CVD and NAFLD are clearly related clinical entities, and there have been efforts to identify a direct relationship between them. Both are multifactorial conditions that share common risk factors, and a direct causal relationship between NAFLD and CVD morbidity and mortality has not yet been conclusively shown.

There are several potential reasons for mixed results in the studies that have been conducted in this area thus far. One possibility may be related to competing risks of non-CV death (ie, confounding due to other causes of death, which might include malignancies, liver-related events, or deaths from natural causes). These studies are largely observational, and many are retrospective, as prospective studies would be difficult to design and expensive to perform, in part due to the typically slow progression of NAFLD over a period of years. Another possible reason is that existing studies do not account for genetic polymorphisms that could differentially impact liver- and cardiac-related outcomes. The TM6SF2 E167K variant, for instance, appears to predispose children with obesity to NAFLD, yet it is also associated with lower levels of CV risk factors.

I do believe that it should be possible to design a prospective trial that overcomes many of these obstacles, perhaps using a surrogate CV marker such as the coronary artery calcium score. Another area that may benefit from further exploration is the risk of CVD in lean vs obese patients with NAFLD. So far, the CVD risk appears to be similar in both populations, but this is based on limited data.

CVD risk in patients with progressive NAFLD takes on a slightly different meaning when you begin to consider the liver transplant population. Protocols are increasingly incorporating noninvasive imaging studies to assess CV risk, and, depending on the scenario, NAFLD itself may be considered to be a risk factor that warrants cardiac assessment. That is, the threshold for checking coronaries in a noninvasive fashion, even if a patient does not have a positive stress test or a history of coronary artery disease, is much lower in individuals with NAFLD than in those without it.

In summary, many studies have confirmed the link between NAFLD and CVD, showing a negative impact on patient outcomes. However, studies have yet to confirm a direct causal relationship between NAFLD and CVD morbidity and mortality. Based on the current data, we cannot exclude the possibility that NAFLD is an independent risk factor for CV events. Further, NAFLD is associated with an increased long-term risk of fatal and nonfatal CV events, a risk that increases in patients with more advanced liver disease, especially those with a higher fibrosis stage.