Patients with Nonalcoholic Steatohepatitis and Advanced Liver Disease Have the Lowest Cardiorespiratory Fitness.

BACKGROUND & AIMS: Cardiorespiratory fitness and liver fibrosis are independently associated with poor outcomes in patients with nonalcoholic steatohepatitis (NASH), however, conflicting reports exist about their relationship. We aimed to better characterize the relationship between cardiorespiratory fitness and liver histology in a cross-sectional study of patients with biopsy-proven NASH. METHODS: Participants aged 18-75 years completed VO2peak fitness assessment using symptom-limited graded exercise testing. Participants were compared by liver fibrosis stage and NAFLD Activity Score (NAS). Multivariable models were constructed to assess factors related to relative VO2peak, including liver fibrosis and NAS. RESULTS: Thirty-five participants with mean age 48 ± 12 years and body mass index 33.5 ± 7.6 kg/m2 were enrolled. Seventy-four percent of participants were female and 49% had diabetes. A dose-dependent relationship was found between relative VO2peak and liver fibrosis. Relative VO2peak was significantly lower in participants with advanced fibrosis (F3 disease- 15.7 ± 5.3 vs. ≤ F2 disease- 20.7 ± 5.9 mL/kg/min, p = 0.027). NAS > 5 was also associated with lower relative VO2peak (22.6 ± 5.7 vs. 16.5 ± 5.1 mL/kg/min, p = 0.012) compared to NAS ≤ 5. With multivariable modeling, advanced fibrosis remained independently predictive of relative VO2peak while NAS trended towards significance. DISCUSSION AND CONCLUSIONS: Advanced liver fibrosis is independently associated with cardiorespiratory fitness in patients with NASH. This may explain the incremental increase in mortality as liver fibrosis stage increases. Further research is needed to determine if exercise training can improve cardiorespiratory fitness across multiple stages of liver fibrosis and directly reduce morbidity and mortality in patients with NASH.

Change in MRI-PDFF and Histologic Response in Patients With Nonalcoholic Steatohepatitis: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Magnetic resonance imaging proton density fat fraction (MRI-PDFF) offers promise as a non-invasive biomarker of treatment response in early-phase nonalcoholic steatohepatitis (NASH) trials. We performed a systematic review to quantify the association between a ≥ 30% reduction in MRI-PDFF and histologic response in NASH. METHODS: We searched the Cochrane Library, Embase, Medline and trial registries through May 2020 for early-phase clinical trials that incorporated MRI-PDFF and examined histologic response following intervention in adults with NASH. Subjects were classified as MRI-PDFF responders (relative decline in liver fat ≥30%) or non-responders (relative decline in liver fat <30%). MRI-PDFF responders versus non-responders were compared. Primary outcome was histologic response defined as a 2-point improvement in NAFLD Activity Score with at least 1-point improvement in lobular inflammation or ballooning. Secondary outcome was NASH resolution. Proportions and random effects odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated. RESULTS: Seven studies met inclusion criteria, comprising 346 subjects (median age 51 years; 59% female; 46% with diabetes). MRI-PDFF responders were significantly more likely to have a histologic response (51% vs 14%, P < .001; OR 6.98, 95% CI 2.38-20.43, P < .001) and NASH resolution (41% vs 7%, P < .001; OR 5.45, 95% CI 1.53-19.46, P = .009) compared to non-responders. CONCLUSIONS: This meta-analysis demonstrates that a ≥30% relative decline in MRI-PDFF is associated with higher odds of histologic response and NASH resolution. These results support the use of MRI-PDFF in non-invasive monitoring of treatment response in early-phase NASH clinical trials and provide helpful data for sample-size estimation for histology-based assessment.

Clinical Cirrhosis Dilemmas: Survey of Practice from the 7th International Coagulation in Liver Disease Conference.

INTRODUCTION AND AIM: Hemostatic disorders in chronic liver disease and cirrhosis show continued expansion of research efforts. However, clinical decision making is often practiced on an individual patient level as consensus guidelines are lacking. We aimed to better assess individual day-to-day clinical practice through gauging clinicians' responses to common clinical scenarios. MATERIALS AND METHODS: A series of ten clinical scenarios (seven procedural coagulation and three thrombosis management) were posed to conference attendees utilizing real-time polling software (Poll Everywhere). Responses were binomial and were submitted as "Agree" or "Disagree." Results were displayed real time following a standardized response period and an open-forum discussion ensued between conference faculty and attendees following response submission. RESULTS: Twenty conference attendees participated in the clinical scenario plenary session. In general, agreement rates were high. All but one of the ten clinical scenarios had ≥ 70% agreement. Agreement was based both on procedural risk, with greatest agreement seen for low-risk procedures (80-93%), and on peri-procedural coagulation parameters of platelet count and fibrinogen level where > 50,000µ/L and 120 mg/dL were the most agreed upon thresholds, respectively. 75-95% agreement was reached when surveying the need for anticoagulation for mesenteric vein thrombosis in liver transplant candidates; slightly less (71%) agreement was found when deciding to proceed with anticoagulation in non-liver transplant candidates with mesenteric vein thrombosis. CONCLUSIONS: While large-scale, methodologically rigorous randomized controlled trials are lacking to guide clinical decision making in patients with coagulation disorders and chronic liver disease, consensus expert opinion regarding mitigating peri-procedural bleeding risk and treatment of thrombosis appears consistent and strong.

Liver transplant candidates have impaired quality of life across health domains as assessed by computerized testing.

INTRODUCTION AND OBJECTIVES: Liver transplantation candidates are among the most comorbid patients awaiting lifesaving intervention. Health related quality of life (HRQOL) measured by instruments that incorporate dynamic computerized adaptive testing, could improve their assessment. We aimed to determine the feasibility of administration of the Patient-Reported Outcomes Measurement Information System (PROMIS-CAT) in liver transplant candidates. MATERIALS AND METHODS: Liver transplantation candidates were prospectively enrolled following a review of their available medical history. Subjects were given a tablet computer (iPad) to access the pre-loaded PROMIS CAT. RESULTS: 109 candidates with mean age 55.6±8.6 years were enrolled in this pilot study. Mean MELD-Na score was 16.3±6.3; 92.6% had decompensated liver disease. Leading etiologies of cirrhosis included hepatitis C (34.8%), nonalcoholic steatohepatitis (25.7%) and alcohol (21.1%). Subjects with MELD-Na score>20 had the most significant impairment in HRQOL (anxiety/fear+5.9±2.7, p=0.0289, depression+5.1±2.5, p=0.0428, fatigue+4.3±2.6, p=0.0973) and physical impairment (-7.8±2.5, p=0.0022). Stage of cirrhosis and decompensated liver disease were predictive of impaired HRQOL but Child-Pugh Turcotte score was not. Hepatic encephalopathy was the strongest independent predictor of impaired HRQOL, with significant impairment across all domains of health. CONCLUSIONS: Liver transplant candidates have significantly impaired HRQOL across multiple domains of health as measured by PROMIS-CAT. HRQOL impairment parallels disease severity. Future study is needed to determine how best HRQOL could be systematically included in liver transplantation listing policy, especially in those candidates with hepatic encephalopathy.

Decreased portal vein velocity is predictive of the development of portal vein thrombosis: A matched case-control study.

BACKGROUND & AIMS: Portal vein thrombosis (PVT) in cirrhosis may lead to hepatic decompensation and increased mortality. We aimed to investigate if decreased portal vein (PV) velocity is associated with future PVT. METHODS: Data on adult patients with cirrhosis and PVT between January 1, 2005 and July 30, 2015 were obtained. Cases with PVT were matched by age, gender and Model for End-stage Liver Disease (MELD) score to corresponding controls without PVT. Cox proportional hazards models, receiver operator curves and Kaplan Meier curves were constructed. RESULTS: One hundred subjects (50 matched pairs) with mean age 53.8±13.1 y and MELD score 14.9±5.5 were included in our analysis. Sixty-four percent were male and 76% were Child-Turcotte-Pugh Class A or B. Baseline characteristics (prior to development of PVT) were similar, except for baseline PV velocity (16.9 cm/s, 95% CI 13.9-20.0 PVT vs 25.0, 95% CI 21.8-28.8 no PVT, P<.001). 30 PVT subjects had PV velocity <15 cm/s compared to five without PVT (P<.001). On adjusted multivariable analysis, PV velocity was the strongest independent risk factor predicting PVT development (HR 0.86, 95% CI 0.80-0.93). The predictive value for PVT development was greatest for flow <15 cm/s (c-statistic 0.77). PV velocity <15 cm/s had a highly significant association with future PVT (HR 6.00, 95% CI 2.20-16.40, P=<.001). CONCLUSIONS: Decreased PV velocity is associated with increased risk of future PVT. Patients with cirrhosis and decreased PV velocity are a high-risk subgroup that warrants further investigation with prospective study.

Predictors of Mortality in Cirrhosis Inpatients With Clostridium difficile Infection.

BACKGROUND: Clostridium difficile is a bacterial pathogen associated with significant morbidity and mortality in patients with cirrhosis. GOALS: Our primary aim is to identify variables that are predictive of poor outcomes in cirrhosis patients with C. difficile infection (CDI). We also aim to further characterize the risk factors for developing CDI and risk of mortality in this patient population. STUDY: A total of 200 subjects with a diagnosis of cirrhosis and CDI were matched to 200 cirrhosis inpatients without CDI. The groups were compared to evaluate variables associated with decreased survival for cirrhosis inpatients with CDI as well as risk factors for developing CDI. RESULTS: Cirrhosis patients with CDI were more frequently prescribed antibiotics during their hospitalization (P=0.002) and cared for in an intensive care unit (ICU) (P<0.001). Preadmission proton pump inhibitor and spontaneous bacterial peritonitis (SBP) prophylactic antibiotic use were not significantly different between the 2 cohorts. CDI subjects had an increased 30-day mortality (44% vs. 28.5%, P=0.034), however overall mortality was not significantly different (P=0.2). The multivariable logistic regression model demonstrated an increased 30-day and overall mortality in the CDI population was independently associated with albumin <3 g/dL and ICU admission. CONCLUSIONS: C. difficile infections are associated with a significant increase in 30-day mortality, but not overall mortality. Risk factors of ICU admission and antibiotic exposure were associated with the diagnosis of CDI in cirrhosis patients. Hypoalbuminemia and ICU admission were found to be strong predictors of increased mortality in cirrhosis patients with CDI.

Geographic variation in liver transplantation persists despite implementation of Share35.

AIM: Geographic disparities persist in the USA despite locoregional organ sharing policies. The impact of national organ sharing policies on waiting-list mortality on a regional basis remains unknown. METHODS: Data on all adult liver transplants between 1 February 2002 and 31 March 2015 were obtained from the United Network for Organ Sharing/Organ and Transplantation Network. Multivariable Cox proportional hazards models were constructed in a time-to-event analysis to estimate waiting-list mortality for the pre- and post-Share35 eras. RESULTS: In the analyzed time period, 134 247 patients were listed for transplantation and 54 510 received organs (42.8%). Listing volume increased following the introduction of the Share35 organ sharing policy (15 976 candidates pre- vs. 18 375 post) without significant regional changes as did the number of transplants (7210 pre- vs. 8224 post). Waiting-list mortality improved from 12.2% to 8.1% (P < 0.001). Adjusted waiting-list mortality ratios remained geographically disparate. Region 10 and region 11 had lower hazard ratios (HR) but still had increased mortality (1.46, 95% confidence interval [CI] 1.34-1.60, P < 0.001; and HR 1.49, 95% CI 1.37-1.62, P < 0.001, respectively). Regions 3 and 6 had increased HR with persistently elevated waiting-list mortality (1.79, 95% CI 1.66-1.93, P < 0.001; and HR 1.29, 95% CI 1.16-1.45, P < 0.001, respectively). Model for End-state Liver Disease (MELD) exception continued to propagate a survival benefit (HR 0.65, 95% CI 0.63-0.68, P < 0.001). CONCLUSIONS: Although overall waiting-list mortality has decreased, geographic disparities persist, but appear reduced despite broader sharing policies enacted by Share35. The advantage afforded by MELD exception, while still present, was diminished by Share35 as organs are being shifted to MELD >35 candidates. The disparities highlighted by our findings imply a need to review current allocation policies to best balance local, regional, and national transplant environments.

Editorial: Severe Acute Liver Injury: Cause Connects to Outcome.

Severe acute liver injury (ALI) is a common condition with little objective study of its natural history and outcomes. In this paper by Koch et al. and the Acute Liver Failure (ALF) Study Group, the authors utilize a consensus definition of ALI requiring newly elevated bilirubin, alanine aminotransferase (ALT), and international normalized ration (INR) without evidence of hepatic encephalopathy (HE), with HE as the key differentiator of ALI from ALF. They show significantly higher rates of progression to ALF, liver transplantation, or death in non-acetaminophen etiologies of ALI. This study's findings provide guidance in supporting careful allocation of scarce critical care and liver transplant resources for ALI patients.

Editorial: "Lean" NAFLD: Metabolic Obesity with Normal BMI Is It in the Genes?

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. "Lean" NAFLD represents a patient subpopulation with hepatic steatosis evident on imaging with normal BMI. This paper by Feldman and Eder et al. illustrates the mild but clear metabolic differences and genetic connections in Caucasian lean NAFLD patients compared with obese NAFLD and healthy controls. Their findings highlight key similarities of lean and obese NAFLD compared with lean healthy subjects. This paper characterizes "lean" NAFLD as a unique phenotype with specific genetic associations deserving of further investigation in the greater scheme of elucidating the pathophysiology of fatty liver.

Liver transplant recipients with portal vein thrombosis receiving an organ from a high-risk donor are at an increased risk for graft loss due to hepatic artery thrombosis.

We hypothesize that recipients with pretransplant portal vein thrombosis (PVT) receiving organs from high-risk donors (HRD) are at an increased risk of HAT. Data on all liver transplants in the United States from February 2002 to March 2015 were analyzed. Recipients were sorted into two groups: those with PVT and those without. HRDs were defined by donor risk index (DRI) >1.7. Multivariable logistic regression models were constructed to assess the independent risk factors for HAT with the resultant graft loss ≤90 days from transplantation. A total of 60 404 candidates underwent liver transplantation; of those recipients, 623 (1.0%) had HAT, of which 66.0% (n = 411) received organs from HRDs compared with 49.3% (n = 29 473) in recipients without HAT (P < 0.001); 2250 (3.7%) recipients had pretransplantation PVT and received organs from HRDs. On adjusted multivariable analysis, PVT with a HRD organ was the most significant independent risk factor (OR 3.56, 95% CI 2.52-5.02, P < 0.001) for the development of HAT. Candidates with pretransplant PVT who receive an organ from a HRD are at the highest risk for postoperative HAT independent of other measurable factors. Recipients with pretransplant PVT would benefit from careful donor selection and possibly anticoagulation perioperatively.

Impact of an Institutional Change in Prothrombin Time Methodology on INR and MELD Scores in Liver Transplant Evaluations.

BACKGROUND: Allocation of liver grafts based on the model for end-stage liver disease (MELD) has been questioned because the prothrombin time (PT) measurement in cirrhosis patients changes with different commercially available thromboplastin reagents due to variations in the international sensitivity index (ISI). Our hospital laboratory electively changed the thromboplastin used in the PT/INR from PT-HS (ISI of 1.464) to Recombiplastin (ISI of 0.870). Theoretically, this change may yield lower INR and MELD scores in cirrhosis patients at our institution and thus impact access to organs. METHODS: 27 patients listed for liver transplant prior to change in thromboplastin (Cohort A) were compared to 36 patients listed after the change (Cohort B). RESULTS: Patients in Cohort A had a mean INR of 1.41 and mean MELD of 13.9 compared to Cohort B with a mean INR of 1.39 and mean MELD of 13.8. Student's t-tests showed no statistically significant difference in INR (p = 0.799) or MELD (p = 0.955) between cohorts. CONCLUSION: We expected overall INR and MELD scores to decrease following the change to a thromboplastin with a lower ISI. On the contrary, we found no evidence of a major trend in these values supporting the relative robustness of the MELD.

Safety profile of boceprevir and telaprevir in chronic hepatitis C: real world experience from HCV-TARGET.

BACKGROUND & AIMS: The safety profiles of boceprevir and telaprevir in the treatment of chronic hepatitis C, administered in academic and community centres across the United States, were evaluated. METHODS: In 90 medical centres, patients with chronic HCV received pegylated interferon, ribavirin, and either telaprevir or boceprevir per local standard of care. Demographic, adverse event, clinical, and virological data were collected during treatment and follow-up. RESULTS: A total of 2084 patients (97% HCV genotype 1) received at least one dose of a protease inhibitor. At baseline, 38% of patients had cirrhosis, and 57% had received at least one prior treatment for hepatitis C. Serious adverse events occurred in 12% of patients receiving protease inhibitor therapy. Overall, 66% of patients experienced anaemia, leading to frequent ribavirin dose reductions (42%) and erythropoietin use (37%); 11% received blood transfusion. More than 90% of patients had adverse events that led to a prescription, treatment, or dosage change, and 39% of patients discontinued treatment early, most commonly because of adverse events (18%) or lack of efficacy (16%). Hepatic decompensation events occurred in 3% of all patients. Age, female gender, cirrhosis, HCV genotype 1 subtype, creatinine clearance, platelet levels, albumin levels and haemoglobin levels were independent predictors of anaemia. Five deaths occurred. Overall, 52% of all patients achieved a sustained virologic response. CONCLUSIONS: In academic and community centres, where chronic hepatitis C patients commonly have advanced liver disease, triple therapy was associated with a high rate of adverse events and involved frequent treatment modifications and adverse event management.

Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial.

BACKGROUND & AIMS: This study's aim was to assess the histological and metabolic effects of n-3 polyunsaturated fatty acids (PUFAs) vs. placebo while adjusting for the impact of age and weight change in NASH patients. (ClinicalTrials.gov: NCT00681408). METHODS: Forty-one subjects with non-cirrhotic NASH were enrolled, and 34 completed the study. 17 received n-3 fish oil 3000 mg/day and 17 received placebo daily for 1 year with typical counselling on caloric intake and physical activity for all subjects. RESULTS: N-3- and placebo-treated groups showed no significant difference for the primary end point of NASH activity score (NAS) reduction ⩾ 2 points without fibrosis progression after adjustment for known covariates (n-3, 4/17 (23.5%); placebo, 3/17, (17.6%), p = 0.99). Among subjects with increased or stable weight, n-3 subjects showed a larger decrease in liver fat content by MRI than placebo-treated subjects (p = 0.014 for 2nd quartile, p = 0.003 for 3rd quartile of weight change). N-3 treatment showed significant fat reduction on the paired analysis of image-assisted fat morphometry regardless of weight loss or gain. Exercise capacity remained markedly reduced in all subjects. No independent effects on markers of hepatocyte injury or insulin sensitivity indices were observed. CONCLUSION: N-3 PUFAs at 3000 mg/day for one year did not lead to an improvement in the primary outcome of histological activity in NASH patients (⩾ 2 point NAS reduction). N-3 led to reduced liver fat by multiple measures. Other metabolic effects were not seen, although no detrimental effects were apparent. Whether longer duration, higher dose, or different composition of n-3 therapy would lead to additional benefits is uncertain.

Increased risk of portal vein thrombosis in patients with cirrhosis due to nonalcoholic steatohepatitis.

Portal vein thrombosis (PVT) is a common complication of cirrhosis sometimes implicated in hepatic decompensation. There are no consistent epidemiologic data to suggest an increased risk of thrombotic complications in nonalcoholic steatohepatitis (NASH); however, research suggests an increased risk of thrombosis. Our aim was to examine the independent association between NASH cirrhosis and PVT in patients who underwent liver transplantation (LT) in a cross-sectional study. Data on all LTs occurring in the United States between January 1, 2003 and December 31, 2012 were obtained from the United Network for Organ Sharing. Multivariable models were constructed to assess the statistical associations and risk factors for the development of PVT. A total of 33,368 patients underwent transplantation. Of these, 2096 (6.3%) had PVT. Of the patients with PVT, 12.0% had NASH. When we compared these patients to a composite of all other causes of cirrhosis, an increased prevalence of PVT was again found, with 10.1% having PVT at the time of transplantation versus 6.0% without NASH (P < 0.001). The strongest risk factor independently associated with a diagnosis of PVT in a multivariable analysis was NASH cirrhosis (odds ratio, 1.55; 95% confidence interval, 1.33-1.81; P < 0.001). NASH cirrhosis appears to predispose a patient to PVT independently of other risk factors. These epidemiological findings provide support for the idea that NASH is a prothrombotic state, and they should lead to more research in treatment and prevention in this population.

Hepatitis C disease severity in living versus deceased donor liver transplant recipients: an extended observation study.

UNLABELLED: Donor factors influence hepatitis C virus (HCV) disease severity in liver transplant (LT) recipients. Living donors, because they are typically young and have short cold ischemic times, may be advantageous for HCV-infected patients. Among HCV-infected patients in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) surviving >90 days and followed for a median 4.7 years, advanced fibrosis (Ishak stage ≥3) and graft loss were determined. The 5-year cumulative risk of advanced fibrosis was 44% and 37% in living donor LT (LDLT) and deceased donor LT (DDLT) patients (P = 0.16), respectively. Aspartate aminotransferase (AST) activity at LT (hazard ratio [HR] = 1.38 for doubling of AST, P = 0.005) and biliary strictures (HR = 2.68, P = 0.0001) were associated with advanced fibrosis, but LDLT was not (HR = 1.11, 95% confidence interval [CI] 0.73-1.69, P = 0.63). The 5-year unadjusted patient and graft survival probabilities were 79% and 78% in LDLT, and 77% and 75% in DDLT (P = 0.43 and 0.32), with 27% and 20% of LDLT and DDLT graft losses due to HCV (P = 0.45). Biliary strictures (HR = 2.25, P = 0.0006), creatinine at LT (HR = 1.74 for doubling of creatinine, P = 0.0004), and AST at LT (HR = 1.36 for doubling of AST, P = 0.004) were associated with graft loss, but LDLT was not (HR = 0.76, 95% CI: 0.49-1.18, P = 0.23). CONCLUSION: Donor type does not affect the probability of advanced fibrosis or patient and graft survival in HCV-infected recipients. Thus, while LDLT offers the advantage of shorter wait times, there is no apparent benefit for HCV disease progression. Biliary strictures have a negative effect on HCV fibrosis severity and graft survival, and a high AST at LT may be an important predictor of fibrosis risk post-LT.

Hepatic decompensation likely attributable to simeprevir in patients with advanced cirrhosis.

BACKGROUND: Hyperbilirubinemia is a common side effect of protease inhibitors used to treat chronic hepatitis C (HCV), and most patients do not experience without clinically overt hepatotoxicity. The safety of second-wave protease inhibitors, including simeprevir, has not been well studied in patients with advanced cirrhosis. MATERIALS & METHODS: We report two cases of suspected drug-induced liver injury leading to hepatic decompensation in patients with advanced HCV cirrhosis treated with the combination of simeprevir and sofosbuvir on a compassionate basis. Both patients developed marked hyperbilirubinemia out of proportion to their aminotransferases, despite clearance of hepatitis C RNA. RUCAM scoring was probable and possible, respectively. While other factors may have contributed to the liver injury, including infection and concurrent administration of other medications, we believe that the potentially deleterious hepatic effects of simeprevir on transporters or other key functional components were the main reason for their decompensation. CONCLUSIONS: Protease inhibitors should be used with caution, if at all, in patients with cirrhosis, especially in those with the most advanced disease. We await newer, safer, direct-acting antiviral therapies for such patients, especially those on our transplant list.

Hypercoagulation and thrombophilia in nonalcoholic fatty liver disease: mechanisms, human evidence, therapeutic implications, and preventive implications.

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders with a high prevalence in the industrialized world. Despite the high prevalence, the etiology and fundamental pathophysiology for the disease process is poorly understood. There is now a growing fund of knowledge suggesting that the ongoing inflammatory state associated with NAFLD leads to a low-level activation of the coagulation system. Although the data supporting this activation of the coagulation system are significant, the link with end-organ disease, mainly cardiovascular disease, is less firm and mostly epidemiological. In this review, we will explore the evidence for and against a hypercoagulable or thrombophilic state in NAFLD. We will examine possible pathophysiologic explanations and mechanisms, human epidemiologic and population-based data, and the possible therapeutic and preventative implications for treatment of thrombophilia in patients with this disease process.