Alina M. Allen

Fibrosis Progression in Nonalcoholic Fatty Liver vs Nonalcoholic Steatohepatitis: A Systematic Review and Meta-analysis of Paired-Biopsy Studies

BACKGROUND & AIMS Little is known about differences in rates of fibrosis progression between patients with nonalcoholic fatty liver (NAFL) vs nonalcoholic steatohepatitis (NASH). We conducted a systematic review and meta-analysis of all studies that assessed paired liver biopsy specimens to estimate the rates of fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD) including NAFL and NASH. METHODS Through a systematic search of multiple databases and author contact, up to June 2013, we identified studies of adults with NAFLD that collected paired liver biopsy specimens at least 1 year apart. From these, we calculated a pooled-weighted annual fibrosis progression rate (number of stages changed between the 2 biopsy samples) with 95% confidence intervals (CIs), and identified clinical risk factors associated with progression. RESULTS We identified 11 cohort studies including 411 patients with biopsy-proven NAFLD (150 with NAFL and 261 with NASH). At baseline, the distribution of fibrosis for stages 0, 1, 2, 3, and 4 was 35.8%, 32.5%, 16.7%, 9.3%, and 5.7%, respectively. Over 2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, and 22.3% had an improvement in fibrosis stage. The annual fibrosis progression rate in patients with NAFL who had stage 0 fibrosis at baseline was 0.07 stages (95% CI, 0.02-0.11 stages), compared with 0.14 stages in patients with NASH (95% CI, 0.07-0.21 stages). These findings correspond to 1 stage of progression over 14.3 years for patients with NAFL (95% CI, 9.1-50.0 y) and 7.1 years for patients with NASH (95% CI, 4.8-14.3 y). CONCLUSIONS Based on a meta-analysis of studies of paired liver biopsy studies, liver fibrosis progresses in patients with NAFL and NASH.

Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: A systematic review and network meta‐analysis

We performed a Bayesian network meta‐analysis combining direct and indirect treatment comparisons to assess the comparative effectiveness of pharmacological agents for the treatment of nonalcoholic steatohepatitis (NASH). Through systematic literature review, we identified nine randomized, controlled trials (RCTs) including 964 patients with biopsy‐proven NASH, comparing vitamin E, thiazolidinediones (TZDs), pentoxifylline, or obeticholic acid to one another or placebo. The primary outcome was improvement in fibrosis stage; secondary outcomes were improvement in ballooning degeneration, lobular inflammation, and steatosis. We reported relative risks (RRs) and 95% confidence intervals (CIs) from direct meta‐analysis and 95% credible intervals (CrIs) from Bayesian network meta‐analysis, and used Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria to appraise quality of evidence. Moderate‐quality evidence supports the use of pentoxifylline (RR, 0.26; 95% CrI: 0.05‐1.00) and obeticholic acid (RR, 0.81; 95% CI: 0.70‐0.95) over placebo in improving fibrosis. High‐quality evidence supports the effect of vitamin E, TZDs, and obeticholic acid over placebo in improving ballooning degeneration. All four interventions seemed to have at least moderate‐quality evidence over placebo to improve steatosis. Moderate‐quality evidence supports that TZDs, pentoxifylline, and obeticholic acid decrease lobular inflammation. All the head‐to‐head comparisons were supported by very‐low‐quality evidence except for superiority of TZDs over vitamin E on improving steatosis and lobular inflammation, which had moderate‐quality evidence. Conclusions: Based on direct and network meta‐analysis, pentoxifylline and obeticholic acid improve fibrosis, and vitamin E, TZDs, and obeticholic acid improve ballooning degeneration in patients with NASH. Future comparative trials of combination therapies targeting distinct histological features are warranted. (Hepatology 2015;62:1417–1432)

Chronic kidney disease and associated mortality after liver transplantation--a time-dependent analysis using measured glomerular filtration rate.

BACKGROUND & AIMS The accuracy of creatinine-based estimated GFR (eGFR) in assessing the prevalence of chronic kidney disease (CKD) and associated mortality after liver transplantation (LTx) is unknown. Using measured GFR (mGFR) by iothalamate clearance, we determined the prevalence of the entire spectrum of renal dysfunction and the impact of CKD on mortality after LTx. METHODS A database that prospectively tracks all LTx recipients at this academic transplant program from 1985 to 2012 was queried to identify all adult primary LTx recipients. Our post-LTx protocol incorporates GFR measurement by iothalamate clearance at regular intervals. A multistate model was used to assess the prevalence of CKD, kidney transplant, and death after LTx. Time-dependent Cox regression analysis was performed to evaluate the impact of mGFR and eGFR changes on survival. RESULTS A total of 1211 transplant recipients were included. At the time of LTx, the median age was 54 years, 60% were male and 86% were Caucasian. At 25 years after LTx, 54% of patients died, 9% underwent kidney transplantation, whereas 7%, 21%, and 18% had mGFR >60, 59-30, and <30 ml/min/1.73 m(2) respectively. The risk of death increased when mGFR decreased below 30 ml/min/1.73 m(2): HR = 2.67 (95% CI = 1.80-3.96) for GFR = 29-15 ml/min/1.73 m(2) and HR = 5.47 (95% CI = 3.10-9.65) for GFR <15 ml/min/1.73 m(2). Compared to mGFR, eGFR underestimated mortality risk in LTx recipients with an eGFR of 30-90 ml/min/1.73 m(2). CONCLUSIONS An overwhelming majority of LTx recipients develop CKD. The risk of death increases exponentially when GFR <30 ml/min/1.73 m(2). Creatinine-based eGFR underestimates the mortality risk in a large proportion of patients.

Hepatocellular Carcinoma Is the Most Common Indication for Liver Transplantation and Placement on the Waitlist in the United States

Background & Aims Management strategies for patients with hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC) have changed, along with liver allocation policies based on model for end‐stage liver disease score. We investigated etiologic‐specific trends in liver transplantation in the United States during different time periods. Methods We performed a retrospective study, using the United Network for Organ Sharing/Organ Procurement and Transplantation Network registry data, to identify all adult patients registered for liver transplantation in the United States from January 1, 2004, through December 31, 2015. For subjects listed with multiple diagnoses, HCC was considered the primary listing diagnosis. To determine whether availability of direct‐acting antiviral agents, which began in 2011, affected pretransplant (death or drop‐out) and post‐transplant outcomes for patients with HCV infection, we compared data from the time periods of 2004 to 2010 and 2011 to 2014. We used competing‐risk analysis to compare differences in end points between these periods. Differences between periods in pretransplantation and post‐transplantation outcomes were estimated using Kaplan–Maier analysis and compared using the log‐rank test. Associations between year of listing and pre–liver transplant outcome, and year of liver transplant and survival after transplant, were examined using the log‐rank test. Proportional hazard regression was used to evaluate the reliability of the time period effect with potential confounders. Results Among 109,018 registrants, 18.5% were registered for liver transplantation because of HCC. In 2015, HCC was the leading diagnosis among registrants (23.9% of registrations) and recipients (27.2% of recipients). Between 2004 and 2015, the ratio of registrants with vs without HCC increased 5.6‐fold for patients with HCV infection, 1.9‐fold for patients with hepatitis B virus (HBV) infection, 2.7‐fold for patients with alcohol abuse, and 10.2‐fold for patients with nonalcoholic steatohepatitis. After adjusting for covariates, we associated the period of 2011 to 2014 with a decreased probability that HCC registrants would undergo liver transplantation (hazard ratio [HR], 0.62; P < .0001). The period of 2011 to 2014 also was associated with a decreased probability of drop‐out owing to deterioration or death from HCV‐induced (HR, 0.90; P = .0003), HBV‐induced (HR, 0.71; P = .002), or alcohol‐induced (HR, 0.90; P = .01) liver disease, and an increased probability of delisting as a result of clinical improvement in patients with HCV infection (HR, 3.4; P < .0001), HBV infection (HR, 2.3; P = .004), or alcohol abuse (HR, 2.2; P < .0001). The period of 2011 to 2014 was associated with a decreased risk of graft loss or death, with the largest effect seen in HCV‐infected recipients (HR, 0.76; P < .0001). Conclusions HCC was the leading indication for liver transplantation in the United States in 2015. Despite this, the probability of liver transplantation decreased the most in registrants with HCC. Pretransplantation and post‐transplantation outcomes have improved, particularly in patients with HCV infection.

Time trends in the health care burden and mortality of acute on chronic liver failure in the United States

Acute on chronic liver failure (ACLF) is associated with multisystem organ failure and poor prognosis in hospitalized patients with cirrhosis. We aimed to determine time trends in the epidemiology, economic burden, and mortality of ACLF in the United States. The National Inpatient Sample database was queried between 2001 and 2011. ACLF was defined as two or more extrahepatic organ failures in patients with cirrhosis. The primary outcomes were trends in hospitalizations, hospital costs, and inpatient mortality. The number of hospitalizations for cirrhosis in the United States nearly doubled from 371,000 in 2001 to 659,000 in 2011. The prevalence of ACLF among those hospitalizations increased from 1.5% (n = 5,400) to 5% (n = 32,300). The inpatient costs increased 2‐fold for cirrhosis (

Nonalcoholic fatty liver: optimizing pretransplant selection and posttransplant care to maximize survival.

4.8 billion to

Sarcopenia in hiding: The risk and consequence of underestimating muscle dysfunction in nonalcoholic steatohepatitis

9.8 billion) and 5‐fold (

Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: A 20 year-community study

320 million to

Serum Cystatin C as an Indicator of Renal Function and Mortality in Liver Transplant Recipients.

1.7 billion) for ACLF. In 2011, the cost per hospitalization for ACLF was 3.5‐fold higher than that for cirrhosis (

Efficacy and Safety of Treatment of Hepatitis C in Patients With Inflammatory Bowel Disease

53,570 versus