It is evident that a very early diagnosis of HCC can lead to a good prognosis through early treatment with various modalities. To this end, this study investigated whether identifying the WFA+-M2BP levels can overcome the detection limit of imaging tests for HCC diagnosis. One of the strengths of our study was that we could histologically examine the whole liver removed at the time of LT, which enabled us to detect occult HCC that were not detected in imaging tests.
WFA+-M2BP is secreted by hepatic stellate cells (HSCs) and enhances the synthesis of Mac-2 by Kupffer cells, which renders HSCs fibrogenic. (7) Hence, WFA+-M2BP serum levels can be a useful biomarker to identify the degree of liver fibrosis. In addition, several studies have reported that M2BP levels help diagnose and predict the recurrence of HCC in HBV-and HCV-infected patients or patients with non-alcoholic fatty liver disease. (3, 4, 8–10) Patients with chronic viral hepatitis, regardless of the degree or severity of fibrosis, have elevated serum levels of M2BP, indicating an increased occurrence of HCC. (2, 11) A study on liver stiffness also indicated that M2BP might be associated with the development of HCC, independent of fibrogenesis. (4)
Our study showed that the WFA+-M2BP value could not help detect occult HCC that was undetected by imaging examination. We hypothesized that such an occurrence could be attributed to the fact that the liver in the target group was an end-stage cirrhotic liver, and the WFA+-M2BP value was detected as the degree of fibrosis. The incidence of HCC increases in patients with HBV hepatitis when the WFA+-M2BP value is above 0.69–1.8, (11–14) in patients with HCV hepatitis when the WFA+-M2BP value is above 1.75–4.2, (10, 15–17) and in NAFLD/NASH patients when the WFA+-M2BP value is above 1.255. (9) In this study, the median value was 9.53 (0.28–19.44) for all patients and 8.05 (1.25–11.9) for non-carcinoma patients, which was significantly higher than that in the previous studies which led us to recognize the strong fibrotic effect of liver. This may be attributed to the fact that the patients who require LT have decompensated cirrhosis. It was reported in 2002 that some cancer cells expressed M2BP, shedding light on its origin. (18) However, recently, hepatocytes and HSCs have been thought to secrete M2BP. (7, 19) In particular, it has been reported that M2BP-messenger RNA (mRNA) transcription in the fibrotic liver is activated in HSCs. M2BP itself is expressed in Kupffer cells. (19) M2BP-mRNA expression was also correlated with serum WFA+-M2BP levels. The specificity of WFA+-M2BP for HCC is unclear because WFA+-M2BP is a detector index of glycosylation site binding to WFA lectin. If we suppose that M2BP, independent of fibrosis and associated with the development of HCC as suggested by previous studies, can be detected, then it may be possible to detect small HCCs using this research method.
Interestingly, the level of AFP tended to differ between groups; in some groups, the level of AFP was significantly higher than that in the N group. This suggests that AFP is a potential biomarker for HCC. However, we found no significant difference in AFP levels between the N and D groups, indicating a limit of detection. New biomarkers, including DNA, RNA, and protein biomarkers and conventional laboratory metrics for HCC diagnosis were reviewed by Wang et al (20); however, M2BP was not included in the review. Further study is needed to develop early detection methods for occult HCC.
Several limitations to the present study must be noted. The small number of cases in retrospective observational analyses in a single center was one of the limitations. Second, the number of patients with no HCC was small. However, we believe that our data are essential for whole liver histological examination with sectioned small specimens.
In conclusion, serum WFA+-M2BP is not suitable to diagnose occult HCC that had not been detected by imaging tests in decompensated liver cirrhosis patients who needed LT.