To the Editor
We read with interest the article by Kazanko et al. in which levels of soluble (s)CD163 – a protein produced by proteolytic cleavage of CD163 expressed on the surfaces of monocyte/macrophage lineage cells – were associated with biopsy-defined liver fibrosis in patients with chronic hepatitis C virus (HCV) infection.(1) Our group recently measured plasma sCD163, sCD14 and galectin-3–binding protein (Gal-3BP – a protein secreted by classically activated (M1) macrophages) in four groups of women enrolled in the Women’s Interagency HIV Study (WIHS): a) those with HCV/HIV co-infection (N=66), b) HCV monoinfection (N=65), c) HIV monoinfection (N=64), and d) HIV-/HCV-negative controls (N=64).(2) We found that sCD163 and Gal-3BP levels were higher in women with vs. without HCV, while sCD14 levels were elevated in both HIV- and HCV-infected women compared to controls.(2) Because liver biopsy data are not available for these women, we examined cross-sectional associations of sCD163, sCD14 and Gal-3BP levels with two non-invasive measures of liver fibrosis, aspartate aminotransferase to platelet ratio index (APRI) and FIB-4, calculated as previously described.(3) The data were normalized based on log2 (sCD163) and loge (APRI and FIB-4) transformations.
Plasma sCD163 levels were significantly associated with both APRI and FIB-4 in HCV-monoinfected and HCV/HIV co-infected women (Figure 1). No significant associations were observed between sCD163 and APRI/FIB-4 in HIV monoinfected women or uninfected controls (data not shown). Furthermore, no significant associations of sCD14 and Gal-3BP were observed with APRI or FIB-4 in any study group (data not shown). The associations of sCD163 with APRI/FIB-4 in women with HCV remained statistically significant following adjustment for age, race/ethnicity, smoking, body mass index and C-reactive protein (CRP) levels in multivariate linear regression models (e.g., for HCV/HIV co-infected women, the adjusted association of sCD163 with FIB-4 was β=0.58, 95% CI=0.38–0.78; P<0.0001).
Figure 1.
Cross-sectional associations of plasma sCD163 with APRI (panels A and B) and FIB-4 (panels C and D) in HCV monoinfected and HCV/HIV co-infected women.
Our data are consistent with those of Kazanko et al. but extend their findings in important ways. First, we observe that associations of sCD163 with measures of liver fibrosis are similar in both HCV-monoinfected and HCV/HIV co-infected women. Second, the null associations of Gal-3BP and sCD14 with APRI/FIB-4 suggest that sCD163 may be unique among plasma markers of macrophage abundance, polarization, and activation (Gal-3BP, sCD163 and sCD14) in its association with liver fibrosis. However, we note that both our study and that of Kazanko et al. are cross-sectional. Prospective studies are therefore needed to better understand the influence of macrophage activation and polarization on hepatic diseases.
Acknowledgments
Financial support: Funding was provided in part by grants R01HL095140 (R.C.K.) and R01HL083760 (R.C.K.). Dr. Kuniholm is supported in part by the National Center for Advancing Translational Sciences (NCATS), through CTSA grant numbers UL1RR025750 and KL2RR025749. Clinical data and specimens used in this study were collected by the Women’s Interagency HIV Study (WIHS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH). WIHS (Principal Investigators): UAB-MS WIHS (Michael Saag, Mirjam-Colette Kempf, and Deborah Konkle-Parker), U01-AI-103401; Atlanta WIHS (Ighovwerha Ofotokun and Gina Wingood), U01-AI-103408; Bronx WIHS (Kathryn Anastos), U01-AI-035004; Brooklyn WIHS (Howard Minkoff and Deborah Gustafson), U01-AI-031834; Chicago WIHS (Mardge Cohen), U01-AI-034993; Metropolitan Washington WIHS (Mary Young), U01-AI-034994; Miami WIHS (Margaret Fischl and Lisa Metsch), U01-AI-103397; UNC WIHS (Adaora Adimora), U01-AI-103390; Connie Wofsy Women’s HIV Study, Northern California (Ruth Greenblatt, Bradley Aouizerat, and Phyllis Tien), U01-AI-034989; WIHS Data Management and Analysis Center (Stephen Gange and Elizabeth Golub), U01-AI-042590; Southern California WIHS (Alexandra Levine and Marek Nowicki), U01-HD-032632 (WIHS I – WIHS IV). The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute on Mental Health (NIMH). Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and other Communication Disorders (NIDCD), and the NIH Office of Research on Women’s Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA) and UL1-TR000454 (Atlanta CTSA).
List of abbreviations
- HCV
hepatitis C virus
- Gal-3BP
galectin-3–binding protein
- WIHS
Women’s Interagency HIV Study
- APRI
aspartate aminotransferase to platelet ratio index
- CRP
C-reactive protein
Footnotes
Conflicts of interest: All authors, no conflicts of interest.
References
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