Screening for nonalcoholic fatty liver disease in patients with atherosclerotic coronary disease?—In principle yes, in practice not yet
Authors: Mary E. Rinella
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. See Article On Page 754. Increased risk of cardiovascular disease (CVD)‐related mortality in patients with nonalcoholic fatty liver disease (NAFLD) was first described nearly a decade ago.1 These findings have been corroborated in numerous subsequent studies, which further demonstrated that the risk of CVD and all‐cause mortality was highest in those with nonalcoholic steatohepatitis (NASH). Those with simple steatosis were not at increased risk of CVD death, and therefore mortality risk is dependent on the histological phenotype. The only histological feature of NASH that predicts long‐term outcomes is the presence and extent of fibrosis. In a large, multinational NAFLD cohort with a 12.6‐year follow‐up, fibrosis was the only histological determinant of adverse outcomes, including CVD‐related mortality, which occurred in 38.8%.2 Mirroring these findings, a case‐control study confirmed that all‐cause and CVD‐associated mortality in NAFLD was driven by fibrosis.3 The importance of identifying those with NASH or more advanced disease (fibrosis) among a NAFLD population is illustrated by two studies derived from the National Health and Nutrition Examination Survey III, a prospective cohort study of over 11,000 patients that drew opposite conclusions with respect to mortality. In the first, NAFLD and NASH, defined by ultrasound as the absence (NAFLD) or presence of elevated alanine aminotransferase (NASH) and "normal" (no steatosis on ultrasound), found no difference in mortality between the groups.4 Kim et al. then attempted to identify those likely to have fibrosis within the same cohort based on noninvasive measures. Those with intermediate or advanced fibrosis, after multivariable adjustment, had increased all‐cause and cardiovascular‐related mortality.5 Therefore, if screening in high‐risk groups is to be advocated, screening needs to detect those at highest risk (i.e., those with NASH). In this issue of Hepatology, Wong et al.7 present data from their prospective cohort study that screened 612 consecutive patients undergoing coronary angiography with abdominal ultrasound to identify patients with concomitant NAFLD. Prevalence of NAFLD defined by ultrasound in their cohort was 58.2%, nearly double the estimated prevalence of NAFLD among U.S. adults but lower than the prevalence of NAFLD in other high‐risk groups such as type 2 diabetes.8 Patients were recruited and followed for a minimum of 5 years or until death. Outcomes were survival as well as cardiovascular‐ and liver‐related events. Overall, 84.6% of those with evidence of steatosis on ultrasound had significant atherosclerotic CVD (ASCVD), defined as stenosis of >50% in one or more coronary arteries, compared to only 64% of those without steatosis (P < 0.001). Therefore, patients with NAFLD were more likely to require percutaneous coronary intervention (PCI); 68.3% compared to 43.4% in those without NAFLD (P < 0.001). NAFLD or NASH in particular may contribute to atherosclerosis independent of the effects of visceral adiposity or other ASCVD risk factors, and several pathological mechanisms explain the association (Fig. 1). NAFLD is, at minimum, a risk marker for CVD; however, the evidence for an independent contribution is strongest in the setting of NASH, related to a proinflammatory milieu and altered lipid and glucose metabolism that promote atherogenesis. In the current study, despite a higher prevalence of severe ASCVD in the NAFLD group, they had lower rates of composite cardiovascular outcomes and mortality compared to those without NAFLD. Though this contradicts the findings of several population‐based studies, this may have been influenced by several factors. The researchers suggest that this may be related to an increased need for intervention in the NAFLD group; however, less significant, rather than tight, stenoses are more commonly associated with acute myocardial infarction. Differences in outcome between those that underwent PCI and those that did not were not statistically significant; however, this article was not designed to discern the effects of PCI on mortality or events. To put the results of this study into context, the limitations of ultrasound to define NAFLD and inability to identify those at highest risk (NASH) are relevant and render its results more difficult to interpret. The researchers identified older age and type 2 diabetes mellitus (DM) as independent risk factors for CVD. Both are also associated with advanced fibrosis in NAFLD. Interestingly, the prevalence of NAFLD in this cohort was higher than that of DM and dyslipidemia and similar to that of hypertension (HTN). Yet, no one would advocate not screening for DM, dyslipidemia, or HTN in patients with ASCVD.Figure 1: Multiple mechanisms that are integral to the pathophysiology of NAFLD and NASH in particular can promote the development of or worsen various aspects of cardiovascular disease. In each of these, available evidence supports NASH as having an independent effect after controlling for metabolic comorbidities.Although liver biopsy remains the gold standard for the diagnosis of NASH and disease staging, it is limited by risk of procedural complications, sampling error, and interobserver reliability.9 It is not feasible to perform liver biopsies on large populations; thus, most studies exploring the relationship between NAFLD and CVD have used surrogates to diagnose NASH (imaging or liver chemistries). The biggest drawback of ultrasound to define a NAFLD population is its lack of diagnostic accuracy related to limited sensitivity when steatosis is less than 30%, similarities between ultrasound features of fibrosis and steatosis (increased brightness/echotexture and vascular blurring), and its inability to identify those with NASH. Last, steatosis diminishes as NASH progresses, rendering the population arguably at highest risk for CVD less readily identified by the diagnostic test. Unfortunately, there is currently no accurate noninvasive modality to diagnose NASH. However, significant progress has been made in the detection of fibrosis, particularly at advanced stages, though accuracy decreases significantly when assessing those with lesser degrees of fibrosis that are still clinically relevant. Thus, to detect more modest fibrosis or the presence of NASH, histology remains critical. The article by Wong et al. raises important questions regarding the utility of screening for NAFLD in high‐risk populations. For screening to be worthwhile, the test must be inexpensive, cost‐effective, noninvasive, and yield information that will positively impact patient outcomes. Screening for NAFLD in the general population is not feasible; however screening in high‐prevalence groups, such as in obese diabetics, > 50 should be considered, given the high prevalence of advanced disease in this subgroup.8 The risk of NASH in those with ASCVD is less well understood, despite multiple proposed pathogenic links between the two. Other methods to detect advanced fibrosis have been studied on a small scale in this population and may be a better approach to detect those at highest risk. Long‐term prospective data are needed to better understand the relationship between NAFLD and ASCVD, as well as elucidate the potential benefits of successful treatment of NAFLD on CVD outcomes. Though the present study supports the notion that screening for NAFLD using ultrasound in patients with ASCVD may not be clinically useful, patients with ASCVD should be considered a high‐risk group, at minimum based on concomitant comorbidities. If an inexpensive, noninvasive, reliable test to detect those at highest risk of poor outcomes (i.e., NASH with some degree of fibrosis) were available, the answer to the question, "Should we screen for NASH in all patients with ASCVD?" may be yes. At this time, a reasonable approach to such patients may be to apply current guidelines for the diagnosis of NASH (using liver biopsy) in selected patients based on clinically defined risk factors.6 The identification of patients at risk for progression and poor outcomes will become increasingly relevant as the rapidly developing therapeutic landscape in NASH will provide the opportunity to alter the natural history of high‐risk patients.