Reply
Authors: Konstantin Kazankov, Holger Jon Møller, Bo Martin Bibby, Hendrik Vilstrup, Jacob George, Henning Grønbæk
Journal: Hepatology (2014)

This work was supported bt the NOVO Nordisk Foundation, The Danish Strategic Research Council (TRAIN 10‐092797), grants from the National Health and Medical Research Council of Australia (632630, 1049857, and 1053206), and the Robert W. Storr Bequest to the Sydney Medical Foundation of the University of Sydney. Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. We read with interest the letter by Kuniholm et al., demonstrating independent associations between the monocyte/macrophage‐specific activation marker, soluble (s)CD163, and the established fibrosis models, aspartate aminotransferase AST to platelet ratio index (APRI) and FIB‐4, in women with hepatitis C virus (HCV) and HCV/human immunodeficiency virus (HIV) coinfection. Although the study lacks liver biopsy for fibrosis staging, these data support and validate our findings1 and provide additional corroboration of the role for macrophage involvement in liver fibrosis. HIV coinfection did not influence the relationship between sCD163 and the fibrosis models, which is interesting because FIB‐4 was developed for HCV/HIV coinfected patients,2 and both APRI and FIB‐4 have been repeatedly validated in HCV/HIV coinfection.3 These findings suggest that sCD163 may be a good fibrosis marker not only in HCV monoinfection, but also in HCV/HIV coinfection, but this needs validation in coinfected patients with histological data. Kuniholm et al. suggest that sCD163 is a unique macrophage marker of liver fibrosis. We fully endorse this view and provide additional data in support of this contention from the recent literature. First, Sandler et al. demonstrated elevated levels of sCD14 in hepatitis B virus (HBV) and HCV patients with severe fibrosis and reported a prognostic value for CD14+ macrophages and sCD14 for disease progression in chronic viral hepatitis.5 However, this is in contrast with the findings of Kuniholm et al. In a recent study from our group, HCV patients with cirrhosis, as assessed by transient elastography, had higher levels of sCD163 and sCD206 (the shed mannose receptor), compared to those with no/mild fibrosis. However, sCD206 was inferior to sCD163 in cirrhosis prediction,6 supporting the notion that sCD163 may be the best macrophage‐specific biomarker in chronic viral hepatitis. In our published report, liver biopsy data were available for all patients and we focused on the relationship between sCD163 and the histological scores for inflammation and fibrosis.1 For this reason, the associations between sCD163 and APRI/FIB‐4 were omitted, but we are pleased to present them here. Consistent with the data by Kuniholm et al., sCD163 (logarithmically transformed) was strongly associated with APRI (r = 0.64; P < 0.001) and FIB‐4 (r = 0.59; P < 0.001) in our 551 HCV patients. In the 203 HBV patients, sCD163 was associated with APRI (r = 0.51; P < 0.001) and showed a trend toward association with FIB‐4 (r = 0.14; P = 0.09). To investigate the adjusted relationship between sCD163 and fibrosis, we performed multiple ordered logistic regression analysis with the fibrosis score as the dependent variable and sCD163, APRI, and FIB‐4 (all logarithmically transformed) as the explanatory. In this model, we observed a clear significant association between sCD163 and the fibrosis score after adjustment for APRI and FIB‐4, both in patients with HCV and HBV infection (Table 1). Taken together, the data indicate that sCD163 correlates with APRI and FIB‐4, but possesses the capability for fibrosis prediction beyond both models, and this is further illustrated by the very good performance of sCD163‐based fibrosis scores, particularly in HCV patients.1 Table 1 - Multiple Ordered Logistic Regression Analysis in Patients With HCV and HBV Infection OR (95% CI) P Value Patients with hepatitis C infection Log sCD163 1.20 (1.09‐1.33) <0.001 Log APRI 1.08 (0.99‐1.19) 0.092 Log FIB‐4 1.31 (1.18‐1.46) <0.001 Patients with hepatitis B infection Log sCD163 1.32 (1.11‐1.58) 0.002 Log APRI 1.11 (0.94‐1.31) 0.203 Log FIB‐4 1.03 (0.89‐1.18) 0.722 The ORs for sCD163 describe the increase in the odds for a given fibrosis stage, for example, F ≥2, for a patient with 25% higher sCD163, compared with another patient, provided that the 2 patients have the same APRI and FIB‐4. The ORs for APRI and FIB‐4 are calculated similarly.With the fibrosis score as the dependent variable and sCD163, APRI, and FIB‐4 as the explanatory.Abbreviations: OR, odds ratio; CI, confidence interval. Finally, we entirely agree with Kuniholm et al. that longitudinal studies of sCD163 and other macrophage markers, preferably under antiviral treatment with repeated liver biopsies, are needed to further elucidate the role of macrophages and the prognostic value of macrophage markers in chronic viral hepatitis.