28 Using those definitions, the investigators found that neither NAFLD nor NASH had any PD-0332991 nmr effect on subsequent mortality. The main limitation of the study was the use of serum ALT in defining NASH, which, as discussed above, is a suboptimal surrogate. Using the same data set, but employing a more-specific diagnostic marker for fibrosis, namely, the NFS, APRI, and FIB-4, we came to a slightly different conclusion—that is, NAFLD associated with evidence of fibrosis has a significant effect on subsequent mortality. It is noteworthy that most of the increase in mortality was the result of cardiovascular causes,

even when typical risk factors for atherosclerotic disease, such as hypertension, diabetes, tobacco smoking, history of CVD, and lipid disorders, were already taken into account. This observation is consistent with previous data that NAFLD is an independent predictor of cardiovascular morbidity.29-31 With regard to mortality from liver disease, the lack of significant association between NAFLD with or without fibrosis and mortality in this study should not be construed as a proof that NAFLD does not lead to morbidity and mortality from CLD. Instead, we believe

that it is likely a type II error that, despite the large sample size of the NHANES study, the number of deaths from liver disease in the data set was too low to draw a firm conclusion. In addition, in patients with NAFLD, CVD represents such a strong competing risk that the study of the effect of NAFLD on liver-related mortality may require a selleck kinase inhibitor Fluorometholone Acetate much larger sample and/or longer follow-up. In the meantime, it may be fair to point out that the absolute risk of liver mortality in subjects with NAFLD in the general population is quite small. This is in contrast to previous investigations, frequently conducted in NAFLD patients who underwent liver biopsies at specialty liver clinics, which showed increased mortality from liver disease.5-7, 32 The difference between those and population-based studies

such as ours is probably attributable to selection bias entailed in referral patients. Based on our data, we believe that, although it is wise to follow NAFLD patients with advanced fibrosis from the liver standpoint, it may be more important to pay attention to their cardiovascular risk to improve their overall outcome. We do acknowledge limitations of this study. With regard to the assessment for steatosis and fibrosis, neither USG nor the fibrosis markers used in the study is an ideal diagnostic modality in an individual patient. For population-based epidemiological studies like ours, a balance needs to be sought between the accuracy of the diagnostic tools and feasibility of obtaining the diagnostic information.