Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries that is predicted to become also the most frequent indication for liver transplantation by 2030. Over the last decade, it has been shown that the clinical burden of NAFLD is not only confined to liver-related morbidity and mortality, but there is now growing evidence that NAFLD is a multisystem disease, affecting extra-hepatic organs and regulatory pathways. For example, NAFLD increases risk of type 2 diabetes mellitus (T2DM), cardiovascular (CVD) and cardiac diseases, and chronic kidney disease (CKD). Although the primary liver pathology in NAFLD affects hepatic structure and function to cause morbidity and mortality from cirrhosis, liver failure and hepatocellular carcinoma, the majority of deaths among NAFLD patients are attributable to CVD. This narrative review focuses on the rapidly expanding body of clinical evidence that supports the concept of NAFLD as a multisystem disease. The review discusses the factors involved in the progression of liver disease in NAFLD and the factors linking NAFLD with other extra-hepatic chronic diseases, such as T2DM, CVD, cardiac diseases and CKD. The review will not discuss NAFLD treatments as these are discussed elsewhere in this issue of the Journal. For this review, PubMed was searched for articles using the keywords "non-alcoholic fatty liver disease" or "fatty liver" combined with "diabetes", "cardiovascular (or cardiac) disease", "cardiovascular mortality" or "chronic kidney disease" between 1990 and 2014. Articles published in languages other than English were excluded.

Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common chronic liver disease globally and is currently estimated to affect up to 38% of the global adult population. NAFLD is a multisystem disease where systemic insulin resistance and related metabolic dysfunction play a pathogenic role in the development of NAFLD and its most relevant liver-related morbidities (cirrhosis, liver failure and hepatocellular carcinoma) and extrahepatic complications, such as cardiovascular disease (CVD), type 2 diabetes mellitus, chronic kidney disease, and certain types of extrahepatic cancers. In 2023, three large multinational liver associations proposed that metabolic dysfunction-associated steatotic liver disease (MASLD) should replace the term NAFLD; the name chosen to replace non-alcoholic steatohepatitis was metabolic dysfunction-associated steatohepatitis (MASH). Emerging epidemiological evidence suggests an excellent concordance rate between NAFLD and MASLD definitions—that is, ~99% of individuals with NAFLD meet MASLD criteria. In this narrative review, we provide an overview of the literature on (a) the recent epidemiological data on MASLD and the risk of developing CVD and malignant complications, (b) the underlying mechanisms by which MASLD (and factors strongly linked with MASLD) may increase the risk of these extrahepatic complications and (c) the diagnosis and assessment of CVD risk and potential treatments to reduce CVD risk in people with MASLD or MASH.

Non-alcoholic fatty liver disease (NAFLD) is a public health problem, affecting up to a third of the world’s adult population. Several cohort studies have consistently documented that NAFLD (especially in its more advanced forms) is associated with a higher risk of all-cause mortality and that the leading causes of death among patients with NAFLD are cardiovascular diseases (CVDs), followed by extrahepatic malignancies and liver-related complications. A growing body of evidence also indicates that NAFLD is strongly associated with an increased risk of major CVD events and other cardiac complications (ie, cardiomyopathy, cardiac valvular calcification and cardiac arrhythmias), independently of traditional cardiovascular risk factors. This narrative review provides an overview of the literature on: (1) the evidence for an association between NAFLD and increased risk of cardiovascular, cardiac and arrhythmic complications, (2) the putative pathophysiological mechanisms linking NAFLD to CVD and other cardiac complications and (3) the current pharmacological treatments for NAFLD that might also benefit or adversely affect risk of CVD.

OBJECTIVE Several studies have explored the impact of nonalcoholic fatty liver disease (NAFLD) on risk of incident type 2 diabetes. However, the extent to which NAFLD may confer risk of incident diabetes remains uncertain. We performed a meta-analysis of relevant studies to quantify the magnitude of the association between NAFLD and risk of incident diabetes. RESEARCH DESIGN AND METHODS We collected data using PubMed, Scopus, and Web of Science from January 2000 to July 2017. We included only large (n ≥500) observational studies with a follow-up duration of at least 1 year in which NAFLD was diagnosed on imaging methods. Eligible studies were selected according to predefined keywords and clinical outcomes. Data from selected studies were extracted, and meta-analysis was performed using random-effects modeling. RESULTS A total of 19 observational studies with 296,439 individuals (30.1% with NAFLD) and nearly 16,000 cases of incident diabetes over a median of 5 years were included in the final analysis. Patients with NAFLD had a greater risk of incident diabetes than those without NAFLD (random-effects hazard ratio [HR] 2.22, 95% CI 1.84–2.60; I² = 79.2%). Patients with more “severe” NAFLD were also more likely to develop incident diabetes; this risk increased across the ultrasonographic scores of steatosis (n = 3 studies), but it appeared to be even greater among NAFLD patients with advanced high NAFLD fibrosis score (n = 1 study; random-effects HR 4.74, 95% CI 3.54–5.94). Sensitivity analyses did not alter these findings. Funnel plot and Egger test did not reveal significant publication bias. Study limitations included high heterogeneity, varying degrees of confounder adjustment across individual studies, and lack of studies using liver biopsy. CONCLUSIONS NAFLD is significantly associated with a twofold increased risk of incident diabetes. However, the observational design of the eligible studies does not allow for proving causality.