Molecular signatures of nonalcoholic fatty liver disease: The present and future

Abstract

We read with great interest the study by Bell and coworkers1who identified by using label-free quantitative proteomics three dif-ferent panels of serum biomarkers that can be potentially used fornoninvasive diagnosis of the nonalcoholic fatty liver disease(NAFLD) spectrum. Specifically, a panel of six proteins (fibrinogenbchain, retinol binding protein 4, serum amyloid P component,lumican, transgelin 2, and CD5 antigen-like) were found to differ-entiate between all conditions in the spectrum of NAFLD. In addi-tion, a group of three proteins (complement component C7, insu-lin-like growth factor acid labile subunit, and transgelin 2)distinguished between NAFLD (simple steatosis and nonalcoholicsteatohepatitis [NASH]) versus NASH with advanced bridging fi-brosis. Finally, two proteins (prothrombin fragment and paraoxo-nase 1) discriminated with 100% accuracy between control subjectsand patients with all forms of NAFLD.1These interesting findingshighlight some important considerations. First, part of the chal-lenge for establishing a molecular signature for NAFLD is that themetabolic syndrome, which is commonly associated with NAFLD,2leads to activation of the same pathways as does NAFLD. Thissuggests that we need approaches to separate the effects of NAFLDfrom that of the metabolic syndromeper se. For instance, paraoxo-nase 13and retinol binding protein 44have been both previouslyassociated with the metabolic syndrome. Second, it is noteworthythat the use of plasma is considered superior to serum becauseapproximately 40% of signals found in serum are not found inplasma because ofex vivogeneration during clotting.5Therefore,the important results by Bell et al. need to be replicated by usingplasma samples. Those proteins related to the pathophysiology ofNAFLD displaying stable levels in both serum and plasma shouldbe good candidates to be tested in larger populations. Finally, anobvious prerequisite for the clinical use of proteomics-discoveredbiomarkers is elucidation of analytical features, standardization ofanalytical methods, assessment of performance characteristics, anddemonstration of cost-effectiveness.6Proteomics offers a great op-portunity for the development of novel, noninvasive assays for thediagnosis and monitoring of NAFLD without liver biopsy.Unfortunately, we remain some way from integrating any of thenew NAFLD biomarkers into clinical practice. As more data likethose by Bell and coworkers become available, it will be imperative that biomarkers of NAFLD with potential clinical utility areindependently validated before investment is made into producinga diagnostic test