Letter to the editor: Circulating thrombospondin‐2 as a biomarker in patients with NAFLD with and without diabetes—Are we convinced yet?

To the editor, We read with interest the study by Kozumi et al. which demonstrated, using hepatic transcriptome profiling of liver tissues from patients with NAFLD, that the thrombospondin‐2 (TSP2) gene was most significantly up‐regulated in NASH and that its expression exhibited a stepwise increase along with fibrosis severity.[1] The authors highlighted the utility of circulating TSP2 as a noninvasive diagnostic biomarker of NASH and advanced fibrosis (AF) on histology. Notably, while most patients with NAFLD do not progress, type 2 diabetes (T2D) doubles the risk of developing advanced liver disease in NAFLD.[2] Therefore, there is a more pressing need for prognostic biomarkers in patients with T2D and fatty liver, especially when hepatic steatosis is highly prevalent in T2D. Interestingly, our group recently also reported significant associations between circulating TSP2 and the presence of AF in 820 exclusive patients with T2D and NAFLD using vibration‐controlled transient elastography (VCTE). More importantly, our prospective analysis found that the baseline circulating TSP2 level was independently associated with incident AF.[3] However, in contrast to the study by Kozumi et al., which found comparable performance between circulating TSP2 and conventional noninvasive fibrosis scores including the NAFLD fibrosis score (NFS) and Fibrosis‐4 (FIB‐4) index, we demonstrated significant superiority of circulating TSP2 over NFS and FIB‐4 in identifying AF among patients with T2D. Although the two studies differ in the methods of fibrosis assessment, VCTE is accurate in detecting histological fibrosis. Rather, it might be related to the suboptimal performance of these conventional fibrosis scores in T2D, as reported.[4] Moreover, the higher tissue TSP2 expression previously observed in T2D could have possibly led to its better discriminatory ability for AF in patients with T2D.[5] A subgroup analysis with participants stratified by T2D in the study by Kozumi et al. would be helpful to address this question. Nonetheless, we found that the two studies complement each other and have provided convincing evidence that circulating TSP2 is a clinically useful fibrosis biomarker in NAFLD. However, because most cases of HCC in Southeast Asia are related to viral hepatitis, further studies from Western populations are required to clarify the role of TSP2 in NAFLD‐related HCC. CONFLICT OF INTEREST Dr. Lam is an advisory board member of Merck Sharp and Dohme. Dr. Lee received speaker's fees from AstraZeneca, Bayer, and Sanofi Aventis. The remaining author has no conflict of interests.