Noninvasive disease severity assessment in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease affecting one-fourth population globally. It is also anticipated to be the major cause of liver-related morbidity and transplantation worldwide in the future decades.¹ Of note the Asia-Pacific has a tremendous burden because of the rapid Westernization of the region and the racial characteristics.^2-4 Currently, NAFLD represents a clinical field possessing several unmet needs. The major one is currently no reliable biomarker for disease severity, disease course, or outcome measurement. Therefore, a reliable and confident biomarker for the purposes deserves exploration. The effort  is no doubt more challenging than for viral hepatitis infection.

Cheng et al. presented the study results of the correlation of Mac-2 binding protein glycosylation isomer (M2BPGi) serum level with the other documented noninvasive biomarkers or panels in a single-center retrospective NAFLD database.⁵ M2BPGi has been vigorously studied as a marker for fibrosis in chronic hepatitis B virus infection, chronic hepatitis C virus infection, nonalcoholic steatohepatitis, and even hepatocellular carcinoma.^6-9 The cross-sectional study measured the serum levels of the recently-identified glycosylation isoform of Mac-2 binding protein in both NAFLD and healthy controls. The results showed that the serum levels of M2BPGi were significantly correlated with the levels of AST to platelet ratio index, fibrosis 4 score (FIB-4), and NAFLD fibrosis score, respectively. The M2BPGi levels were significantly higher in females and had an incremental increase with age in both NAFLD patients and the healthy controls. In addition, the M2BPGi level was significantly higher in those intermediate or high risk for advanced fibrosis (defined as FIB-4 level ≥ 1.45) than their low-risk counterparts (FIB-4 level < 1.45). The results thus provided a piece of work addressing the noninvasive fibrosis assessment for the complex metabolic liver disorder.

Generally, the degree of liver fibrosis is the major determinant and the significant predictor of long-term outcomes in patients with NAFLD. There is a higher risk of mortality associated with a higher stage of fibrosis in NAFLD.^{10, 11} Moreover, the risk of liver-related mortality increased on an exponential rather than linear scale with an increase in fibrosis stage.¹² Liver biopsy remains an expensive and invasive procedure associated with potential complications, sampling error, and interobserver variability. Besides imaging- and elastography-based methods, several serum-based panels have been developed for the noninvasive approach to disease severity. Recently, the easy-to-access FIB-4 method has been validated in providing an accurate prediction of liver fibrosis and liver-related events. The algorithm has been adapted by major societies as a clinically useful tool for advanced fibrosis assessment.^13-15 Nonetheless, further validation efforts across disease etiology, ethnicities, and other clinical factors are mandatory. In this direction, the current study provided a real-world validation approach for the performance of the serum biomarker in a clinical setting.

Some issues remain under investigation despite the achievements of the study. The transition between fibrosis stages in the disease spectrum of NAFLD remains elusive, which mainly depends on histopathological interpretation. The lack of histopathological data could partly undermine the results and clinical implications. Second, although FIB-4 is widely used to predict the presence of advanced fibrosis, it is a tool for excluding advanced fibrosis rather than diagnosis per se. The cut-off values for FIB-4 in determining different risk levels have been extensively validated in the past decade. The results of the current study could be affected by using different values. In addition, the performance of a single biomarker could be significantly increased by combination with other biomarkers.⁷ Last but not least, results from a longitudinal follow-up study, preferably with other noninvasive methods, will provide more sufficient and convincing evidence in this regard.

In conclusion, M2BPGi is a useful noninvasive biomarker for liver fibrosis assessment in NAFLD patients. Future validation of the performance for outcome prediction in a longitudinal manner will be a promising perspective.

Jee-Fu Huang: Consultant of Roche, BMS, Gilead, Merck, Sysmex, Pharmaessential, Polaris, Aligos, and Instylla. Speaker for Abbvie, BMS, Gilead, Merck, Sysmex, and Roche.