(Cleaved) <scp>CK</scp>18 serum and tissue expression levels differentiate acute <scp>HCV</scp> reinfection from acute rejection in liver allografts

Reis, Henning; Wohlschläger, J.; Hagemann, Sascha; Wenzel, Patricia; Bechmann, Lars P.; Suttorp, Anna-Carinna; Schlattjan, Martin; Herzer, Kerstin; Canbay, Ali; Baba, Hideo A.

doi:10.1111/liv.12572

Cited by 5 publications

(7 citation statements)

References 29 publications

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“…While this was the first analysis of the predictive value of CK18 levels for graft injury after liver transplantation beyond hepatitis C 28 , the association of DSA with graft injury in general is a well described phenomenon 4,12,14,16,18,20,21 . However, we are not aware of another study with a specific focus on non-invasive capacities of both parameters in comparison to the routine blood markers to detect subclinical graft injury in adults.…”

Section: Discussionmentioning

confidence: 99%

Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies

Höfer

Jonigk

Hartleben

et al. 2020

Sci Rep

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The majority of liver grafts exhibit abnormal histological findings late after transplantation, even when liver enzymes are normal. Such subclinical graft injuries were associated with rejection and fibrosis progression in recent studies. The identification of non-invasive biomarkers for subclinical graft injury might help to individualize immunosuppression. Therefore, graft injury was assessed in 133 liver biopsies with normal/near normal liver enzymes from a prospective liver biopsy program. Cytokeratin-18 cell death marker (M65) and donor specific anti-HLA antibodies (DSA) were measured as non-invasive markers in paired plasma samples in addition to routine parameters. M65 was associated with subclinical graft injury but this association was too weak for reasonable clinical application. DSA positivity was associated with more graft inflammation (OR = 5.4) and more fibrosis (OR = 4.2). Absence of DSA excluded fibrosis in 87-89%, while presence of DSA excluded histological criteria for immunosuppression minimization attempts in 92-97%. While CK18 cell death marker had no diagnostic value for the detection of subclinical liver graft injury, DSA testing can help to preselect patients for immunosuppression reduction in case of DSA negativity, while DSA positivity should prompt elastography or liver biopsy for the assessment of subclinical graft injury. Abbreviations ALP Alkaline phosphatase ALT Alanine transaminase AMR Antibody-mediated rejection AST Aspartate transaminase cAMR Possible chronic antibody-mediated rejection CK18 Cytokeratin-18 CI 95% Confidence interval CNI Calcineurin inhibitor CsA Cyclosporine A cTCMR Clinical T cell-mediated rejection DSA Donor-specific anti-human leukocyte antigen antibodies gGT Gamma-glutamyltransferase GH Graft hepatitis HCMini Histological criteria for minimization of immunosuppression HLA Anti-human leukocyte antigens IND Indeterminate histological findings LAF Liver allograft fibrosis

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Section: Discussionmentioning

confidence: 99%

Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies

Höfer

Jonigk

Hartleben

et al. 2020

Sci Rep

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“…In the study of Joka et al [ 35 ], it was found that M65 was an additional indicator of a complementary M30, since it reflects the processes of necrosis. Reis et al [ 36 ] in a study involving 76 patients with CHC after OLTx (orthotopic liver transplantation) measured M30S, M30H CK-18, and M65 CK-18 concentrations and found that these markers were able to discriminate between acute reinfection and acute transplant rejection ( P = 0.048, P = 0.001, and P = 0.010). Only few studies have evaluated both fragments of M30 and M65-CK 18 in CHB.…”

Section: Discussionmentioning

confidence: 99%

Serum Cytokeratin 18 M30 Levels in Chronic Hepatitis B Reflect Both Phase and Histological Activities of Disease

Świderska

Jaroszewicz

Parfieniuk‐Kowerda

et al. 2017

Mediators of Inflammation

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Chronic hepatitis B has highly a dynamic course with significant fluctuations of HBV-DNA and ALT impeding assessment of disease activity. New biomarkers of inflammatory versus noninflammatory stages of HBV infection are urgently needed. Cytokeratin 18 epitope M30 (M30 CK-18) is a sensitive marker of cell death. We aimed to investigate an association between serum M30 CK-18 and histological activity and phase of HBV infection. 150 Caucasian patients with HBV-infection were included in the study. Serum M30 CK-18 levels reflected phase of disease, being significantly higher in both HBeAg(+) and HBeAg(−) hepatitis B in comparison to HBsAg(+) carrier groups. The highest serum M30 CK-18 levels were observed in subjects with the most advanced stages of HBV. Moreover, its serum concentrations correlated with both inflammatory activity and fibrosis advancement (ANOVA P < 0.001). Importantly, serum M30 CK-18 levels were able to discriminate patients with mild versus moderate-advanced fibrosis (AUC: 0.86) and mild versus active liver inflammation (AUC: 0.79). M30 CK-18 serum concentration has good sensitivity and specificity in discriminating mild versus moderate/severe fibrosis and inflammation even in patients with normal ALT activity. This study suggests M30 CK-18 as a potential noninvasive marker of disease activity and also a marker of phase of persistent HBV infection.

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“…Validation of CK-18, CK-18 fragments and ELF have been conducted in NAFLD and NASH. [28][29][30]56 The very fact that biomarkers can differentiate between NAFLD and NASH [30][31][32] indicates that the manifestations of changes in hepatic biomarkers can be defined by aetiology.…”

Section: Discussionmentioning

confidence: 99%

Long‐term hepatic safety of lomitapide in homozygous familial hypercholesterolaemia

Larrey

D’Erasmo

O’Brien³

et al. 2022

Liver International

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Introduction: Lomitapide is a microsomal triglyceride transfer protein inhibitor for patients with homozygous familial hypercholesterolaemia. Due to its mechanism of action, potential hepatic effects of lomitapide are of clinical interest. This study aimed to determine the long-term hepatic safety of lomitapide. Methods: Data were aggregated from the pivotal phase 3 and extension phase clinical trial with lomitapide (median 5.1 years; serum total bilirubin, transaminases, cytokeratin-18 [CK-18] and enhanced liver fibrosis [ELF] score, fat-soluble vitamins and essential fatty acids), 8-year data from the Lomitapide Observational Worldwide Evaluation Registry (LOWER) and real-world evidence from a cohort of patients treated with lomitapide in Italy (hepatic elastography, and FIB-4 score for hepatic fibrosis).Results: In the phase 3 trial and the LOWER registry, any asymptomatic excursions in liver transaminase levels were not associated with elevations in bilirubin, and no Hy's law cases were detected in up to 8 years follow-up. There were no clinically relevant increases among hepatic biomarkers CK-18, CK-18 fragments or ELF score and fatsoluble vitamins and essential fatty acids remained above normal levels. In 34 patients treated in Italy with lomita pide for more than 9 years, elevations in hepatic fat were mild-to-moderate; hepatic stiffness remained normal, and the mean FIB-4 score remained below the fibrosis threshold value of 2.67. Conclusions:These data indicate that the hepatic safety of lomitapide remains favourable with no clinically significant elevations in hepatic biomarkers and hepatic stiffness remained normal for more than 9 years follow-up.

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(Cleaved) CK18 serum and tissue expression levels differentiate acute HCV reinfection from acute rejection in liver allografts

Cited by 5 publications

References 29 publications

Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies

Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies

Serum Cytokeratin 18 M30 Levels in Chronic Hepatitis B Reflect Both Phase and Histological Activities of Disease

Long‐term hepatic safety of lomitapide in homozygous familial hypercholesterolaemia

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