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Published in: BMC Gastroenterology 1/2023

Open Access 01-12-2023 | Fatty Liver | Research

Soluble CD163 is a predictor of fibrosis and hepatocellular carcinoma development in nonalcoholic steatohepatitis

Authors: Miwa Kawanaka, Ken Nishino, Mayuko Kawada, Katsunori Ishii, Tomohiro Tanikawa, Ryo Katsumata, Noriyo Urata, Jun Nakamura, Mitsuhiko Suehiro, Ken Haruma, Hirofumi Kawamoto

Published in: BMC Gastroenterology | Issue 1/2023

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Abstract

Background

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. The serum level of soluble CD163 (sCD163), a macrophage activation marker, is associated with liver tissue changes; however, its prognostic value is unknown. Here, we determined the utility of sCD163 as a marker for hepatocellular carcinoma (HCC) and prognostic marker for NAFLD.

Methods

This retrospective study obtained data regarding serum sCD163 levels, liver histology, and background factors associated with NAFLD in 287 patients (men/women, 140/147; average age, 53 ± 14 years) with NAFLD who underwent liver biopsy. Repeated liver biopsies of 287 patients with NAFLD (5.0 ± 2.7 years) were compared regarding serum sCD163 levels and liver tissue changes (stage, grade, steatosis, and NAFLD activity score).

Results

Serum sCD163 levels increased with the progression of liver fibrosis and inflammation (both P < 0.05) and were particularly helpful in distinguishing cases of Grade 4 fibrosis (P < 0.001). Levels of sCD163 significantly decreased in patients with NAFLD exhibiting alleviated fibrosis and inflammation (P < 0.05). We could also predict the development of HCC and associated mortality based on serum sCD163 levels at the time of NAFLD diagnosis. Serum sCD163 levels were higher in patients with HCC than in patients without HCC (1074 ± 379 ng/ml vs. 669 ± 261 ng/ml; P < 0.0001), and the same trend was observed for mortality.

Conclusions

The serum sCD163 level reflects the progression of fibrosis and inflammation in liver tissues, showing much promise as a noninvasive biomarker for nonalcoholic steatohepatitis and NAFLD as well as a possible predictor of HCC development and patient prognosis.
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Literature
1.
go back to reference Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.CrossRefPubMed Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.CrossRefPubMed
2.
go back to reference European Association for the Study of the Liver (EASL). European Association for the study of diabetes (EASD); European Association for the study of obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388–402.CrossRef European Association for the Study of the Liver (EASL). European Association for the study of diabetes (EASD); European Association for the study of obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388–402.CrossRef
3.
go back to reference Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the study of Liver Diseases. Hepatology. 2018;67:328–57.CrossRefPubMed Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the study of Liver Diseases. Hepatology. 2018;67:328–57.CrossRefPubMed
4.
go back to reference Huang DQ, EI-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2021:18223–38. Huang DQ, EI-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2021:18223–38.
5.
go back to reference McGlynn KA, Petrick JL, EI-Serag H. Epidemiology of hepatocellular carcinoma. Hepatology. 2021;73:4–13.CrossRefPubMed McGlynn KA, Petrick JL, EI-Serag H. Epidemiology of hepatocellular carcinoma. Hepatology. 2021;73:4–13.CrossRefPubMed
6.
go back to reference Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43:617–49.CrossRefPubMed Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43:617–49.CrossRefPubMed
7.
go back to reference Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13:643–54.CrossRefPubMed Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13:643–54.CrossRefPubMed
8.
go back to reference Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149: 389 – 97.e10. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149: 389 – 97.e10.
9.
go back to reference Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology. 2017;65:1557–65.CrossRefPubMed Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology. 2017;65:1557–65.CrossRefPubMed
10.
go back to reference Hagström H, Nasr P, Ekstedt M, Hammar U, Stål P, Hultcrantz R, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67:1265–73.CrossRefPubMed Hagström H, Nasr P, Ekstedt M, Hammar U, Stål P, Hultcrantz R, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67:1265–73.CrossRefPubMed
12.
go back to reference Hegazy MA, Mogawer SM, Alnaggar ARLR, Ghoniem OA, Abdel Samie RM. Serum LPS and CD163 biomarkers confirming the role of gut dysbiosis in overweight patients with NASH. Diabetes Metab Syndr Obes. 2020;13:3861–72.CrossRefPubMedPubMedCentral Hegazy MA, Mogawer SM, Alnaggar ARLR, Ghoniem OA, Abdel Samie RM. Serum LPS and CD163 biomarkers confirming the role of gut dysbiosis in overweight patients with NASH. Diabetes Metab Syndr Obes. 2020;13:3861–72.CrossRefPubMedPubMedCentral
13.
go back to reference Mǿller HJ, Peterslund NA, Graversen JH, Moestrup SK. Identification of the hemoglobin scavenger receptor/CD163 as a natural soluble protein in plasma. Blood. 2002;99:378–80.CrossRefPubMed Mǿller HJ, Peterslund NA, Graversen JH, Moestrup SK. Identification of the hemoglobin scavenger receptor/CD163 as a natural soluble protein in plasma. Blood. 2002;99:378–80.CrossRefPubMed
14.
go back to reference Hintz KA, Rassias AJ, Wardwell K, Moss ML, Morganelli PM, Pioli PA, et al. Endotoxin induces rapid metalloproteinase-mediated shedding followed by up-regulation of the monocyte hemoglobin scavenger receptor CD163. J Leukoc Biol. 2002;72:711–7.CrossRefPubMed Hintz KA, Rassias AJ, Wardwell K, Moss ML, Morganelli PM, Pioli PA, et al. Endotoxin induces rapid metalloproteinase-mediated shedding followed by up-regulation of the monocyte hemoglobin scavenger receptor CD163. J Leukoc Biol. 2002;72:711–7.CrossRefPubMed
15.
go back to reference Rittig NR, Svart M, Jessen N, Møller N, Møller HJ, Grønbæk H. Macrophage activation markers sCD163 correlates with accelerated lipolysis following LPS exposure: a human-randomised clinic trial. Endocr Connect. 2018;7:107–14.CrossRefPubMed Rittig NR, Svart M, Jessen N, Møller N, Møller HJ, Grønbæk H. Macrophage activation markers sCD163 correlates with accelerated lipolysis following LPS exposure: a human-randomised clinic trial. Endocr Connect. 2018;7:107–14.CrossRefPubMed
16.
go back to reference Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA, NASH Clinical Research Network (CRN). Nonalcoholic fatty liver disease (NAFLD) activity score and the histologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011;53:810–20.CrossRefPubMed Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA, NASH Clinical Research Network (CRN). Nonalcoholic fatty liver disease (NAFLD) activity score and the histologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011;53:810–20.CrossRefPubMed
17.
go back to reference Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.CrossRefPubMed Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.CrossRefPubMed
18.
go back to reference Sǿrensen LP, Parkner T, Sǿndergaard E, Bibby BM, Møller HJ, Nielsen S. Visceral obesity is associated with increased soluble CD163 concentration in men with type 2 diabetes mellitus. Endocr Connect. 2015;4:27–36.CrossRefPubMedPubMedCentral Sǿrensen LP, Parkner T, Sǿndergaard E, Bibby BM, Møller HJ, Nielsen S. Visceral obesity is associated with increased soluble CD163 concentration in men with type 2 diabetes mellitus. Endocr Connect. 2015;4:27–36.CrossRefPubMedPubMedCentral
19.
go back to reference Kazankov K, Berrera F, Mǿller HJ, Rosso C, Bugianesi E, David E et al. The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease. Liver Int. 2016;36:1449 – 557. Kazankov K, Berrera F, Mǿller HJ, Rosso C, Bugianesi E, David E et al. The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease. Liver Int. 2016;36:1449 – 557.
20.
go back to reference Rosso C, Kazankov K, Younes R, Esmaili S, Marietti M, Sacco M, et al. Crosstalk between adipose tissue insulin resistance and liver macrophages in non-alcoholic fatty liver disease. J Hepatol. 2019;71:1012–21.CrossRefPubMed Rosso C, Kazankov K, Younes R, Esmaili S, Marietti M, Sacco M, et al. Crosstalk between adipose tissue insulin resistance and liver macrophages in non-alcoholic fatty liver disease. J Hepatol. 2019;71:1012–21.CrossRefPubMed
21.
go back to reference Rǿdgaard-Hansen S, St George A, Kazankov K, Bauman A, George J, Grønbæk H, et al. Effects of lifestyle intervention on soluble CD163, a macrophage activation marker, in patients with non-alcoholic fatty liver disease. Scand J Clin Lab Invest. 2017;77:498–504.CrossRefPubMed Rǿdgaard-Hansen S, St George A, Kazankov K, Bauman A, George J, Grønbæk H, et al. Effects of lifestyle intervention on soluble CD163, a macrophage activation marker, in patients with non-alcoholic fatty liver disease. Scand J Clin Lab Invest. 2017;77:498–504.CrossRefPubMed
22.
go back to reference Kazankov K, Tordjman J, Mǿller HJ, Vilstrup H, Poitou C, Bedossa P, et al. Macrophage activation marker soluble CD163 and non-alcoholic fatty liver disease in morbidly obese patients undergoing bariatric surgery. J Gastroenterol Hepatol. 2015;30:1293–300.CrossRefPubMed Kazankov K, Tordjman J, Mǿller HJ, Vilstrup H, Poitou C, Bedossa P, et al. Macrophage activation marker soluble CD163 and non-alcoholic fatty liver disease in morbidly obese patients undergoing bariatric surgery. J Gastroenterol Hepatol. 2015;30:1293–300.CrossRefPubMed
23.
go back to reference Mueller JL, Feeney ER, Zheng H, Misdraji J, Kruger AJ, Alatrakchi N, et al. Circulating soluble CD163 is associated with steatohepatitis and advanced fibrosis in nonalcoholic fatty liver disease. Clin Transl Gastroenterol. 2015;6:e114.CrossRefPubMedPubMedCentral Mueller JL, Feeney ER, Zheng H, Misdraji J, Kruger AJ, Alatrakchi N, et al. Circulating soluble CD163 is associated with steatohepatitis and advanced fibrosis in nonalcoholic fatty liver disease. Clin Transl Gastroenterol. 2015;6:e114.CrossRefPubMedPubMedCentral
24.
go back to reference De Vito R, Alisi A, Masotti A, Ceccarelli S, Panera N, Citti A, et al. Markers of activated inflammatory cells correlate with severity of liver damage in children with nonalcoholic fatty liver disease. Int J Mol Med. 2012;30:49–56.PubMed De Vito R, Alisi A, Masotti A, Ceccarelli S, Panera N, Citti A, et al. Markers of activated inflammatory cells correlate with severity of liver damage in children with nonalcoholic fatty liver disease. Int J Mol Med. 2012;30:49–56.PubMed
25.
go back to reference Kazankov K, Mǿller HJ, Lange A, Birkebaek NH, Holland-Fischer P, Solvig J, et al. The macrophage activation marker sCD163 associated with changes in NAFLD and metabolic profile during lifestyle intervention in obese children. Pediatr Obes. 2015;10:226–33.CrossRefPubMed Kazankov K, Mǿller HJ, Lange A, Birkebaek NH, Holland-Fischer P, Solvig J, et al. The macrophage activation marker sCD163 associated with changes in NAFLD and metabolic profile during lifestyle intervention in obese children. Pediatr Obes. 2015;10:226–33.CrossRefPubMed
26.
go back to reference Testro AG, Visvanathan K. Toll-like receptors and their role in gastrointestinal disease. J Gastroenterol Hepatol. 2009;24:943–54.CrossRefPubMed Testro AG, Visvanathan K. Toll-like receptors and their role in gastrointestinal disease. J Gastroenterol Hepatol. 2009;24:943–54.CrossRefPubMed
27.
go back to reference Iwaki M, Kessoku T, Ozaki A, Kasai Y, Kobayashi T, Nogami A, et al. Gut microbiota composition associated with hepatic fibrosis in non-obese patients with non-alcoholic fatty liver disease. Gastroenterol Hepatol. 2021;36:2275–84.CrossRef Iwaki M, Kessoku T, Ozaki A, Kasai Y, Kobayashi T, Nogami A, et al. Gut microbiota composition associated with hepatic fibrosis in non-obese patients with non-alcoholic fatty liver disease. Gastroenterol Hepatol. 2021;36:2275–84.CrossRef
28.
go back to reference Ambade A, Satishchandran A, Saha B, Gyongyosi B, Lowe P, Kodys K, et al. Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1 α induced IL-10. Oncoimmunlogy. 2016;5:e1221557.CrossRef Ambade A, Satishchandran A, Saha B, Gyongyosi B, Lowe P, Kodys K, et al. Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1 α induced IL-10. Oncoimmunlogy. 2016;5:e1221557.CrossRef
29.
go back to reference Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140:197–208.CrossRefPubMedPubMedCentral Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140:197–208.CrossRefPubMedPubMedCentral
30.
go back to reference Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10:656–65.CrossRefPubMed Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10:656–65.CrossRefPubMed
31.
go back to reference Gantzel RH, Kjær MB, Laursen TL, Kazankov K, George J, et al. Macrophage activation markers, Soluble CD163 and mannose receptor, in Liver Fibrosis. Front Med. 2021;7:615599.CrossRef Gantzel RH, Kjær MB, Laursen TL, Kazankov K, George J, et al. Macrophage activation markers, Soluble CD163 and mannose receptor, in Liver Fibrosis. Front Med. 2021;7:615599.CrossRef
32.
go back to reference Watany M, Badawi R, Elkhalawany W, Abd-Elsalam S. Study of dickkopf-1 (DKK-1) gene expression in hepatocellular carcinoma patients. J Clin Diagn Res. 2017;11:OC32–4.PubMedPubMedCentral Watany M, Badawi R, Elkhalawany W, Abd-Elsalam S. Study of dickkopf-1 (DKK-1) gene expression in hepatocellular carcinoma patients. J Clin Diagn Res. 2017;11:OC32–4.PubMedPubMedCentral
33.
go back to reference Elhendawy M, Abdul-Baki EA, Abd-Elsalam S, Hagras MM, Zidan AA, et al. MicroRNA signature in hepatocellular carcinoma patients: identification of potential markers. Mol Biol Rep. 2020;47:4945–53.CrossRefPubMed Elhendawy M, Abdul-Baki EA, Abd-Elsalam S, Hagras MM, Zidan AA, et al. MicroRNA signature in hepatocellular carcinoma patients: identification of potential markers. Mol Biol Rep. 2020;47:4945–53.CrossRefPubMed
34.
go back to reference El-Gebaly F, Abou-Saif S, Elkadeem M, Helmy A, Abd-Elsalam S, et al. Study of serum soluble programmed death ligand 1 as a prognostic factor in Hepatocellular Carcinoma in Egyptian Patients. Curr Cancer Drug Targets. 2019;19:896–905.CrossRefPubMed El-Gebaly F, Abou-Saif S, Elkadeem M, Helmy A, Abd-Elsalam S, et al. Study of serum soluble programmed death ligand 1 as a prognostic factor in Hepatocellular Carcinoma in Egyptian Patients. Curr Cancer Drug Targets. 2019;19:896–905.CrossRefPubMed
Metadata
Title
Soluble CD163 is a predictor of fibrosis and hepatocellular carcinoma development in nonalcoholic steatohepatitis
Authors
Miwa Kawanaka
Ken Nishino
Mayuko Kawada
Katsunori Ishii
Tomohiro Tanikawa
Ryo Katsumata
Noriyo Urata
Jun Nakamura
Mitsuhiko Suehiro
Ken Haruma
Hirofumi Kawamoto
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Gastroenterology / Issue 1/2023
Electronic ISSN: 1471-230X
DOI
https://doi.org/10.1186/s12876-023-02786-4

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