We read with great interest the study by Bell and coworkers1 who identified by using label-free quantitative proteomics three different panels of serum biomarkers that can be potentially used for noninvasive diagnosis of the nonalcoholic fatty liver disease (NAFLD) spectrum. Specifically, a panel of six proteins (fibrinogen β chain, retinol binding protein 4, serum amyloid P component, lumican, transgelin 2, and CD5 antigen-like) were found to differentiate between all conditions in the spectrum of NAFLD. In addition, a group of three proteins (complement component C7, insulin-like growth factor acid labile subunit, and transgelin 2) distinguished between NAFLD (simple steatosis and nonalcoholic steatohepatitis [NASH]) versus NASH with advanced bridging fibrosis. Finally, two proteins (prothrombin fragment and paraoxonase 1) discriminated with 100% accuracy between control subjects and patients with all forms of NAFLD.1 These interesting findings highlight some important considerations. First, part of the challenge for establishing a molecular signature for NAFLD is that the metabolic syndrome, which is commonly associated with NAFLD,2 leads to activation of the same pathways as does NAFLD. This suggests that we need approaches to separate the effects of NAFLD from that of the metabolic syndrome per se. For instance, paraoxonase 13 and retinol binding protein 44 have been both previously associated with the metabolic syndrome. Second, it is noteworthy that the use of plasma is considered superior to serum because approximately 40% of signals found in serum are not found in plasma because of ex vivo generation during clotting.5 Therefore, the important results by Bell et al. need to be replicated by using plasma samples. Those proteins related to the pathophysiology of NAFLD displaying stable levels in both serum and plasma should be good candidates to be tested in larger populations. Finally, an obvious prerequisite for the clinical use of proteomics-discovered biomarkers is elucidation of analytical features, standardization of analytical methods, assessment of performance characteristics, and demonstration of cost-effectiveness.6 Proteomics offers a great opportunity for the development of novel, noninvasive assays for the diagnosis and monitoring of NAFLD without liver biopsy. Unfortunately, we remain some way from integrating any of the new NAFLD biomarkers into clinical practice. As more data like those by Bell and coworkers become available, it will be imperative that biomarkers of NAFLD with potential clinical utility are independently validated before investment is made into producing a diagnostic test.
To the Editor:
Yusuf Yilmaz M.D.*, Engin Ulukaya M.D., Ph.D., * Department of Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey, Department of Biochemistry, Uludag University Medical School, Bursa, Turkey.