Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, strongly associated with insulin resistance and the metabolic syndrome. Nonalcoholic steatohepatitis, i.e., fatty liver accompanied by necroinflammatory changes, is mostly defined by the NAFLD activity score (NAS). The aim of the current study was to determine disease‐specific mortality in NAFLD, and evaluate the NAS and fibrosis stage as prognostic markers for overall and disease‐specific mortality. In a cohort study, data from 229 well‐characterized patients with biopsy‐proven NAFLD were collected. Mean follow‐up was 26.4 (±5.6, range 6‐33) years. A reference population was obtained from the National Registry of Population, and information on time and cause of death were obtained from the Registry of Causes of Death. NAFLD patients had an increased mortality compared with the reference population (hazard ratio [HR] 1.29, confidence interval [CI] 1.04‐1.59, P = 0.020), with increased risk of cardiovascular disease (HR 1.55, CI 1.11‐2.15, P = 0.01), hepatocellular carcinoma (HR 6.55, CI 2.14‐20.03, P = 0.001), infectious disease (HR 2.71, CI 1.02‐7.26, P = 0.046), and cirrhosis (HR 3.2, CI 1.05‐9.81, P = 0.041). Overall mortality was not increased in patients with NAS 5‐8 and fibrosis stage 0‐2 (HR 1.41, CI 0.97‐2.06, P = 0.07), whereas patients with fibrosis stage 3‐4, irrespective of NAS, had increased mortality (HR 3.3, CI 2.27‐4.76, P < 0.001). Conclusion: NAFLD patients have increased risk of death, with a high risk of death from cardiovascular disease and liver‐related disease. The NAS was not able to predict overall mortality, whereas fibrosis stage predicted both overall and disease‐specific mortality. (Hepatology 2015;61:1547–1554)

Biopsy-confirmed liver fibrosis is a prognostic factor for patients with nonalcoholic fatty liver disease (NAFLD). We performed a systematic review to quantify the prognostic value of fibrosis stage in patients with NAFLD and the subgroup of patients with nonalcoholic steatohepatitis (NASH) and to assess the evidence that change in fibrosis stage is a surrogate endpoint. We searched the MEDLINE, Embase, Cochrane Library, and trial registry databases through August 2018 for prospective or retrospective cohort studies of liver-related clinical events and outcomes in adults with NAFLD or NASH. We collected data on mortality (all cause and liver related) and morbidity (cirrhosis, liver cancer, and all liver-related events) by stage of fibrosis, determined by biopsy, for patients with NAFLD or NASH. Using fibrosis stage 0 as a reference population, we calculated fibrosis stage-specific relative risk (RR) and 95% confidence interval (CI) values for mortality and morbidities. We performed fixed-effect and random-effect model meta-analyses. Metaregression was used to examine associations among study design (prospective vs retrospective cohort), overall risk of bias (medium or high), and mean duration of follow-up (in years). Our meta-analysis included 13 studies, comprising 4428 patients with NAFLD; 2875 of these were reported to have NASH. Compared with no fibrosis (stage 0), unadjusted risk increased with increasing stage of fibrosis (stage 0 vs 4): all-cause mortality RR, 3.42 (95% CI, 2.63-4.46); liver-related mortality RR, 11.13 (95% CI, 4.15-29.84); liver transplant RR, 5.42 (95% CI, 1.05-27.89); and liver-related events RR, 12.78 (95% CI, 6.85-23.85). The magnitude of RR did not differ significantly after adjustment for confounders, including age or sex in the subgroup of NAFLD patients with NASH. Three studies examined the effects of increasing fibrosis on quality of life had inconsistent findings. In a systematic review and meta-analysis, we found biopsy-confirmed fibrosis to be associated with risk of mortality and liver-related morbidity in patients with NAFLD, with and without adjustment for confounding factors and in patients with reported NASH. Further studies are needed to assess the association between fibrosis stage and patient quality of life and establish that change in liver fibrosis stage is a valid endpoint for use in clinical trials.

Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common liver disease globally and is currently estimated to affect 38% of the global population. Only a minority of patients with NAFLD will progress to cirrhosis or hepatocellular carcinoma, but from this vast population the total number of patients who are at risk of such severe outcomes is increasing. Worryingly, individuals are increasingly being affected by NAFLD at an earlier age, meaning there is more time for them to develop severe complications. With considerable changes in dietary composition and urbanisation, alongside the growth in obesity and type 2 diabetes in the global population, in particular in developing countries, the global proportion of persons affected by NAFLD is projected to increase further. Yet, there are large geographical discrepancies in the prevalence rates of NAFLD and its inflammatory component non-alcoholic steatohepatitis (NASH). Such differences are partly related to differing socio-economic milieus, but also to genetic predisposition. In this narrative review, we discuss recent changes in the epidemiology of NAFLD and NASH from regional and global perspectives, as well as in special populations. We also discuss the potential consequences of these changes on hepatic and extrahepatic events.

Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD. English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m² or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14–8.61) and incidence (HR 3.29, 95% CI 2.30–4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies. The presence and severity of NAFLD are associated with an increased risk and severity of CKD. Please see later in the article for the Editors' Summary Chronic kidney disease (CKD)—the gradual loss of kidney function—is becoming increasingly common. In the US, for example, more than 10% of the adult population (about 26 million people) and more than 25% of individuals older than 65 years have CKD. Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. CKD gradually destroys the kidneys' filtration units, the rate of blood filtration decreases, and dangerous amounts of waste products build up in the blood. Symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, particularly at night. There is no cure for CKD, but progression of the disease can be slowed by controlling high blood pressure and diabetes (two risk factors for CKD), and by adopting a healthy lifestyle. The same interventions also reduce the chances of CKD developing in the first place. CKD is associated with an increased risk of end-stage renal (kidney) disease and of cardiovascular disease. These life-threatening complications are potentially preventable through early identification and treatment of CKD. Because early recognition of CKD has the potential to reduce its health-related burden, the search is on for new modifiable risk factors for CKD. One possible new risk factor is non-alcoholic fatty liver disease (NAFLD), which, like CKD is becoming increasingly common. Healthy livers contain little or no fat but, in the US, 30% of the general adult population and up to 70% of patients who are obese or have diabetes have some degree of NAFLD, which ranges in severity from simple fatty liver (steatosis), through non-alcoholic steatohepatitis (NASH), to NASH with fibrosis (scarring of the liver) and finally cirrhosis (extensive scarring). In this systematic review and meta-analysis, the researchers investigate whether NAFLD is a risk factor for CKD by looking for an association between the two conditions. A systematic review identifies all the research on a given topic using predefined criteria, meta-analysis uses statistical methods to combine the results of several studies. The researchers identified 33 studies that assessed NAFLD and CKD in nearly 64,000 participants, including 20 cross-sectional studies in which participants were assessed for NAFLD and CKD at a single time point and 13 longitudinal studies in which participants were assessed for NAFLD and then followed up to see whether they subsequently developed CKD. Meta-analysis of the data from the cross-sectional studies indicated that NAFLD was associated with a 2-fold increased risk of prevalent (pre-existing) CKD (an odds ratio [OR]of 2.12; an OR indicates the chance that an outcome will occur given a particular exposure, compared to the chance of the outcome occurring in the absence of that exposure). Meta-analysis of data from the longitudinal studies indicated that NAFLD was associated with a nearly 2-fold increased risk of incident (new) CKD (a hazard ratio [HR] of 1.79; an HR indicates often a particular event happens in one group compared to how often it happens in another group, over time). NASH was associated with a higher prevalence and incidence of CKD than simple steatosis. Similarly, advanced fibrosis was associated with a higher prevalence and incidence of CKD than non-advanced fibrosis. These findings suggest that NAFLD is associated with an increased prevalence and incidence of CKD and that increased severity of liver disease is associated with an increased risk and severity of CKD. Because these associations persist after allowing for established risk factors for CKD, these findings identify NAFLD as an independent CKD risk factor. Certain aspects of the studies included in this meta-analysis (for example, only a few studies used biopsies to diagnose NAFLD; most used less sensitive tests that may have misclassified some individuals with NAFLD as normal) and the methods used in the meta-analysis may limit the accuracy of these findings. Nevertheless, these findings suggest that individuals with NAFLD should be screened for CKD even in the absence of other risk factors for the disease, and that better treatment of NAFLD may help to prevent CKD. Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001680.

Objective: Population-based data are lacking regarding the risk of overall and cause-specific mortality across the complete histological spectrum of non-alcoholic fatty liver disease (NAFLD). Design: This nationwide, matched cohort study included all individuals in Sweden with biopsy-confirmed NAFLD (1966 to 2017; n=10 568). NAFLD was confirmed histologically from all liver biopsies submitted to Sweden’s 28 pathology departments, after excluding other etiologies of liver disease, and further categorised as, simple steatosis, non-fibrotic steatohepatitis (NASH), non-cirrhotic fibrosis and cirrhosis. NAFLD cases were matched to ≤5 general population comparators by age, sex, calendar year and county (n=49 925). Using Cox regression, we estimated multivariable-adjusted HRs (aHRs) and 95% CIs. Results: Over a median of 14.2 years, 4,338 NAFLD patients died. Compared with controls, NAFLD patients had significantly increased overall mortality (16.9 vs 28.6/1000 PY; difference=11.7/1000 PY; aHR=1.93, 95% CI=1.86 to 2.00). Compared with controls, significant excess mortality risk was observed with simple steatosis (8.3/1000 PY, aHR=1.71, 95% CI=1.64 to 1.79), non-fibrotic NASH (13.4/1000 PY, aHR=2.14, 95% CI=1.93 to 2.38), non-cirrhotic fibrosis (18.4/1000 PY, aHR=2.44, 95% CI=2.22 to 2.69) and cirrhosis (53.6/1000 PY, aHR=3.79, 95% CI=3.34 to 4.30)(p _trend <0.01). This dose-dependent gradient was similar when simple steatosis was the reference (p _trend <0.01). The excess mortality associated with NAFLD was primarily from extrahepatic cancer (4.5/1000 PY, aHR=2.16, 95% CI=2.03 to 2.30), followed by cirrhosis (2.7/1000 PY, aHR=18.15, 95% CI=14.78 to 22.30), cardiovascular disease (1.4/1000 PY, aHR=1.35, 95% CI=1.26 to 1.44) and hepatocellular carcinoma (HCC) (1.2/1000 PY, aHR=11.12, 95% CI=8.65 to 14.30). Conclusion: All NAFLD histological stages were associated with significantly increased overall mortality, and this risk increased progressively with worsening NAFLD histology. Most of this excess mortality was from extrahepatic cancer and cirrhosis, while in contrast, the contributions of cardiovascular disease and HCC were modest.