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Sphingosine-1-phosphate (S1P) regulates pathophysiological processes, including liver regeneration, vascular tone control, and immune response. In patients with liver cirrhosis, acute deterioration of liver function is associated with high mortality rates. The present study investigated whether serum S1P concentrations are associated with disease severity in patients with chronic liver disease from compensated cirrhosis (CC), acute decompensation (AD), or acute-on-chronic liver failure (ACLF). From August 2013 to October 2017, patients who were admitted to the University Hospital Frankfurt with CC, AD, or ACLF were enrolled in our cirrhosis cohort study. Tandem mass spectrometry was performed on serum samples of 127 patients to assess S1P concentration. Our study comprised 19 patients with CC, 55 with AD, and 51 with ACLF, aged 29 to 76 years. We observed a significant decrease of S1P according to advanced liver injury from CC and AD up to ACLF ( P  < 0.001). S1P levels further decreased with progression to ACLF grade 3 ( P  < 0.05), and S1P highly inversely correlated with the Model for End-Stage Liver Disease score ( r  = -0.508; P  < 0.001). In multivariate analysis, S1P remained an independent predictor of 7-day mortality with high diagnostic accuracy (area under the curve, 0.874; P  < 0.001). Conclusion: In patients with chronic liver disease, serum S1P levels dramatically decreased with advanced stages of liver disease and were predictive of early mortality. Because S1P is a potent regulator of endothelial integrity and immune response, low S1P levels may significantly influence progressive multiorgan failure. Our data justify further elucidation of the diagnostic and therapeutic role of S1P in ACLF., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Interleukin-22 (IL-22) has context-dependent hepatoprotective or adverse properties in vitro and in animal models. IL-22 binding protein (IL-22BP) is a soluble inhibitor of IL-22 signaling. The role of IL-22 and IL-22BP in patients with acute-on-chronic liver failure (ACLF) is unclear. Beginning in August 2013, patients with liver cirrhosis with and without ACLF were prospectively enrolled and followed at predefined time points. IL-22 and IL-22BP concentrations were quantified and associated with clinical endpoints. The impact of IL-22BP on hepatocellular IL-22 signaling was assessed by functional experiments. A total of 139 patients were analyzed, including 45 (32%), 52 (37%), and 42 (30%) patients with compensated/stable decompensated liver cirrhosis, acute decompensation of liver cirrhosis, and ACLF at baseline, respectively. Serum levels of IL-22 and IL-22BP were strongly associated with the presence of, or progression to, ACLF ( P < 0.001), and with mortality ( P < 0.01). Importantly, the mean IL-22BP levels exceeded IL-22 levels more than 300-fold. Furthermore, IL-22BP/IL-22 ratios were lowest in patients with adverse outcomes (i.e., ACLF and death). In vitro experiments showed that IL-22BP at these concentrations inhibits hepatocellular IL-22 signaling, including the induction of acute-phase proteins. The capacity of patient serum to induce signal transducer and activator of transcription 3 phosphorylation was substantially higher in the presence of low versus high IL-22BP/IL-22 ratios. Conclusion: Our study reveals that high IL-22 levels and low ratios of IL-22BP/IL-22 are associated with ACLF and mortality of patients with cirrhosis. Excessive secretion of IL-22BP can neutralize IL-22 in vitro and may prevent-likely in a context-specific manner-hepatoprotective, but also adverse effects, of IL-22 in patients with cirrhosis.

Platelets participate in the development of liver fibrosis in animal models, but little is known about the benefit of antiplatelet agents in preventing liver fibrosis in humans. We therefore explored the relationship between the use of antiplatelet agents and liver fibrosis in a prospective cohort study of patients at high risk of liver fibrosis and cardiovascular events. Consecutive patients undergoing elective coronary angiography at the University Hospital Frankfurt were prospectively included in the present study. Associations between use of antiplatelet agents (acetyl salicylic acid, P2Y12 receptor antagonists) and liver fibrosis were assessed in regression models, and the relationship between platelet-derived growth factor beta (PDGF-β) serum concentration, platelets, liver fibrosis, and use of antiplatelet agents was characterized. Out of 505 included patients, 337 (67%) received antiplatelet agents and 134 (27%) had liver fibrosis defined as a FibroScan transient elastography (TE) value ≥7.9 kPa. Use of antiplatelet agents was inversely associated with the presence of liver fibrosis in univariate and multivariate analyses (multivariate odds ratio [OR], 0.67; 95% confidence interval [CI], 0.51-0.89; P = 0.006). Use of antiplatelet agents was also inversely associated with FibroTest values (beta, -0.38; SD beta, 0.15; P = 0.02). Furthermore, there was a significant correlation between platelet counts and PDGF-β serum concentration (rho, 0.33; P < 0.0001), but PDGF-β serum levels were not affected by antiplatelet agents. Conclusion : There is a protective association between the use of antiplatelet agents and occurrence of liver fibrosis. A randomized controlled trial is needed to explore causality and the potential of antiplatelet agents as antifibrotic therapy in patients at risk for liver fibrosis progression.

Single nucleotide polymorphism (SNP) rs738409 C>G in the patatin-like phospholipase domain containing 3 ( PNPLA3 ) gene results in an amino acid exchange from isoleucin to methionine at position I148M of PNPLA3. The expression of this loss-of-function mutation leads to impaired hepatocellular triglyceride hydrolysis and is associated with the development of liver steatosis, fibrosis, and hepatocellular carcinoma. In contrast to these well-established associations, the relationship of the PNPLA3 rs738409 variant with other metabolic traits is incompletely understood. We therefore assessed the association of the PNPLA3 rs738409 genotype with relevant metabolic traits in a prospective study of patients at high risk for cardiovascular events, i.e., patients undergoing coronary angiography. In a total of 270 patients, known associations of the PNPLA3 rs738409 GG genotype with nonalcoholic steatohepatitis and liver fibrosis were confirmed. In addition, we found an association of the PNPLA3 rs738409 G allele with the presence of diabetes (22% versus 28% versus 58% for CC versus CG versus GG genotype, respectively; P = 0.02). In contrast to its association with nonalcoholic fatty liver disease, liver fibrosis, and diabetes, the minor G allele of PNPLA3 rs738409 was inversely associated with total serum cholesterol and low-density lipoprotein serum levels ( P = 0.003 and P = 0.02, respectively). Finally, there was a trend toward an inverse association between the presence of the PNPLA3 rs738409 G allele and significant coronary heart disease. Comparable trends were observed for the transmembrane 6 superfamily member 2 (TM6SF2) 167 K variant, but the sample size was too small to evaluate this rarer variant. Conclusion : The PNPLA3 rs738409 G allele is associated with liver disease but also with a relatively benign cardiovascular risk profile. ( Hepatology Communications 2018;2:798-806).