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

Abstract

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.

Inhibition of microRNA-24 increases liver fibrosis by enhanced menin expression in Mdr2 −/− mice

“…Studies have shown that cytokeratin-18 fragments (K18), a marker of apoptosis, are elevated in patients with PSC and correlate with disease severity. 28 Our data add to these studies and suggest that increased menin expression may help promote apoptosis in late-stage PSC.…”

N-3 Polyunsaturated Fatty Acids Stimulate Bile Acid Detoxification in Human Cell Models

“…Interestingly, similar antiapoptotic effects are thought to participate in the therapeutic benefits observed for ursodeoxycholic acid (UDCA) that is currently used in clinical practice to treat patients with chronic cholestatic liver diseases [ 45 ]. Together, these observations further confirm that n-3 PUFAs could be important protective agents against apoptosis, a process participating in the pathogenesis of the chronic cholestatic liver disease, PSC [ 46 , 47 ]. It is therefore tempting to speculate that the reduction of BA-induced apoptosis participates in the beneficial effects of n-3 PUFAs recently reported in PSC patients [ 20 ].…”

Biliary bile acids in hepatobiliary injury – What is the link?

“…In PBC and PSC, there is evidence for increased apoptosis of cholangiocytes and hepatocytes, since different studies observed increased TUNNEL assay activity and induced expression of FAS (CD95) and FAS ligand in PBC and PSC liver, as well as increased CK18 serum fragments in PSC. [117][118][119][120] However, a direct effect of BAs is questionable, since patients with severely increased serum BA levels, due to obstructive cholestasis, did not show increased serum caspase-3 or CK18 fragments reminiscent of apoptosis, nor increased signs of oncosis/necrosis. 14 This supports the concept that increased rates of apoptosis in PBC and PSC may not primarily be related to BA effects themselves, but may alternatively be mediated by immune cells eventually involved in disease development and progression.…”