Nonalcoholic fatty liver disease, metabolic syndrome, and the fight that will define clinical practice for a generation of hepatologists

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic. Worldwide, 1 in 4 people have NAFLD. Further, increasing in parallel with the rising prevalence of obesity and metabolic syndrome, the prevalence and public health impact of NAFLD will worsen. In the coming post–hepatitis C era, NAFLD will be the hepatologist’s greatest foe; NAFLD is the fastest-growing cause of cirrhosis and hepatocellular carcinoma. At the same time, as is well known, the presence of NAFLD is inextricably linked to cardiovascular risk. Indeed, for patients with NAFLD, cardiovascular complications may prove more common and impactful than liver-related morbidity. Associations between NAFLD and cardiovascular risk, however, have been established with observational data that do not have the power to discern causality or to disentangle cross-sectional from longitudinal effects. Study design matters. At present, the relationship between NAFLD and cardiovascular risk represents a classic chicken-versus-egg problem. Data are needed to clarify the temporal interaction between NAFLD, advanced liver disease, and cardiovascular risk. Such an understanding will guide both the focal points of preventive efforts and the structure of our collaborative relationship with colleagues in primary care, endocrinology, and cardiology for patients at various stages of NAFLD. To this end, Allen and her colleagues present the new data to date from 3,869 patients with NAFLD defined by diagnosis codes with careful exclusion of patients with any codes consistent with viral hepatitis, alcohol use disorder, and other liver diseases, matched to 15,209 controls included in the Rochester Epidemiology Project database (19972014). At first glance, like all retrospective observational cohort studies, any conclusions are intrinsically limited by selection and information biases. In this case, however, each variable used data that integrate not only billing codes but also laboratory values (e.g., FIB-4, hemoglobin A1C) and medication use (e.g., antihypertensives, insulin secretagogues). These features enhance the accuracy of exposure and outcome ascertainment substantially. By combining longitudinal, population-based data with rigorously defined comorbidities, these data raise the bar for epidemiological associations and provide a better picture of how NAFLD and comorbidities fit into a sequence. This study advances the epidemiology of NAFLD in two principal ways. First, the study suggests that NAFLD may be an accelerant for cardiovascular risk. The authors confirm that NAFLD is associated with increased overall mortality but that this risk is driven by the burden of metabolic comorbidities. However, in patients with limited or no metabolic comorbidities, NAFLD is significantly associated with death and the Abbreviation: NAFLD, nonalcoholic fatty liver disease.