal IgG4 group (<70 mg/dL). Laboratory parameters, clinical characteristics, and outcomes were compared between the groups. RESULTS: One hundred and ten patients were followed over a mean period of 7.3 (SD 5) years. Seventy-two patients (66%) were male, the mean age at diagnosis of PSC was 35 (SD 15) years, and inflammatory bowel disease (IBD) was present in 80 patients (73%). High IgG4 levels were found in 37 patients (34%). PSC patients with high IgG4 had a shorter mean cholangitis-free survival time (5.3 versus 10.4 years, p = 0.02), cirrhosis-free survival time (8.7 versus 13.0 years, p = 0.02), and LT-free survival time (9.3 years versus 18.9 years, p <0.001). IgG4 ≥70 mg/dL was independently associated with liver decompensation and LT-free outcomes. A cut-off IgG4 value of ≥70 mg/dL performed better than a cut-off value of ≥140 mg/dL to predict time to LT (area under the curve [AUC] 0.68, p = 0.03, sensitivity 72%, specificity 78%). CONCLUSIONS: Serum IgG4 ≥70 mg/dL in PSC predicts a shorter time to cirrhosis decompensation and LT.

A randomized controlled trial of a multicomponent online stress reduction intervention in inflammatory bowel disease.

Background: Psychological stress negatively impacts inflammatory bowel disease (IBD) outcomes. Patients have prioritized access to online interventions; yet, the data on these have been limited by mixed in-person/online interventions, low adherence, and non-randomized controlled trial (RCT) design. Objectives: We assessed the efficacy of and adherence to a 12-week online multicomponent stress reduction intervention in IBD. Design: This is a RCT. Methods: Adult participants on stable IBD medical therapy with elevated stress levels from four centers were randomized to intervention or control groups. Intervention participants received a 12-week online program including a weekly yoga, breathwork and meditation video (target 2-3 times/week), a weekly cognitive behavioral therapy/positive psychology informed video activity, and weekly 10-min check-ins by a study team member. Control participants received weekly motivational messages by email. All patients received standard of care IBD therapy. The primary outcome was Cohen's Perceived Stress Scale (PSS). Secondary outcomes evaluated mental health, resilience, health-related quality of life (HRQoL), symptom indices, acceptability, adherence, and inflammatory biomarkers. Analysis of covariance was used to determine between-group differences. Results: Of 150 screened patients, 101 were randomized to the intervention (n = 49) and control (n = 52) groups (mean age: 42.5 ± 14.1 years; M:F 1:3, 48% with ulcerative colitis and 52% with Crohn's disease). The between-group PSS improved by 22.4% (95% confidence interval, 10.5-34.3, p < 0.001). Significant improvements were seen in mental health, resilience, and HRQoL measures, with a median satisfaction score of 89/100 at the end of the 12 weeks. In the 44/49 patients who completed the intervention, 91% achieved program adherence targets. Conclusion: This 12-week online intervention improved perceived stress, mental health, and HRQoL, but did not impact IBD symptom indices or inflammatory biomarkers. The program was readily adopted and adhered to by participants with high retention rates. After iterative refinement based on participant feedback, future studies will evaluate the impact of a longer/more intense intervention on disease course. Registration: ClinicalTrials.gov Identifier NCT03831750. Plain Language Summary: An online stress reduction intervention in inflammatory bowel disease patients improves stress, mental health, and quality of life People with inflammatory bowel disease (IBD) have high levels of stress, anxiety, and depression. Although IBD patients have expressed the need for online mental wellness interventions, the existing data to support these interventions in IBD are limited. In this trial, 101 IBD patients had the chance to participate in a 12-week online stress reduction intervention. In those patients randomly selected to participate in the online intervention, each week they received the following: a 20- to 30-min yoga, breathwork, and meditation video that they were asked to do 2-3 times a week, a 10- to 20-min mental wellness activity they were asked to do once during the week, and a 10-min telephone check-in with a study team member. Participants who were not selected to use the online intervention received a weekly motivational message by email. In all, 90 of the 101 participants (89%) completed the study with the mean age of participants being 43 years and the majority being females (75%). Ninety-one percent of participants who completed the intervention met the program target of doing the yoga, breathwork, and meditation video at least 2 times per week. Significant improvements were seen in perceived stress (by 22.4%), depression (by 29.5%), anxiety (by 23.7%), resilience (by 10.6%), and quality of life (by 8.9%). No changes were seen in IBD severity or in blood markers of inflammation. In conclusion, this study demonstrates evidence that a 12-week online stress reduction intervention had low dropout rates, high adherence and beneficial effects on stress, mental health, and quality of life measures. Continued feedback will be sought from study participants and our IBD patient partners to refine the intervention and assess the impact in future studies of patients with active IBD, as well as the impact of a longer/more intense intervention.

Depression in cirrhosis - a prospective evaluation of the prevalence, predictors and development of a screening nomogram.

BACKGROUND: Depression is associated with substantial morbidity and mortality in cirrhosis, but is underdiagnosed and undertreated. AIMS: Using the Mini International Neuropsychiatric Interview (MINI) as a gold-standard, to determine prevalence, predictors, and outcomes of depression, and to develop a screening nomogram for use in cirrhosis patients. METHODS: Cirrhotic outpatients 18-80 years of age, not on anti-depressants, were consecutively recruited from liver clinics at three tertiary care hospitals. Baseline health-related quality of life (HRQoL) and frailty were determined by the chronic liver disease questionnaire, EQ-VAS, Clinical Frailty Scale and Fried Frailty Criteria. Depression was identified using the MINI and participants were followed up to 6 months to determine unplanned hospitalization/death. RESULTS: Of 305 patients, 62% were male; mean age 55(10) years; mean MELD 12.5(5), 61% Child Pugh B/C. Prevalence of depression 18% by MINI. Patients with depression had lower baseline HRQoL and higher frailty scores. Five independently predictive factors were used to develop a clinical nomogram for the diagnosis of clinical depression. These included three Hospital Anxiety and Depression Screening tool variables: "I have lost interest in my appearance" (adjusted odds ratio [aOR] 2.2, P = 0.006), "I look forward with enjoyment to things" (aOR 2.0, P = 0.02), "I feel cheerful" (aOR 2.8, P = 0.002), and two demographic variables: younger age (aOR 0.92, P = 0.001) and not being married or in a common-law relationship (aOR 0.30, P = 0.008). CONCLUSIONS: Depression is common in patients with cirrhosis. It has a significant impact on HRQoL and functional status. The developed clinical nomogram is promising for the rapid screening of depression in patients with cirrhosis.

Epidemiologic and clinical features of chronic hepatitis B virus infection in 8 Canadian provinces: a descriptive study by the Canadian HBV Network.

BACKGROUND: Published Canadian epidemiologic data on hepatitis B virus (HBV) infection include single-centre studies or are focused on Indigenous populations. We performed a study to characterize the demographic and clinical features, liver disease status and treatment of people with chronic hepatitis B in Canada. METHODS: In this descriptive, opportunistic, cross-sectional study, available data for people known to be monoinfected with HBV were collected by the Canadian HBV Network from existing clinical databases, with support from the National Microbiology Laboratory, Public Health Agency of Canada. Data were collected in all provinces with the exception of New Brunswick and Newfoundland and Labrador. We analyzed the data using parametric and nonparametric statistical methods, with a significance level of p < 0.05. RESULTS: In the 9380 unique patient records reviewed, the median age was 48 years, and 5193 patients (55.4%) were male. Ethnicity information was available for 7858 patients, of whom 5803 (73.8%) were Asian, 916 (11.6%) were black and 914 (11.6%) were white. Most of those tested (5556/6796 [81.8%]) were negative for HBV e-antigen, and most of those with fibrosis data (3481/4260 [81.7%]) had minimal liver fibrosis, with more advanced fibrosis noted in older people (> 40 yr). Of the 980 patients with genotype data, 521 (53.2%) had genotype B or C infection. Most of the 9241 patients with known confirmed treatment status received tenofovir disoproxil fumarate (1655 [17.9%]), lamivudine (1434 [15.5%]) or entecavir (548 [5.9%]). INTERPRETATION: Based on available data, Canadian patients with chronic hepatitis B are predominantly Asian and negative for HBV e-antigen, and have genotype B or C infection. Interprovincial variations were noted in antiviral treatment regimen. This multicentre nationwide study provides data regarding patients with chronic hepatitis B and may inform future studies on the epidemiologic features of HBV infection in Canada.

Safety and antiviral activity of albinterferon alfa-2b dosed every four weeks in genotype 2/3 chronic hepatitis C patients.

BACKGROUND & AIMS: A phase 2, randomized, multicenter, open-label study evaluated the safety and efficacy of albinterferon alfa-2b in interferon-alpha treatment-naïve patients with genotype 2/3, chronic hepatitis C virus infection. METHODS: Forty-three patients were randomly assigned in a 1:1 ratio to receive subcutaneous albinterferon alfa-2b 1500 microg every 4 weeks (q4wk) or every 2 weeks (q2wk) with oral ribavirin 800 mg/day for 24 weeks. Primary efficacy end point was sustained virologic response (undetectable hepatitis C virus RNA 24 weeks after completion of treatment). Insulin resistance was also assessed. RESULTS: The safety of albinterferon alfa-2b was acceptable, with a similar adverse event profile in both treatment arms. Discontinuation as a result of adverse events occurred in 4.5% and 14.3% of patients in the q4wk and q2wk arms, respectively. No dose reductions caused by adverse events were reported in the q4wk arm versus 9.5% in the q2wk arm. Rapid viral response rates at week 4 were 68.2% and 76.2% for the q4wk and q2wk arms, respectively; the corresponding sustained virologic response rates were 77.3% and 61.9%. Insulin resistance at baseline was significantly associated with lower sustained virologic response rates independent of body mass index. CONCLUSIONS: Albinterferon alfa-2b administered at 4-week intervals was safe and well-tolerated and demonstrated significant antiviral activity in patients with genotype 2/3, chronic hepatitis C virus. Insulin resistance appeared to have an independent effect on treatment response.

Relative contribution of direct and indirect allorecognition in developing tolerance after liver transplantation.

The interaction of donor passenger leukocytes and host leukocytes in recipient secondary lymphoid tissues during the early posttransplantation period is crucial in directing host immune reactions toward allograft rejection or acceptance. Responsible T cell clones could be activated through the direct and indirect pathways of allorecognition. We examined the role of the indirect pathway in liver transplantation (LT) tolerance by depleting host antigen-presenting cells (APC) with phagocytic activity [e.g., cluster domain (CD)68+/CD163+ macrophages, CD11c+ dendritic cells (DC)] using liposome-encapsulating clodronate (LP-CL). After Lewis rat cell or liver graft transplantation, Brown Norway (BN) rat recipients pretreated with LP-CL showed a significantly reduced type 1 helper T cell cytokine up-regulation than control-LP-treated recipients. In the LT model, LP-CL treatment and host APC depletion abrogated hepatic tolerance; Lewis liver grafts in LP-CL-treated-BN recipients developed mild allograft rejection, failed to maintain donor major histocompatibility complex (MHC) class II+ leukocytes, and developed chronic rejection in challenged donor heart allografts, while control-LP-treated BN recipients maintained tolerance status and donor MHC class II+ hepatic leukocytes. Furthermore, in the BN to Lewis LT model, LP-CL recipient treatment abrogated spontaneous hepatic allograft acceptance, and graft survival rate was reduced to 43% from 100% in the control-LP group. In conclusion, the study suggests that host cells with phagocytic activity could play significant roles in developing LT tolerance.

Outcomes of peginterferon alpha-2a and ribavirin hepatitis C therapy in Aboriginal Canadians.

BACKGROUND: There is little published information on baseline characteristics and therapeutic outcomes in hepatitis C virus (HCV)-infected Aboriginal Canadians. It is unclear what proportion of HCV-infected Aboriginal people receive therapy relative to other populations. METHODS: Adults with chronic HCV infection, quantifiable serum HCV-RNA levels and compensated liver disease were assigned, at the physician's discretion, to either 24 or 48 weeks of treatment with peginterferon alpha-2a 180 mug/week plus ribavirin at a dose of 800 mg/day, or 1000 mg/day or 1200 mg/day in an open-label, expanded access program. The primary outcome was sustained virological response, defined as undetectable HCV-RNA by qualitative polymerase chain reaction (less than 50 IU/mL) at the end of 24 weeks of untreated follow-up. Baseline characteristics and outcomes in Aboriginal and non-Aboriginal patients were compared. RESULTS: A total of 2614 patients were eligible for the analysis; 44 individuals (1.7%) self-identified as being of Aboriginal heritage. The baseline characteristics of these two groups were similar. An overall sustained virological response was achieved in 47.7% and 46.5% of Aboriginal and non-Aboriginal patients, respectively. The overall frequencies of adverse events and laboratory abnormalities were similar between the two groups, although cytopenias occurred less frequently in Aboriginal patients. INTERPRETATION: Aboriginal patients were greatly under-represented in the present 'community'-based treatment program, yet viral responses were similar to those of a non-Aboriginal cohort. To increase the uptake of HCV therapy in the Aboriginal population, clarification of the obstacles to treatment is warranted.

Helicobacter pylori infection in Canada's arctic: searching for the solutions.

The Canadian North Helicobacter pylori (CANHelp) working group is a team composed of investigators, health officials and community leaders from Alberta and the Northwest Territories. The group's initial goals are to investigate the impact of H pylori infection on Canada's Arctic communities; subsequent goals include identifying treatment strategies that are effective in this region and developing recommendations for health policy aimed at management of H pylori infection. The team's investigations have begun with the Aklavik H pylori Project in the Aboriginal community of Aklavik, Northwest Territories.

Home Exercise Training Improves Exercise Capacity in Cirrhosis Patients: Role of Exercise Adherence.

Cirrhosis patients have reduced peak aerobic power (peak VO2) that is associated with reduced survival. Supervised exercise training increases exercise tolerance. The effect of home-based exercise training (HET) in cirrhosis is unknown. The objective was to evaluate the safety and efficacy of 8 weeks of HET on peak VO2, 6-minute walk distance (6MWD), muscle mass, and quality of life in cirrhosis. Random assignment to 8 weeks of HET (moderate to high intensity cycling exercise, 3 days/week) or usual care. Exercise adherence defined as completing ≥80% training sessions. Paired t-tests and analysis of covariance used for comparisons. Forty patients enrolled: 58% male, mean age 57 y, 70% Child Pugh-A. Between group increases in peak VO2 (1.7, 95% CI: -0.33 to 3.7 ml/kg/min, p = 0.09) and 6MWD (33.7, 95% CI: 5.1 to 62.4 m, p = 0.02) were greater after HET versus usual care. Improvements even more marked in adherent subjects for peak VO2 (2.8, 95% CI: 0.5-5.2 mL/kg/min, p = 0.02) and 6MWD (46.4, 95% CI: 12.4-80.5 m, p = 0.009). No adverse events occurred during testing or HET. Eight weeks of HET is a safe and effective intervention to improve exercise capacity in cirrhosis, with maximal benefits occurring in those who complete ≥80% of the program.

Patient-perceived barriers to lifestyle interventions in cirrhosis.

BACKGROUND/AIMS: Sarcopenia, muscle weakness, and physical frailty are independent predictors of mortality in cirrhosis. These adverse prognostic factors are potentially modifiable with lifestyle interventions, including adequate nutritional intake and physical activity. Our aim was to identify patient-perceived barriers and enablers to these interventions. PATIENTS AND METHODS: Adult patients with cirrhosis were prospectively recruited from two tertiary care liver clinics. Patients were excluded if they had hepatocellular carcinoma beyond transplant criteria, other active malignancy, or advanced chronic disease. RESULTS: A total of 127 patients (mean age: 60 ± 9 years, 58% males, and 48% with Child-Pugh-B/C (CP-B/C) disease) were included. Two-thirds of the patients had cirrhosis related to alcohol or hepatitis C. CP-B/C patients were more likely to take oral nutritional supplements (56% vs 29%) and less likely to consume animal protein daily (66% vs 85%) when compared to CP-A patients. Early satiety, altered taste, and difficulty in buying/preparing meals were more common in CP-B/C patients and even present in 20-30% of CP-A patients. Most patients reported adequate funds to purchase food. As quantified by the International Physical Activity Questionnaire-Short Form, 47% reported low activity levels, with no significant differences between groups. CP-B/C patients were more fatigued with exercise, however, overall Exercise Benefits/Barriers Scale scores were similar across groups. CONCLUSIONS: Barriers to nutritional intake and physical activity are common in cirrhosis and should be evaluated and treated in all patients. Asking simple screening questions in clinic and referring at-risk patients to expert multidisciplinary providers is a reasonable strategy to address these barriers. Future research should evaluate techniques to overcome modifiable barriers and enhance enablers.

The Effect of Bariatric Surgery on the Spectrum of Fatty Liver Disease.

Nonalcoholic fatty liver disease is becoming one of the most common causes of liver disease in the western world. The most significant risk factors are obesity and the metabolic syndrome for which bariatric surgery has been shown to be an effective treatment. However, the effects of bariatric surgery on nonalcoholic fatty liver disease, specifically liver fibrosis and cirrhosis, are not well established. We review published bariatric surgery outcomes with respect to nonalcoholic liver disease. On the basis of this review we suggest that bariatric surgery may provide a viable treatment option for the treatment of nonalcoholic fatty liver disease, including patients with fibrosis and compensated cirrhosis, and that this topic should be a target of future investigation.

Thiopurine methyltransferase enzyme activity determination before treatment of inflammatory bowel disease with azathioprine: effect on cost and adverse events.

BACKGROUND: Azathioprine (AZA), used to treat inflammatory bowel disease (IBD), is metabolized by thiopurine methyltransferase (TPMT). The accumulation of individual metabolites varies because humans display genetic polymorphism for TPMT expression. Deficiencies in TPMT result in accumulation of toxic metabolites, followed by neutropenia and hepatic inflammation. Concern over acute toxicity frequently leads to under dosing and frequent monitoring tests and visits. OBJECTIVE: To determine whether assessment of TPMT activity before the administration of AZA would predict acute toxicity and, thus, allow for reductions in health care costs related to biochemical screening for, and management of, AZA-induced adverse events. METHODS: Before AZA treatment, 29 patients with IBD were prospectively randomized to one of two groups: group 1, in which no TPMT assay was performed, was started on AZA at 1 mg/kg/day and then titrated every two weeks to a target dose of 2.5 mg/kg/day; and group 2, in which TPMT assays were performed, was started on AZA at the target dose of 2.5 mg/kg/day. For both groups, complete blood count and liver enzymes were monitored weekly for six weeks and at monthly intervals thereafter. Additional tests and health care interventions were undertaken at the discretion of the attending physicians. RESULTS: Of the 29 patients in the study, 15 were randomly assigned to group 1 and 14 to group 2. Demographics and disease activity were similar for both groups. Mean follow-up time was 7.1 months (range 3.5 to 10.7 months). Eight patients from group 1 and six patients from group 2 withdrew as a result of AZA-induced adverse events. There was no correlation between the TPMT activity and the development of AZA-induced adverse events. The direct health care costs for group 1 (300.11 dollars per patient) were lower than in group 2 (348.87 dollars per patient). CONCLUSION: The prospective assessment of TPMT enzyme activity before initiating AZA therapy in IBD patients incurred additional cost and did not predict AZA-induced toxicity.