Circulating levels of endotrophin and cross-linked type III collagen reflect liver fibrosis in people with HIV

Leona Dold; Mette J. Nielsen; Michael Praktiknjo; Carolynne Schwarze-Zander; Christoph Boesecke; Jan Christian Wasmuth; Jenny Bischoff; Jürgen Kurt Rockstroh; Morten A. Karsdal; Ulrich Spengler; Jonel Trebicka; Christian P. Strassburg; Diana J. Leeming; Bettina Langhans

doi:10.1186/s12879-023-08000-w

Circulating levels of endotrophin and cross-linked type III collagen reflect liver fibrosis in people with HIV

Leona Dold^*, Mette J. Nielsen, Michael Praktiknjo, Carolynne Schwarze-Zander, Christoph Boesecke, Jan Christian Wasmuth, Jenny Bischoff, Jürgen Kurt Rockstroh, Morten A. Karsdal, Ulrich Spengler, Jonel Trebicka, Christian P. Strassburg, Diana J. Leeming, Bettina Langhans

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Abstract

Background and aims: Liver-associated complications still frequently lead to mortality in people with HIV (PWH), even though combined antiretroviral treatment (cART) has significantly improved overall survival. The quantification of circulating collagen fragments released during collagen formation and degradation correlate with the turnover of extracellular matrix (ECM) in liver disease. Here, we analysed the levels of ECM turnover markers PC3X, PRO-C5, and PRO-C6 in PWH and correlated these with hepatic fibrosis and steatosis. Methods: This monocentre, retrospective study included 141 PWH. Liver stiffness and liver fat content were determined using transient elastography (Fibroscan) with integrated CAP function. Serum levels of formation of cross-linked type III collagen (PC3X), formation of type V collagen (PRO-C5) and formation type VI collagen (PRO-C6), also known as the hormone endotrophin, were measured with ELISA. Results: Twenty-five (17.7%) of 141 PWH had clinical significant fibrosis with liver stiffness ≥ 7.1 kPa, and 62 PWH (44.0%) had steatosis with a CAP value > 238 dB/m. Study participants with fibrosis were older (p = 0.004) and had higher levels of AST (p = 0.037) and lower number of thrombocytes compared to individuals without fibrosis (p = 0.0001). PC3X and PRO-C6 were markedly elevated in PWH with fibrosis. Multivariable cox regression analysis confirmed PC3X as independently associated with hepatic fibrosis. PRO-C5 was significantly elevated in participants with presence of hepatic steatosis. Conclusion: Serological levels of cross-linked type III collagen formation and endotrophin were significantly associated with liver fibrosis in PWH receiving cART and thus may be suitable as a non-invasive evaluation of liver fibrosis in HIV disease.

Originalsprog	Engelsk
Artikelnummer	52
Tidsskrift	BMC Infectious Diseases
Vol/bind	23
Antal sider	9
ISSN	1471-2334
DOI	https://doi.org/10.1186/s12879-023-08000-w
Status	Udgivet - 24. jan. 2023

Bibliografisk note

Funding Information:
Jonel Trebicka is supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57 to P18), European Union’s Horizon 2020 Research and Innovation Programme (Galaxy, No. 668031 and MICROB-PREDICT, No. 825694) and Societal Challenges—Health, Demographic Change and Wellbeing (No. 731875), and Cellex Foundation (PREDICT). Jonel Trebicka has received speaking and/or consulting fees from Gore, MSD, Grifols, Versantis, and Falk Pharma. Jürgen Kurt Rockstroh has received honoraria for speaking at educational eventsor consulting from Abivax, Galapagos, Gilead, Janssen, Merck, Theratechnologies and ViiV. JKR is past-president of the European Clinical AIDS Society and co-chair of EuroTEST. Christoph Boesecke has received honoraria for lectures and/or consultancies from AbbVie, Gilead, Janssen, MSD, ViiV. Funding from Dt. Leberstiftung, DZIF, Hector Stiftung and NEAT ID. Diana J. Leeming, Morten A. Karsdal, and Mette J Nielsen are employees of Nordic Bioscience, a company engaged in the development of biochemical markers. Morten A. Karsdal, Diana J. Leeming and Mette J Nielsen are stockholders of Nordic Bioscience. All authors declare that they have no competing interests related to this work.

Publisher Copyright:
© 2023, The Author(s).

Dokumenter og links

10.1186/s12879-023-08000-wLicens: CC BY

Open Access VersionForlagets udgivne version, 943 KBLicens: CC BY

Citationsformater

Dold, L., Nielsen, M. J., Praktiknjo, M., Schwarze-Zander, C., Boesecke, C., Wasmuth, J. C., Bischoff, J., Rockstroh, J. K., Karsdal, M. A., Spengler, U., Trebicka, J., Strassburg, C. P., Leeming, D. J., & Langhans, B. (2023). Circulating levels of endotrophin and cross-linked type III collagen reflect liver fibrosis in people with HIV. BMC Infectious Diseases, 23, Artikel 52. https://doi.org/10.1186/s12879-023-08000-w

@article{8a57c4199d7a4beaab2de77da361e33c,

title = "Circulating levels of endotrophin and cross-linked type III collagen reflect liver fibrosis in people with HIV",

abstract = "Background and aims: Liver-associated complications still frequently lead to mortality in people with HIV (PWH), even though combined antiretroviral treatment (cART) has significantly improved overall survival. The quantification of circulating collagen fragments released during collagen formation and degradation correlate with the turnover of extracellular matrix (ECM) in liver disease. Here, we analysed the levels of ECM turnover markers PC3X, PRO-C5, and PRO-C6 in PWH and correlated these with hepatic fibrosis and steatosis. Methods: This monocentre, retrospective study included 141 PWH. Liver stiffness and liver fat content were determined using transient elastography (Fibroscan) with integrated CAP function. Serum levels of formation of cross-linked type III collagen (PC3X), formation of type V collagen (PRO-C5) and formation type VI collagen (PRO-C6), also known as the hormone endotrophin, were measured with ELISA. Results: Twenty-five (17.7%) of 141 PWH had clinical significant fibrosis with liver stiffness ≥ 7.1 kPa, and 62 PWH (44.0%) had steatosis with a CAP value > 238 dB/m. Study participants with fibrosis were older (p = 0.004) and had higher levels of AST (p = 0.037) and lower number of thrombocytes compared to individuals without fibrosis (p = 0.0001). PC3X and PRO-C6 were markedly elevated in PWH with fibrosis. Multivariable cox regression analysis confirmed PC3X as independently associated with hepatic fibrosis. PRO-C5 was significantly elevated in participants with presence of hepatic steatosis. Conclusion: Serological levels of cross-linked type III collagen formation and endotrophin were significantly associated with liver fibrosis in PWH receiving cART and thus may be suitable as a non-invasive evaluation of liver fibrosis in HIV disease.",

keywords = "Endotrophin, Hepatic steatosis, HIV, Liver fibrosis, PC3X, PRO-C5, PRO-C6, Extracellular Matrix/metabolism, Humans, Procollagen/blood, Liver Cirrhosis/blood, Antiretroviral Therapy, Highly Active, Fatty Liver/blood, Collagen Type III/blood, HIV Infections/blood, Collagen Type VI/blood, Biomarkers/blood, Collagen Type V/blood, Retrospective Studies, Liver/diagnostic imaging",

author = "Leona Dold and Nielsen, {Mette J.} and Michael Praktiknjo and Carolynne Schwarze-Zander and Christoph Boesecke and Wasmuth, {Jan Christian} and Jenny Bischoff and Rockstroh, {J{\"u}rgen Kurt} and Karsdal, {Morten A.} and Ulrich Spengler and Jonel Trebicka and Strassburg, {Christian P.} and Leeming, {Diana J.} and Bettina Langhans",

note = "Funding Information: Jonel Trebicka is supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57 to P18), European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme (Galaxy, No. 668031 and MICROB-PREDICT, No. 825694) and Societal Challenges—Health, Demographic Change and Wellbeing (No. 731875), and Cellex Foundation (PREDICT). Jonel Trebicka has received speaking and/or consulting fees from Gore, MSD, Grifols, Versantis, and Falk Pharma. J{\"u}rgen Kurt Rockstroh has received honoraria for speaking at educational eventsor consulting from Abivax, Galapagos, Gilead, Janssen, Merck, Theratechnologies and ViiV. JKR is past-president of the European Clinical AIDS Society and co-chair of EuroTEST. Christoph Boesecke has received honoraria for lectures and/or consultancies from AbbVie, Gilead, Janssen, MSD, ViiV. Funding from Dt. Leberstiftung, DZIF, Hector Stiftung and NEAT ID. Diana J. Leeming, Morten A. Karsdal, and Mette J Nielsen are employees of Nordic Bioscience, a company engaged in the development of biochemical markers. Morten A. Karsdal, Diana J. Leeming and Mette J Nielsen are stockholders of Nordic Bioscience. All authors declare that they have no competing interests related to this work. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = jan,

day = "24",

doi = "10.1186/s12879-023-08000-w",

language = "English",

volume = "23",

journal = "BMC Infectious Diseases",

issn = "1471-2334",

publisher = "BioMed Central",

}

Dold, L, Nielsen, MJ, Praktiknjo, M, Schwarze-Zander, C, Boesecke, C, Wasmuth, JC, Bischoff, J, Rockstroh, JK, Karsdal, MA, Spengler, U, Trebicka, J, Strassburg, CP, Leeming, DJ & Langhans, B 2023, 'Circulating levels of endotrophin and cross-linked type III collagen reflect liver fibrosis in people with HIV', BMC Infectious Diseases, bind 23, 52. https://doi.org/10.1186/s12879-023-08000-w

TY - JOUR

T1 - Circulating levels of endotrophin and cross-linked type III collagen reflect liver fibrosis in people with HIV

AU - Dold, Leona

AU - Nielsen, Mette J.

AU - Praktiknjo, Michael

AU - Schwarze-Zander, Carolynne

AU - Boesecke, Christoph

AU - Wasmuth, Jan Christian

AU - Bischoff, Jenny

AU - Rockstroh, Jürgen Kurt

AU - Karsdal, Morten A.

AU - Spengler, Ulrich

AU - Trebicka, Jonel

AU - Strassburg, Christian P.

AU - Leeming, Diana J.

AU - Langhans, Bettina

N1 - Funding Information: Jonel Trebicka is supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57 to P18), European Union’s Horizon 2020 Research and Innovation Programme (Galaxy, No. 668031 and MICROB-PREDICT, No. 825694) and Societal Challenges—Health, Demographic Change and Wellbeing (No. 731875), and Cellex Foundation (PREDICT). Jonel Trebicka has received speaking and/or consulting fees from Gore, MSD, Grifols, Versantis, and Falk Pharma. Jürgen Kurt Rockstroh has received honoraria for speaking at educational eventsor consulting from Abivax, Galapagos, Gilead, Janssen, Merck, Theratechnologies and ViiV. JKR is past-president of the European Clinical AIDS Society and co-chair of EuroTEST. Christoph Boesecke has received honoraria for lectures and/or consultancies from AbbVie, Gilead, Janssen, MSD, ViiV. Funding from Dt. Leberstiftung, DZIF, Hector Stiftung and NEAT ID. Diana J. Leeming, Morten A. Karsdal, and Mette J Nielsen are employees of Nordic Bioscience, a company engaged in the development of biochemical markers. Morten A. Karsdal, Diana J. Leeming and Mette J Nielsen are stockholders of Nordic Bioscience. All authors declare that they have no competing interests related to this work. Publisher Copyright: © 2023, The Author(s).

PY - 2023/1/24

Y1 - 2023/1/24

N2 - Background and aims: Liver-associated complications still frequently lead to mortality in people with HIV (PWH), even though combined antiretroviral treatment (cART) has significantly improved overall survival. The quantification of circulating collagen fragments released during collagen formation and degradation correlate with the turnover of extracellular matrix (ECM) in liver disease. Here, we analysed the levels of ECM turnover markers PC3X, PRO-C5, and PRO-C6 in PWH and correlated these with hepatic fibrosis and steatosis. Methods: This monocentre, retrospective study included 141 PWH. Liver stiffness and liver fat content were determined using transient elastography (Fibroscan) with integrated CAP function. Serum levels of formation of cross-linked type III collagen (PC3X), formation of type V collagen (PRO-C5) and formation type VI collagen (PRO-C6), also known as the hormone endotrophin, were measured with ELISA. Results: Twenty-five (17.7%) of 141 PWH had clinical significant fibrosis with liver stiffness ≥ 7.1 kPa, and 62 PWH (44.0%) had steatosis with a CAP value > 238 dB/m. Study participants with fibrosis were older (p = 0.004) and had higher levels of AST (p = 0.037) and lower number of thrombocytes compared to individuals without fibrosis (p = 0.0001). PC3X and PRO-C6 were markedly elevated in PWH with fibrosis. Multivariable cox regression analysis confirmed PC3X as independently associated with hepatic fibrosis. PRO-C5 was significantly elevated in participants with presence of hepatic steatosis. Conclusion: Serological levels of cross-linked type III collagen formation and endotrophin were significantly associated with liver fibrosis in PWH receiving cART and thus may be suitable as a non-invasive evaluation of liver fibrosis in HIV disease.

AB - Background and aims: Liver-associated complications still frequently lead to mortality in people with HIV (PWH), even though combined antiretroviral treatment (cART) has significantly improved overall survival. The quantification of circulating collagen fragments released during collagen formation and degradation correlate with the turnover of extracellular matrix (ECM) in liver disease. Here, we analysed the levels of ECM turnover markers PC3X, PRO-C5, and PRO-C6 in PWH and correlated these with hepatic fibrosis and steatosis. Methods: This monocentre, retrospective study included 141 PWH. Liver stiffness and liver fat content were determined using transient elastography (Fibroscan) with integrated CAP function. Serum levels of formation of cross-linked type III collagen (PC3X), formation of type V collagen (PRO-C5) and formation type VI collagen (PRO-C6), also known as the hormone endotrophin, were measured with ELISA. Results: Twenty-five (17.7%) of 141 PWH had clinical significant fibrosis with liver stiffness ≥ 7.1 kPa, and 62 PWH (44.0%) had steatosis with a CAP value > 238 dB/m. Study participants with fibrosis were older (p = 0.004) and had higher levels of AST (p = 0.037) and lower number of thrombocytes compared to individuals without fibrosis (p = 0.0001). PC3X and PRO-C6 were markedly elevated in PWH with fibrosis. Multivariable cox regression analysis confirmed PC3X as independently associated with hepatic fibrosis. PRO-C5 was significantly elevated in participants with presence of hepatic steatosis. Conclusion: Serological levels of cross-linked type III collagen formation and endotrophin were significantly associated with liver fibrosis in PWH receiving cART and thus may be suitable as a non-invasive evaluation of liver fibrosis in HIV disease.

KW - Endotrophin

KW - Hepatic steatosis

KW - HIV

KW - Liver fibrosis

KW - PC3X

KW - PRO-C5

KW - PRO-C6

KW - Extracellular Matrix/metabolism

KW - Humans

KW - Procollagen/blood

KW - Liver Cirrhosis/blood

KW - Antiretroviral Therapy, Highly Active

KW - Fatty Liver/blood

KW - Collagen Type III/blood

KW - HIV Infections/blood

KW - Collagen Type VI/blood

KW - Biomarkers/blood

KW - Collagen Type V/blood

KW - Retrospective Studies

KW - Liver/diagnostic imaging

U2 - 10.1186/s12879-023-08000-w

DO - 10.1186/s12879-023-08000-w

M3 - Journal article

C2 - 36694115

AN - SCOPUS:85146755389

SN - 1471-2334

VL - 23

JO - BMC Infectious Diseases

JF - BMC Infectious Diseases

M1 - 52

ER -

Circulating levels of endotrophin and cross-linked type III collagen reflect liver fibrosis in people with HIV

Abstract

Bibliografisk note

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