Evidence related to a vegetarian diet and metabolic dysfunction-associated steatotic liver disease: protocol for a scoping review.

INTRODUCTION: Metabolic dysfunction-associated fatty liver disease (MASLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease worldwide. Given that there is no pharmacological treatment for MASLD, it is imperative to understand whether lifestyle modifications may improve biochemical and pathological outcomes. One commonly proposed dietary modification is the Mediterranean diet; however, vegetarianism may also be a promising intervention. Vegetarianism has been shown to be associated with reduced morbidity and mortality in metabolic syndrome outcomes in coronary artery disease and diabetes; however, the relationship between vegetarian diet and MASLD is less clear. In this scoping review, we will provide a comprehensive overview of the current body of evidence related to a vegetarian diet and MASLD. METHODS AND ANALYSIS: The aim of this scoping review is to describe and summarise the current body of evidence related to MASLD and a vegetarian diet. This review will be conducted using Arksey and O'Malley's framework. The literature review will be conducted using the following databases: SCOPUS, Web of Science, CINAHL-Plus, Cochrane Library and Medline. No restriction will be made on publication date. Included studies will encompass clinical trials and observational designs that examine effects or association of vegetarian diet in adults (≥16 years) and report on the incidence, prevalence or progression of MASLD. Grey literature, non-human studies and articles focusing on changes in a specific food or nutraceutical will be excluded. Articles must have an English-language abstract available to be considered for inclusion. Screening and data extraction will be conducted by two independent reviewers. The findings will be summarised with descriptive statistics. ETHICS AND DISSEMINATION: Approval from a medical ethics committee is not required for this review. Once the review is complete, the findings will be submitted to a peer-reviewed journal.

Nonresolving Axillary Lymphadenopathy: An Unexpected Case of Metastatic Jejunal Adenocarcinoma in a Small-Bowel Transplant Recipient Masquerading as Posttransplant Lymphoproliferative Disorder.

Intestinal transplant is an uncommon treatment of intestinal failure that has provided many patients with reduced morbidity and mortality. However, there are associated risks, including an increased risk of cancer, such as posttransplant lymphoproliferative disorder and solid-organ malignancy. Here, we report a unique case of primary jejunal adenocarcinoma presenting initially only with axillary lymphadenopathy in a patient with recurrent posttransplant lymphoproliferative disorder after multiple solid-organ transplants, including small intestine and 2 renal transplants.

Isolated Hepatic Chronic Ductopenic Rejection Requiring Liver Retransplant in the Absence of Kidney Graft Rejection After Combined Liver-Kidney Transplant: A Case Report.

The liver is considered the most immunotolerant organ among all solid-organ transplants. Liver transplant recipients have a lower incidence of rejection and better outcomes after episodes of rejection, with spontaneous operational tolerance developing in up to 20%. In multiorgan transplants, a protective effect of the liver allograft on simultaneously transplanted organs from the same donor has been demonstrated. We describe an unusual case of isolated liver allograft rejection in a patient with polycystic liver and kidney disease who received a combined liver-kidney transplant from the same donor. After initial discharge from the hospital, our patient had 2 episodes of biopsy-proven late acute cellular rejections, despite higher levels of immunosuppression required for her kidney allograft, which were addressed with pulsed steroid therapy. She had no evidence of ischemic cholangiopathy on imaging. Later, a subsequent liver biopsy demonstrated features consistent with chronic ductopenic rejection. She was eventually listed for liver retransplant and has recently received a second liver transplant while continuing to have no concerns with her kidney allograft function. Examination of the explanted liver confirmed graft loss from chronic ductopenic rejection. The exact reasons why our patient developed acute graft rejection progressing to chronic end-stage rejection of the liver allograft despite not developing graft rejection in the kidney allograft from the same donor remains elusive. Our experience demonstrates that graft tolerance in multiorgan transplant recipients can be organ specific and despite the belief of "immunologic privilege," isolated liver allograft rejection can occur in multiorgan transplant, resulting in graft loss.

Liver biochemical flare with immune checkpoint therapy in metastatic Merkel cell carcinoma: A liver biopsy is always necessary.

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine carcinoma of the skin. Treatment for locoregional MCC includes local excision with regional lymphadenectomy, followed by adjuvant radiotherapy. Immune checkpoint inhibitors (ICI) have emerged as a breakthrough treatment of metastatic MCC. Nevertheless, T-cell immune response is triggered against self-antigens resulting in immune-mediated toxicities, including ICI-mediated hepatotoxicity. We report a case of recurrent metastatic MCC treated with avelumab, a PD-L1 inhibitor, with subsequent significant liver biochemical flare. The initial clinical diagnosis was ICI-mediated hepatotoxicity. Workup to rule out competing causes of liver injury came back negative. Hence, avelumab was discontinued, and the patient was initiated on steroid therapy with stepwise escalation. Owing to clinical and laboratory deterioration, it was then decided to perform a percutaneous liver biopsy to document steroid-refractory ICI-mediated hepatotoxicity and/or rule out other causes of potential liver injury. The liver biopsy showed MCC tumor cells almost entirely infiltrating the hepatic parenchyma, confirmed by immunohistochemistry. At that point, steroid therapy was discontinued, and the patient was transitioned into palliative care. In conclusion, patients with apparent ICI-related hepatotoxicity should always be considered for a liver biopsy to exclude massive infiltrative malignancy as the true cause of liver dysfunction.

Outcomes of liver transplant recipients with high MELD scores: an experience from a Canadian centre.

BACKGROUND: The frequency with which patients with high Model for End-Stage Liver Disease (MELD) scores undergo liver transplantation has been increasing. Canadian literature regarding the outcomes of liver transplantation in recipients with high MELD scores is limited. The primary objective of this study was to assess patient and graft survival among recipients with high (> 35) and low (≤ 35) MELD scores. Secondary objectives were to potentially identify independent predictors of graft failure and patient mortality. METHODS: We conducted a retrospective chart review of patients undergoing liver transplantation at a single Canadian centre from 2012 to 2017. RESULTS: A total of 332 patients were included in the study: 280 patients had a MELD score of 35 or lower, and 52 had a MELD score above 35. Patients with high MELD scores had higher rates of pretransplant acute kidney injury and dialysis (p < 0.001), admission to the intensive care unit (ICU) or intubation (p < 0.001), intraoperative blood product transfusions (p < 0.001) and post-transplantation acute kidney injury and dialysis (p < 0.001), as well as longer ICU (p < 0.001) and hospital stays (p = 0.002). One- and 3-year patient survival in recipients with MELD scores of 35 or lower was 93.1% and 84.9% versus 85.0% and 80.0% in recipients with MELD scores above 35 (p = 0.37). One- and 3-year graft survival in recipients with MELD scores of 35 or lower was 91.7% and 90.9% versus 77.2% and 72.8% in recipients with MELD scores above 35 (p < 0.001). Prior liver transplant was an independent predictor of patient mortality, and no independent predictors of graft failure were identified. When MELD was replaced with D-MELD (donor age × recipient MELD), it predicted graft failure but not patient survival. CONCLUSION: No difference in patient mortality was found between MELD groups. Graft survival was significantly lower in recipients with MELD scores above 35. D-MELD may potentially be used as an adjunct in determining risk of graft failure in recipients with high MELD scores.

Reduced immune responses to hepatitis B primary vaccination in obese individuals with nonalcoholic fatty liver disease (NAFLD).

Obesity and cirrhosis are associated with poor hepatitis B virus (HBV) vaccine responses, but vaccine efficacy has not been assessed in nonalcoholic fatty liver disease (NAFLD). Sixty-eight HBV-naïve adults with NAFLD were enrolled through the Canadian HBV network and completed three-dose HBV or HBV/HAV vaccine (Engerix-B®, or Twinrix®, GlaxoSmithKline). Anti-HBs titers were measured at 1-3 months post third dose. In 31/68 subjects enrolled at the coordinating-site, T-cell proliferation and follicular T-helper cells (pTFH) were assessed using PBMC. Immune response was also studied in NAFLD mice. NAFLD patients were stratified as low-risk-obesity, BMI < 35 (N = 40) vs. medium-high-risk obesity, BMI > 35 (N = 28). Anti-HBs titers were lower in medium/high-risk obesity, 385 IU/L ± 79 vs. low-risk obesity class, 642 IU/L ± 68.2, p = 0.02. High-risk obesity cases, N = 14 showed lower vaccine-specific-CD3+ CD4+ T-cell response compared to low-risk obesity patients, N = 17, p = 0.02. Low vaccine responders showed dysfunctional pTFH. NAFLD mice showed lower anti-HBs levels and T-cell response vs. controls. In conclusion, we report here that obese individuals with NAFLD exhibit decreased HBV vaccine-specific immune responses.

Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial.

BACKGROUND AND AIMS: We evaluated the safety and efficacy of cilofexor (formerly GS-9674), a small-molecule nonsteroidal agonist of farnesoid X receptor, in patients with nonalcoholic steatohepatitis (NASH). APPROACH AND RESULTS: In this double-blind, placebo-controlled, phase 2 trial, 140 patients with noncirrhotic NASH, diagnosed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥8% and liver stiffness ≥2.5 kPa by magnetic resonance elastography (MRE) or historical liver biopsy, were randomized to receive cilofexor 100 mg (n = 56), 30 mg (n = 56), or placebo (n = 28) orally once daily for 24 weeks. MRI-PDFF, liver stiffness by MRE and transient elastography, and serum markers of fibrosis were measured at baseline and week 24. At baseline, median MRI-PDFF was 16.3% and MRE-stiffness was 3.27 kPa. At week 24, patients receiving cilofexor 100 mg had a median relative decrease in MRI-PDFF of -22.7%, compared with an increase of 1.9% in those receiving placebo (P = 0.003); the 30-mg group had a relative decrease of -1.8% (P = 0.17 vs. placebo). Declines in MRI-PDFF of ≥30% were experienced by 39% of patients receiving cilofexor 100 mg (P = 0.011 vs. placebo), 14% of those receiving cilofexor 30 mg (P = 0.87 vs. placebo), and 13% of those receiving placebo. Serum gamma-glutamyltransferase, C4, and primary bile acids decreased significantly at week 24 in both cilofexor treatment groups, whereas significant changes in Enhanced Liver Fibrosis scores and liver stiffness were not observed. Cilofexor was generally well-tolerated. Moderate to severe pruritus was more common in patients receiving cilofexor 100 mg (14%) than in those receiving cilofexor 30 mg (4%) and placebo (4%). CONCLUSIONS: Cilofexor for 24 weeks was well-tolerated and provided significant reductions in hepatic steatosis, liver biochemistry, and serum bile acids in patients with NASH. ClinicalTrials.gov No. NCT02854605.

An update from the Canadian Association for the Study of the Liver on the management of liver disease during the COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) has challenged how care is delivered to patients with chronic liver disease (CLD). In an attempt to update Canadian health care practitioners taking care of individuals with CLD, the Canadian Association for the Study of the Liver (CASL) hosted a webinar on May 7, 2020, with more than 120 participants. The resultant article is a partnership between members of CASL's executive and education committees to provide best practice management principles on liver disease during COVID-19 to the broader hepatology community.

Acoustic Radiation Force Impulse and Conventional Ultrasound in the Prediction of Cirrhosis Complicating Fatty Liver: Does Body Mass Index Independently Alter the Results?

We investigated whether ultrasound (US) could quantify steatosis and fibrosis in non-alcoholic fatty liver disease (NAFLD). Estimates of fat by gray-scale, hepatorenal index (HRI) and fibrosis by acoustic radiation force impulse (ARFI) were made using the interquartile range (IQR)/median for ARFI quality. Biopsy was the gold standard. US fat assessment correlated with histologic grade and predicted steatosis. HRI predicted steatosis but did not improve accuracy. ARFI of good quality was highly sensitive toward severe fibrosis. The median ARFI value depended linearly on body mass index (BMI). Poor quality ARFI data had higher histologic steatosis, leading to higher mean steatosis grades in rejected data (p = 0.018). The ARFI quality cut with IQR/median >0.15 or >0.3 excluded many more patients with severe steatosis versus normal, influenced by increasing BMI. By combining the baseline US with ARFI, patients can be concurrently diagnosed for steatosis and fibrosis, two of the key pathologies of NAFLD and non-alcoholic steatohepatitis (NASH). However, severe steatosis and high BMI may falsely alter ARFI results.

Review article: emerging role of the gut microbiome in the progression of nonalcoholic fatty liver disease and potential therapeutic implications.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a prevalent disorder associated with obesity and diabetes. Few treatment options are effective for patients with NAFLD, but connections between the gut microbiome and NAFLD and NAFLD-associated conditions suggest that modulation of the gut microbiota could be a novel therapeutic option. AIM: To examine the effect of the gut microbiota on pathophysiologic causes of NAFLD and assess the potential of microbiota-targeting therapies for NAFLD. METHODS: A PubMed search of the literature was performed; relevant articles were included. RESULTS: The composition of bacteria in the gastrointestinal tract can enhance fat deposition, modulate energy metabolism and alter inflammatory processes. Emerging evidence suggests a role for the gut microbiome in obesity and metabolic syndrome. NAFLD is often considered the hepatic manifestation of metabolic syndrome, and there has been tremendous progress in understanding the association of gut microbiome composition with NAFLD disease severity. We discuss the role of the gut microbiome in NAFLD pathophysiology and whether the microbiome composition can differentiate the two categories of NAFLD: nonalcoholic fatty liver (NAFL, the non-progressive form) vs nonalcoholic steatohepatitis (NASH, the progressive form). The association between gut microbiome and fibrosis progression in NAFLD is also discussed. Finally, we review whether modulation of the gut microbiome plays a role in improving treatment outcomes for patients with NAFLD. CONCLUSIONS: Multiple pathophysiologic pathways connect the gut microbiome with the pathophysiology of NAFLD. Therefore, therapeutics that effectively target the gut microbiome may be beneficial for the treatment of patients with NAFLD.

Histological improvement of non-alcoholic steatohepatitis with a prebiotic: a pilot clinical trial.

PURPOSE: In obesity and diabetes the liver is highly susceptible to abnormal uptake and storage of fat. In certain individuals hepatic steatosis predisposes to the development of non-alcoholic steatohepatitis (NASH), a disease marked by hepatic inflammation and fibrosis. Although the precise pathophysiology of NASH is unknown, it is believed that the gut microbiota-liver axis influences the development of this disease. With few treatment strategies available for NASH, exploration of gut microbiota-targeted interventions is warranted. We investigated the therapeutic potential of a prebiotic supplement to improve histological parameters of NASH. METHODS: In a placebo-controlled, randomized pilot trial, 14 individuals with liver-biopsy-confirmed NASH [non-alcoholic fatty liver activity score (NAS) ≥ 5] were randomized to receive oligofructose (8 g/day for 12 weeks followed by 16 g/day for 24 weeks) or isocaloric placebo for 9 months. The primary outcome measure was the change in liver biopsy NAS score and the secondary outcomes included changes in body weight, body composition, glucose tolerance, inflammatory markers, and gut microbiota. RESULTS: Independent of weight loss, oligofructose improved liver steatosis relative to placebo and improved overall NAS score (P = 0.016). Bifidobacterium was enhanced by oligofructose, whereas bacteria within Clostridium cluster XI and I were reduced with oligofructose (P < 0.05). There were no adverse side effects that deterred individuals from consuming oligofructose for treatment of this disease. CONCLUSIONS: Independent of other lifestyle changes, prebiotic supplementation reduced histologically-confirmed steatosis in patients with NASH. Larger follow-up studies are warranted. CLINICAL TRIAL: This trial was registered at Clinicaltrials.com as NCT03184376.

Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: Analysis of data from a phase II trial of selonsertib.

BACKGROUND & AIMS: Non-invasive tools for monitoring treatment response and disease progression in non-alcoholic steatohepatitis (NASH) are needed. Our objective was to evaluate the utility of magnetic resonance (MR)-based hepatic imaging measures for the assessment of liver histology in patients with NASH. METHODS: We analyzed data from patients with NASH and stage 2 or 3 fibrosis enrolled in a phase II study of selonsertib. Pre- and post-treatment assessments included centrally read MR elastography (MRE)-estimated liver stiffness, MR imaging-estimated proton density fat fraction (MRI-PDFF), and liver biopsies evaluated according to the NASH Clinical Research Network classification and the non-alcoholic fatty liver disease activity score (NAS). RESULTS: Among 54 patients with MRE and biopsies at baseline and week 24, 18 (33%) had fibrosis improvement (≥1-stage reduction) after undergoing 24 weeks of treatment with the study drug. The area under the receiver operating characteristic curve (AUROC) of MRE-stiffness to predict fibrosis improvement was 0.62 (95% CI 0.46-0.78) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRE had 67% sensitivity, 64% specificity, 48% positive predictive value, 79% negative predictive value. Among 65 patients with MRI-PDFF and biopsies at baseline and week 24, a ≥1-grade reduction in steatosis was observed in 18 (28%). The AUROC of MRI-PDFF to predict steatosis response was 0.70 (95% CI 0.57-0.83) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRI-PDFF had 89% sensitivity and 47% specificity, 39% positive predictive value, and 92% negative predictive value. CONCLUSIONS: These preliminary data support the further evaluation of MRE-stiffness and MRI-PDFF for the longitudinal assessment of histologic response in patients with NASH. LAY SUMMARY: Liver biopsy is a potentially painful and risky method to assess damage to the liver due to non-alcoholic steatohepatitis (NASH). We analyzed data from a clinical trial to determine if 2 methods of magnetic resonance imaging - 1 to measure liver fat and 1 to measure liver fibrosis (scarring) - could potentially replace liver biopsy in evaluating NASH-related liver injury. Both imaging methods were correlated with biopsy in showing the effects of NASH on the liver.

The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial.

Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastography, magnetic resonance imaging-estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography, collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusion: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatology 2018;67:549-559).

Association Between Obesity and Discordance in Fibrosis Stage Determination by Magnetic Resonance vs Transient Elastography in Patients With Nonalcoholic Liver Disease.

BACKGROUND & AIMS: Magnetic resonance elastography (MRE) and transient elastography (TE) are noninvasive techniques used to detect liver fibrosis in nonalcoholic fatty liver disease. MRE detects fibrosis more accurately than TE, but MRE is more expensive, and the concordance between MRE and TE have not been optimally assessed in obese patients. It is important to determine under which conditions TE and MRE produce the same readings, so that some patients can simply undergo TE evaluation to detect fibrosis. We aimed to assess the association between body mass index (BMI) and discordancy between MRE and TE findings, using liver biopsy as the reference, and validated our findings in a separate cohort. METHODS: We performed a cross-sectional study of 119 adults with nonalcoholic fatty liver disease who underwent MRE, TE with M and XL probe, and liver biopsy analysis from October 2011 through January 2017 (training cohort). MRE and TE results were considered to be concordant if they found patients to have the same stage fibrosis as liver biopsy analysis. We validated our findings in 75 adults with nonalcoholic fatty liver disease who underwent contemporaneous MRE, TE, and liver biopsy at a separate institution from March 2010 through May 2013. The primary outcome was rate of discordance between MRE and TE in determining stage of fibrosis (stage 2-4 vs 0-1). Secondary outcomes were the rate of discordance between MRE and TE in determining dichotomized stage of fibrosis (1-4 vs 0, 3-4 vs 0-2, and 4 vs 0-3). RESULTS: In the training cohort, there was 43.7% discordance in findings from MRE versus TE. BMI associated significantly with discordance in findings from MRE versus TE (odds ratio, 1.69; 95% confidence interval, 1.15-2.51; P = .008) after multivariable adjustment by age and sex. The findings were confirmed in the validation cohort: there was 45.3% discordance in findings from MRE versus TE. BMI again associated significantly with discordance in findings from MRE versus TE (odds ratio, 1.52; 95% confidence interval, 1.04-2.21; P = .029) after multivariable adjustment by age and sex. CONCLUSIONS: We identified and validated BMI as a factor significantly associated with discordance of findings from MRE versus TE in assessment of fibrosis stage. The degree of discordancy increases with BMI.

Hepatitis B virus testing and linkage to care in a Canadian urban tertiary referral centre: a retrospective cohort study.

BACKGROUND: Despite universal vaccination, chronic hepatitis B virus (HBV) infection remains a public health concern in North America owing to immigration. We aimed to characterize the number of people with a positive result of testing for HBV surface antigen (HBsAg) in Calgary, a large urban Canadian health care region, and to assess whether recommended laboratory tests and specialist consultation were done for those identified as HBsAg-positive. METHODS: Based on laboratory and Alberta Health Services administrative data, we identified all adults (age > 18 yr) with a positive HBsAg test result from Jan. 1 to Dec. 31, 2014 within the Calgary Zone. Demographic and relevant laboratory data were extracted within 6 months of a positive HBsAg test result, and referral to hepatology (2011-2014) was identified from data on referral to a centralized clinic. Parametric and nonparametric statistical methods were used for analyses. RESULTS: We identified 1214 HBsAg-positive people (584 women [48.1%]; median age 44 [interquartile range (IQR) 36-55] yr). A total of 1192 people (98.2%) had alanine aminotransferase testing (median level 23 [IQR 16-34] U/L; 117 [9.8%] with elevated levels), 682 (56.2%) had testing for HBV DNA (median level 2.8 [IQR 2.1-3.8] logIU/mL), 630 (51.9%) had HBV e antigen testing (negative result in 548 [87.0%]), and 145 (11.9%) had HBV e antibody testing (positive result in 111 [76.6%]). Overall, 144 people (11.9%) received anti-HBV treatment, and 390 (32.1%) were referred to a hepatologist. INTERPRETATION: Many HBsAg-positive people in Calgary did not receive the recommended laboratory assessments. The results highlight the necessity of continual public health efforts to screen for chronic HBV infection in Canada and to ensure adequate follow-up in order to reach the World Health Organization's goal of viral hepatitis elimination by 2030.

Cirrhotic cardiomyopathy: Implications for liver transplantation.

The majority of patients on a waiting list for liver transplantation have end-stage liver disease. Because of the marked peripheral vasodilatation of end-stage cirrhosis that masks a latent myocardial dysfunction, cardiac abnormalities in the resting state are usually subclinical and escape the attention of physicians. However, when challenged, the systolic and diastolic contractile responses are attenuated. In addition to these contractile abnormalities, morphological changes, such as enlargement or hypertrophy of cardiac chambers, and electrophysiological repolarization changes, including a prolonged QT interval, can be observed. The constellation of these cardiac abnormalities is termed cirrhotic cardiomyopathy. Liver transplantation induces significant cardiovascular stress. Clamping of the inferior vena cava and portal vein, hemorrhage and blood/volume infusion, and ischemia/reperfusion all cause hemodynamic fluctuation. The changing cardiac preload and afterload status increases the cardiac workload, and thus, the previously subclinical ventricular dysfunction may manifest as overt heart failure during the operative and perioperative periods. Cardiac dysfunction contributes to morbidity and mortality associated with liver transplantation. Cardiovascular events are the third leading cause of death in liver recipients. However, because liver transplantation is the only definitive treatment for end-stage liver failure and also appears to reverse cardiac abnormalities, it is important to understand the challenges of the heart in liver transplantation. This review focuses on cardiac status before, during, and after liver transplantation. Liver Transplantation 23 826-835 2017 AASLD.

Noninvasive Markers of Fibrosis and Inflammation in Nonalcoholic Fatty Liver Disease.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Nonalcoholic steatohepatitis (NASH) and fibrosis are associated with elevated morbidity and mortality, and a means of differentiating these diseases from simple steatosis (SS) is needed. Liver biopsy in all patients with NAFLD is not feasible, thus necessitating a noninvasive method for discerning the presence of inflammation and fibrosis. Of the various serum markers, cytokeratin-18 seems to best predict NASH, the NAFLD Fibrosis Score is most closely correlated with fibrosis, and transient elastography can be used for diagnosis of cirrhosis, or to exclude cirrhosis, although its utility is limited by obesity.

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.

Risk of Bacterial Infection in Patients With Cirrhosis and Acute Variceal Hemorrhage, Based on Child-Pugh Class, and Effects of Antibiotics.

BACKGROUND & AIMS: Antibiotics frequently are overused and are associated with serious adverse events in patients with cirrhosis. However, these drugs are recommended for all patients presenting with acute variceal hemorrhage (AVH). We investigated whether patients should be stratified for antibiotic prophylaxis based on Child-Pugh scores, to estimate risks of bacterial infection, rebleeding, and mortality, and whether antibiotics have equal effects on patients of all Child-Pugh classes. We performed a sensitivity analysis using model for end-stage liver disease (MELD) scores. METHODS: In a retrospective study, we analyzed data from 381 adult patients with cirrhosis and AVH (70% men; mean age, 56 y), admitted from 2000 through 2009 to 2 tertiary care hospitals in Edmonton, Alberta, Canada. We excluded patients with bacterial infection on the day of AVH. The association between antibiotic prophylaxis and outcomes was adjusted by liver disease severity and by a propensity score. RESULTS: The patients included in the study had mean MELD scores of 16, and 54% received antibiotic prophylaxis. Overall, antibiotic therapy was associated with lower risks of infection (adjusted odds ratio, 0.37; 95% confidence interval, 0.91-0.74) and mortality (adjusted odds ratio, 0.63; 95% confidence interval, 0.31-1.29). Among patients categorized as Child-Pugh class A given antibiotics, only 2% developed infections and the mortality rate was 0.4%. Among patients categorized as Child-Pugh class B given antibiotics, 6% developed infections, compared with 14% of patients who did not receive antibiotics; antibiotics did not affect mortality. Administration of antibiotics to patients categorized as Child-Pugh class C reduced infections and mortality by approximately 50%, compared with patients who did not receive antibiotics. MELD scores were not as useful as Child-Pugh class in identifying patients at risk for infection. CONCLUSIONS: Based on a retrospective analysis of patients with cirrhosis and AVH, those categorized as Child-Pugh class A had lower rates of bacterial infection and lower mortality rates in the absence of antibiotic prophylaxis than patients categorized as classes B or C. The recommendation for routine antibiotic prophylaxis for this subgroup requires further evaluation.