Risk for hepatic and extra-hepatic outcomes in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is defined by presence of steatosis in more than 5% of liver cells. The gold standard for diagnosis is liver biopsy, but this is seldom achieved due to costs and risk for side effects, and that is why the diagnosis is mostly made based on a combination of radiology and exclusion of other liver diseases. Disease severity staging can be noninvasively achieved with radiological exams such as elastography or blood-based markers that usually have lower sensitivity and specificity. NAFLD is today the most common chronic liver disease globally with a prevalence estimated to be 25%. Fortunately, for many persons NAFLD is an incidental finding with a good prognosis. Whilst a major focus has been on liver-related outcomes in NAFLD, there has recently been an increased interest in extrahepatic consequences of NAFLD. The most commonly studied outcomes include cardiovascular disease and cancer. The risk of adverse outcomes generally differs according to the baseline fibrosis stage. There is a five-time higher risk of liver-related events in NAFLD patients with fibrosis stage 3 as compared to those with no or little fibrosis. Meanwhile, the presence of nonalcoholic steatohepatitis (NASH) does not seem to influence prognosis in addition to fibrosis stage. Patients with NAFLD clearly have a higher risk for cardiovascular outcomes compared to the general population, with a recent meta-analysis indicating a 37% increased hazard for cardiovascular events as opposed to individuals without NAFLD. The risk of liver cancer is increased, which is mostly driven by presence of cirrhosis, but the increased risk is present also in patients without cirrhosis, and to a greater extent than for other chronic liver disease. Around one-third of patients with NAFLD and liver cancer do not have cirrhosis. Additionally, the risk of extrahepatic malignancies is thought to be moderately increased, with most evidence for a link between NAFLD and colorectal cancer where the risk is approximately 50% higher compared to patients without NAFLD. A particularly salient point is if NAFLD can be considered an independent risk factor for outcomes. Many studies have not been able to adjust for key confounders, or suffer from different forms of bias. The clinical problem is nevertheless to identify persons with an increased risk for adverse hepatic and extrahepatic outcomes. We here discuss the evidence linking NAFLD to severe hepatic and extrahepatic outcomes.