Background Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage-specific risk of all-cause and liver-related mortality in NAFLD. Methods Through a systematic review and meta-analysis, we identified 5 adult NAFLD cohort studies reporting fibrosis stage specific mortality (0–4). Using fibrosis stage 0 as a reference population, fibrosis stage-specific mortality rate ratios (MRR) with 95% confidence intervals (CI), for all-cause and liver-related mortality, were estimated. The study is reported according to the PRISMA statement. Results 1,495 NAFLD patients with 17,452 patient years of follow-up were included. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all-cause mortality and this risk increased with increase in the stage of fibrosis: stage 1, MRR, 1.58 (95% CI 1.19–2.11); stage 2, MRR, 2.52 (95% CI 1.85–3.42); stage 3, MRR, 3.48 (95% CI 2.51–4.83), and stage 4, MRR, 6.40 (95% CI 4.11–9.95). The results were more pronounced as the risk of liver-related mortality increased exponentially with increase in the stage of fibrosis: stage 1, MRR, 1.41 (95% CI 0.17–11.95); stage 2, MRR, 9.57 (95% CI 1.67–54.93); stage 3, MRR, 16.69 (95% CI 2.92–95.36); and stage 4, MRR, 42.30 (95% CI 3.51–510.34). Limitations Inability to adjust for co-morbid conditions or demographics known to impact fibrosis progression in NAFLD, and the inclusion of patients with simple steatosis and NASH without fibrosis in the reference comparison group. Conclusion The risk of liver-related mortality increases exponentially with increase in fibrosis stage. These data have important implications in assessing utility of each stage and benefits of regression of fibrosis from one stage to another.

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 biopsies to estimate the rates of fibrosis progression in patients with 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 biopsies 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 (CI), 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, 33.6% had fibrosis progression, 43.1% had stable fibrosis, and 22.3% had 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 over14.3 years for patients with NAFL (95% CI, 9.1–50.0 years) and 7.1 years for patients with NASH (95% CI, 4.8–14.3 years). Conclusions Based a meta-analysis of studies of paired liver biopsy studies, liver fibrosis progresses in patients with NAFL and NASH.

IMPORTANCE Five medications have been approved for the management of obesity, but data on comparative effectiveness are limited.OBJECTIVE To compare weight loss and adverse events among drug treatments for obesity using a systematic review and network meta-analysis. DATA SOURCES MEDLINE, EMBASE, Web of Science, Scopus, and Cochrane Central from inception to March 23, 2016; clinical trial registries. STUDY SELECTION Randomized clinical trials conducted among overweight and obese adults treated with US Food and Drug Administration-approved long-term weight loss agents (orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, or liraglutide) for at least 1 year compared with another active agent or placebo.DATA EXTRACTION AND SYNTHESIS Two investigators identified studies and independently abstracted data using a predefined protocol. A Bayesian network meta-analysis was performed and relative ranking of agents was assessed using surface under the cumulative ranking (SUCRA) probabilities. Quality of evidence was assessed using GRADE criteria. MAIN OUTCOMES AND MEASURESProportions of patients with at least 5% weight loss and at least 10% weight loss, magnitude of decrease in weight, and discontinuation of therapy because of adverse events at 1 year.RESULTS Twenty-eight randomized clinical trials with 29 018 patients (median age, 46 years; 74% women; median baseline body weight, 100.5 kg; median baseline body mass index, 36.1) were included. A median 23% of placebo participants had at least 5% weight loss vs 75% of participants taking phentermine-topiramate (odds ratio [OR], 9.22; 95% credible interval [CrI], 6.63-12.85; SUCRA, 0.95), 63% of participants taking liraglutide (OR, 5.54; 95% CrI, 4.16-7.78; SUCRA, 0.83), 55% taking naltrexone-bupropion (OR, 3.96; 95% CrI,; SUCRA, 0.60), 49% taking lorcaserin (OR, 3.10; 95% CrI, 2.38-4.05; SUCRA, 0.39), and 44% taking orlistat (OR, 2.70; 95% CrI, 2.34-3.09; SUCRA, 0.22). All active agents were associated with significant excess weight loss compared with placebo at 1 year-phentermine-topiramate, 8.8 kg (95% CrI, −10.20 to −7.42 kg); liraglutide, 5.3 kg (95% CrI, −6.06 to −4.52 kg); naltrexone-bupropion, 5.0 kg (95% CrI, −5.94 to −3.96 kg); lorcaserin, 3.2 kg (95% CrI, −3.97 to −2.46 kg); and orlistat, 2.6 kg (95% CrI, −3.04 to −2.16 kg). Compared with placebo, liraglutide (OR, 2.95; 95% CrI,) and naltrexone-bupropion (OR, 2.64; 95% CrI, 2.10-3.35) were associated with the highest odds of adverse event-related treatment discontinuation. High attrition rates (30%-45% in all trials) were associated with lower confidence in estimates.CONCLUSIONS AND RELEVANCE Among overweight or obese adults, orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide, compared with placebo, were each associated with achieving at least 5% weight loss at 52 weeks. Phentermine-topiramate and liraglutide were associated with the highest odds of achieving at least 5% weight loss.

A history of sexual abuse is associated with an increased risk of a lifetime diagnosis of multiple psychiatric disorders.