Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study

Background & Aims Little is known about the natural course of nonalcoholic fatty liver disease (NAFLD) with advanced fibrosis. We describe long-term outcomes and evaluate the effects of clinical and histologic parameters on disease progression in patients with advanced NAFLD. Methods We conducted a multi-national study of 458 patients with biopsy-confirmed NAFLD with bridging fibrosis (F3, n = 159) or compensated cirrhosis (222 patients with Child-Turcotte-Pugh scores of A5 and 77 patients with scores of A6), evaluated from April 1995 through November 2013 and followed until December 2016, death, or liver transplantation at hepatology centers in Spain, Australia, Hong Kong, and Cuba. Biopsies were re-evaluated and scored; demographic, clinical, laboratory, and pathology data for each patient were collected from the time of liver biopsy collection. Cox proportional and competing risk models were used to estimate rates of transplantation-free survival and major clinical events and to identify factors associated with outcomes. Results During a mean follow-up time of 5.5 years (range, 2.7–8.2 years), 37 patients died, 37 received liver transplants, 88 had initial hepatic decompensation events, 41 developed hepatocellular carcinoma, 14 had vascular events, and 30 developed nonhepatic cancers. A higher proportion of patients with F3 fibrosis survived transplantation-free for 10 years (94%; 95% confidence interval [CI], 86%–99%) than of patients with cirrhosis and Child-Turcotte-Pugh A5 (74%; 95% CI, 61%–89%) or Child-Turcotte-Pugh A6 (17%; 95% CI, 6%–29%). Patients with cirrhosis were more likely than patients with F3 fibrosis to have hepatic decompensation (44%; 95% CI, 32%–60% vs 6%, 95% CI, 2%–13%) or hepatocellular carcinoma (17%; 95% CI, 8%–31% vs 2.3%, 95% CI, 1%–12%). The cumulative incidence of vascular events was higher in patients with F3 fibrosis (7%; 95% CI, 3%–18%) than cirrhosis (2%; 95% CI, 0%–6%). The cumulative incidence of nonhepatic malignancies was higher in patients with F3 fibrosis (14%; 95% CI, 7%–23%) than cirrhosis (6%; 95% CI, 2%–15%). Death or transplantation, decompensation, and hepatocellular carcinoma were independently associated with baseline cirrhosis and mild (<33%) steatosis, whereas moderate alcohol consumption was associated with these outcomes only in patients with cirrhosis. Conclusions Patients with NAFLD cirrhosis have predominantly liver-related events, whereas those with bridging fibrosis have predominantly nonhepatic cancers and vascular events

Type 2 Diabetes and Metformin Use Associate With Outcomes of Patients With Non-alcoholic Steatohepatitis-related, Child-Pugh A Cirrhosis

Background & Aims Factors that affect outcomes of patients with non-alcoholic steatohepatitis (NASH) related cirrhosis are unclear. We studied associations of type 2 diabetes, levels of hemoglobin A1c (HbA1c), and use antidiabetic medications with survival and liver-related events in patients with NASH and compensated cirrhosis. Methods We collected data from 299 patients with biopsy-proven NASH with Child-Pugh A cirrhosis from tertiary hospitals in Spain, Australia, Hong Kong, and Cuba, from April 1995 through December 2016. We obtained information on presence of type 2 diabetes, level of HbA1c, and use of antidiabetic medications. Cox proportional and competing risk models were used to estimate and compare rates of transplant-free survival, hepatic decompensation, and hepatocellular carcinoma (HCC). Results Two-hundred and twelve patients had type 2 diabetes at baseline and 8/87 patients developed diabetes during a median follow-up time of 5.1 y (range, 0.5–10.0 y). A lower proportion of patients with diabetes survived the entire follow-up period (38%) than of patients with no diabetes (81%) (adjusted hazard ratio [aHR], 4.23; 95% CI, 1.93–9.29). Higher proportions of patients with diabetes also had hepatic decompensation (51% vs 26% of patients with no diabetes; aHR, 2.03; 95% CI 1.005–4.11) and HCC (25% vs 7% of patients with no diabetes; aHR, 5.42; 95% CI 1.74–16.80). Averaged annual HbA1c levels over time were not associated with outcomes. Metformin use over time was associated with a significant reduction in risk of death or liver transplantation (aHR, 0.41; 95% CI, 0.26–0.45), hepatic decompensation (aHR, 0.80; 95% CI, 0.74–0.97), and HCC (aHR, 0.78; 95% CI, 0.69–0.96). Metformin significantly reduced risk of hepatic decompensation and HCC only in subjects with HbA1c levels above 7.0% (aHR, 0.97; 95% CI, 0.95–0.99 and aHR, 0.67; 95% CI, 0.43–0.94, respectively). Conclusions In an international cohort of patients with biopsy-proven NASH and Child-Pugh A cirrhosis, type 2 diabetes increased risk of death and liver-related outcomes, including HCC. Patients who took metformin had higher rates of survival and lower rates of decompensation and HCC

Predicting liver-related events in NAFLD: A predictive model

Background and Aims: Management of NAFLD involves noninvasive prediction of fibrosis, which is a surrogate for patient outcomes. We aimed to develop and validate a model predictive of liver-related events (LREs) of decompensation and/or HCC and compare its accuracy with fibrosis models. Approach and Results: Patients with NAFLD from Australia and Spain who were followed for up to 28 years formed derivation (n = 584) and validation (n = 477) cohorts. Competing risk regression and information criteria were used for model development. Accuracy was compared with fibrosis models using time-dependent AUC analysis. During follow-up, LREs occurred in 52 (9%) and 11 (2.3%) patients in derivation and validation cohorts, respectively. Age, type 2 diabetes, albumin, bilirubin, platelet count, and international normalized ratio were independent predictors of LRE and were combined into a model [NAFLD outcomes score (NOS)]. The NOS model calibrated well [calibration slope, 0.99 (derivation), 0.98 (validation)] with excellent overall performance [integrated Brier score, 0.07 (derivation) and 0.01 (validation)]. A cutoff ≥1.3 identified subjects at a higher risk of LRE, (sub-HR 24.6, p < 0.001, 5-year cumulative incidence 38% vs 1.0%, respectively). The predictive accuracy at 5 and 10 years was excellent in both derivation (time-dependent AUC,0.92 and 0.90, respectively) and validation cohorts (time-dependent AUC,0.80 and 0.82, respectively). The NOS was more accurate than the fibrosis-4 or NAFLD fibrosis score for predicting LREs at 5 and 10 years (p < 0.001). Conclusions: The NOS model consists of readily available measures and has greater accuracy in predicting outcomes in patients with NAFLD than existing fibrosis models.Peer reviewe

The Natural Course of Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from “bland steatosis” to the more aggressive necro-inflammatory form, non-alcoholic steatohepatitis (NASH) which may accumulate fibrosis to result in cirrhosis. Emerging data suggests fibrosis, rather than NASH per se, to be the most important histological predictor of liver and non-liver related death. Nevertheless, only a small proportion of individuals develop cirrhosis, however the large proportion of the population affected by NAFLD has led to predictions that NAFLD will become a leading cause of end stage liver disease, hepatocellular carcinoma (HCC), and indication for liver transplantation. HCC may arise in non-cirrhotic liver in the setting of NAFLD and is associated with the presence of the metabolic syndrome (MetS) and male gender. The MetS and its components also play a key role in the histological progression of NAFLD, however other genetic and environmental factors may also influence the natural history. The importance of NAFLD in terms of overall survival extends beyond the liver where cardiovascular disease and malignancy represents additional important causes of death

Modelos pronósticos para la cirrosis hepática Prognostic models for hepatic cirrhosis

Los modelos pronósticos representan un pilar importante en la evaluación de los pacientes con cirrosis hepática, sobre todo a la hora de tomar decisiones como el trasplante hepático. Los 2 modelos más utilizados al nivel mundial, el Child Pugh Turcotte y el Model for end stage liver disease (MELD), presentan ventajas y desventajas en su aproximación a los pacientes. El objetivo de este trabajo fue revisar estos modelos pronósticos utilizados en la enfermedad hepática terminal, así como comparar el modelo MELD y el Child Pugh Turcotte sobre la base del diseño, eficacia predictiva y aplicación practica. Se concluye que ambos modelos son útiles para predecir la mortalidad en los pacientes con cirrosis hepática y que se deben realizar futuras investigaciones para mejorar su poder discriminativo.The prognostic models are a significant pillar in assessment of patients presenting hepatic cirrhosis, mainly at moment to make a decision related to liver transplantation. The two more used models at international level, the Child Pugh Turcotte and the Model for end stage liver disease ( MELD) have advantages and disadvantages in its approximation to patients. The aim of present paper was to review these prognostic models used in the end-terminal liver disease, as well as to compare the above mentioned models on the base of the design, predictive effectiveness and practical application. We conclude that both models are useful to predict mortality in patients presenting with hepatic cirrhosis and also that more future researches must to be performed to improve its discriminatory power