Soluble intracellular adhesion molecule, <scp>M</scp>30 and <scp>M</scp>65 as serum markers of disease activity and prognosis in cholestatic liver diseases

Denk, Gerald; Omary, Areen; Reiter, Florian P.; Hohenester, Simon; Wimmer, Ralf; Holdenrieder, Stefan; Rust, Christian

doi:10.1111/hepr.12304

Cited by 20 publications

(16 citation statements)

References 35 publications

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“…According to our study, M65EpiDeath was a predictor of death and decompensation . High levels of M30 and M65 were also found in another cholestatic liver disease, namely primary sclerosing cholangitis, and the parameters M30 and M65 were associated with more advanced disease . Furthermore, M30 and M65 but not M65EpiDeath were determined in the sera of patients with chronic HBV infection and acute‐on‐chronic liver failure.…”

Section: Discussionmentioning

confidence: 57%

Cytokeratin 18‐based cell death markers indicate severity of liver disease and prognosis of cirrhotic patients

Waidmann

Brunner

Herrmann

et al. 2016

Liver International

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Section: Discussionmentioning

confidence: 57%

Cytokeratin 18‐based cell death markers indicate severity of liver disease and prognosis of cirrhotic patients

Waidmann

Brunner

Herrmann

et al. 2016

Liver International

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“…Therefore, it has been suggested that apoptosis did not play a central role in PSC [8]. However, a recent study measured several serum markers of apoptosis (soluble Fas, M30 and M65) in patients with immune-mediated liver diseases and reported that patients with PSC had increased serum markers of apoptosis that correlated with disease activity [9]. …”

Section: Introductionmentioning

confidence: 99%

“…These fragments are stable to proteolysis and are released into the circulation after hepatocyte plasma membrane disintegration during later stages of apoptosis [10]. The serum K18 fragment levels can be measured by a commercially available ELISA assay, and has shown to be altered in some liver disorders associated with hepatic inflammation and injury [9,13,14]. …”

Section: Introductionmentioning

confidence: 99%

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Individuals with Primary Sclerosing Cholangitis Have Elevated Levels of Biomarkers for Apoptosis but Not Necrosis

et al. 2015

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Background and Aim Hepatocyte apoptosis or necrosis from accumulation of bile salts may play an important role in the disease progression of primary sclerosing cholangitis (PSC). The aim of the current study was to measure serum markers of hepatocyte apoptosis (cytokeratin 18 fragments - K18) and necrosis (high-mobility group protein B1 - HMGB1) in adults with PSC and examine the relationship with disease severity. Methods We measured serum levels of K18 and HMGB1 in well phenotyped PSC (N=37) and 39 control subjects (N=39). Severity of PSC was assessed biochemically, histologically and PSC Mayo Risk Score. Quantification of hepatocyte apoptosis was performed using TUNEL assay. Results The mean age of the study cohort was 49.7 ± 13.3 years and comprised of 67% men and 93% Caucasian. Serum K18 levels were significantly higher in the PSC patients compared to control (217.4 ± 78.1 vs. 157.0 ± 58.2 U/L, p-val=0.001). However, HMGB1 levels were not different between the two groups (5.38 ± 2.99 vs. 6.28 ± 2.85 ng/mL, p-val=0.15). Within the PSC group, K18 levels significantly correlated with AST (r=0.5, p-val=0.002), alkaline phosphatase (r=0.5, p-val=0.001), total bilirubin (r=0.61, p-val= <0.001), and albumin (r=−0.4, p-val =0.02). Serum K18 levels also correlated with the level of apoptosis present on the liver biopsy (r=0.8, p-val = <0.001) and Mayo Risk score (r=0.4, p-val=0.015). Conclusion Serum K18 but not HMGB1 levels were increased in PSC and associated with severity of underlying liver disease and the degree of hepatocyte apoptosis.

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“…Bile-salt-induced hepatocellular apoptosis has mainly been characterized in animal models and in vitro. However, the presence of serum markers of apoptosis in patients with cholestatic liver disease suggests the chronic activation of these pathways in humans [16].…”

Section: Introductionmentioning

confidence: 99%

Glycochenodeoxycholate Promotes Liver Fibrosis in Mice with Hepatocellular Cholestasis

Hohenester

Kanitz

Kremer

et al. 2020

Cells

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Hydrophobic bile salts are considered to promote liver fibrosis in cholestasis. However, evidence for this widely accepted hypothesis remains scarce. In established animal models of cholestasis, e.g., by Mdr2 knockout, cholestasis and fibrosis are both secondary to biliary damage. Therefore, to test the specific contribution of accumulating bile salts to liver fibrosis in cholestatic disease, we applied the unique model of inducible hepatocellular cholestasis in cholate-fed Atp8b1G308V/G308V mice. Glycochenodeoxycholate (GCDCA) was supplemented to humanize the murine bile salt pool, as confirmed by HPLC. Biomarkers of cholestasis and liver fibrosis were quantified. Hepatic stellate cells (HSC) isolated from wild-type mice were stimulated with bile salts. Proliferation, cell accumulation, and collagen deposition of HSC were determined. In cholestatic Atp8b1G308V/G308V mice, increased hepatic expression of αSMA and collagen1a mRNA and excess hepatic collagen deposition indicated development of liver fibrosis only upon GCDCA supplementation. In vitro, numbers of myofibroblasts and deposition of collagen were increased after incubation with hydrophobic but not hydrophilic bile salts, and associated with EGFR and MEK1/2 activation. We concluded that chronic hepatocellular cholestasis alone, independently of biliary damage, induces liver fibrosis in mice in presence of the human bile salt GCDCA. Bile salts may have direct pro-fibrotic effects on HSC, putatively involving EGFR and MEK1/2 signaling.

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Soluble intracellular adhesion molecule, M30 and M65 as serum markers of disease activity and prognosis in cholestatic liver diseases

Cited by 20 publications

References 35 publications

Cytokeratin 18‐based cell death markers indicate severity of liver disease and prognosis of cirrhotic patients

Cytokeratin 18‐based cell death markers indicate severity of liver disease and prognosis of cirrhotic patients

Individuals with Primary Sclerosing Cholangitis Have Elevated Levels of Biomarkers for Apoptosis but Not Necrosis

Glycochenodeoxycholate Promotes Liver Fibrosis in Mice with Hepatocellular Cholestasis

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