Low PCSK9 levels are correlated with mortality in patients with end-stage liver disease

<div><p>Introduction</p><p>Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in the cholesterol metabolism and is synthesized by the liver. It interacts with the LDL-receptor to promote its degradation. The model of end-stage liver disease (MELD) score is a well-established tool to estimate the risk of mortality in patients with end-stage chronic liver disease. The study aims to assess the associations between PCSK9, hypocholesterinemia, liver synthesis, cholestasis, MELD score and mortality in patients with end-stage liver disease.</p><p>Methods</p><p>Serum samples were obtained from 74 patients with severe liver disease. The study participants were aged between 23 and 70 y (mean: 55.8 y; 47 males [63.5%], 27 females [36.5%]). Samples were selected from those with a wide range of MELD scores (7 to 40).</p><p>Patients that underwent liver transplantation (17 / 74) were censored at the time of transplantation for mortality analysis.</p><p>Results</p><p>PCSK9 values ranged from 31.47 ng/mL to 261.64 ng/mL. The median value was 106.39 ng/ml. PCSK9 was negatively correlated with markers of liver function and cholestasis (INR, bilirubin). Over a 90-d follow-up, 15 of 57 (26,3%) patients died within the 90-d follow-up without receiving liver transplantation. Thirteen of 31 (42%) patients with PCSK9 levels below the median died compared to 2/26 (8%) patients with higher PCSK9 levels (<i>p</i> = 0.006). In this cohort, there were no significant correlations between PCSK9, cholesterol, its precursors and several phytosterols.</p><p>Conclusions</p><p>Low PCSK9 serum concentrations were associated with higher mortality in patients with end-stage liver disease. The mean PCSK9 levels in the study population were much lower than those found in normal or healthy populations. Further studies are required to acquire a more detailed understanding of the role of PCSK9 in liver-related mortality.</p></div

Correlation coefficients for PCSK9 with biomarkers of cholesterol synthesis and liver function.

<p>(The correlation was significant at the *<i>p</i> = 0.05, **<i>p</i> = 0.01 and ***<i>p</i> = 0001 level).</p

PCSK9 levels below the median (<106.39 ng/mL) were significantly associated with higher mortality during the 90-d follow-up (<i>p</i> = 0.002).

<p>(+ indicates censored patients due to liver transplantation).</p

Comparison of the levels of different biomarkers in patients with PCSK9 levels above and below the median value.

<p>Comparison of the levels of different biomarkers in patients with PCSK9 levels above and below the median value.</p

Low sphingosine-1-phosphate plasma levels are predictive for increased mortality in patients with liver cirrhosis

<div><p>Background & aim</p><p>The association of circulating sphingosine-1-phosphate (S1P), a bioactive lipid involved in various cellular processes, and related metabolites such as sphinganine-1-phosphate (SA1P) and sphingosine (SPH) with mortality in patients with end-stage liver disease is investigated in the presented study. S1P as a bioactive lipid mediator, is involved in several cellular processes, however, in end-stage liver disease its role is not understood.</p><p>Methods</p><p>The study cohort consisted of 95 patients with end-stage liver disease and available information on one-year outcome. The median MELD (Model for end-stage liver disease) score was 12.41 (Range 6.43–39.63). The quantification of sphingolipids in citrated plasma specimen was performed after methanolic protein precipitation followed by hydrophilic interaction liquid chromatography and tandem mass spectrometric detection.</p><p>Results</p><p>S1P and SA1P displayed significant correlations with the MELD score. Patients with circulating S1P levels below the lowest tertile (110.68 ng/ml) showed the poorest one-year survival rate of only 57.1%, whereas one-year survival rate in patients with S1P plasma levels above 165.67 ng/ml was 93.8%. In a multivariate cox regression analysis including platelet counts, concentrations of hemoglobin and MELD score, S1P remained a significant predictor for three-month and one-year mortality.</p><p>Conclusions</p><p>Low plasma S1P concentrations are highly significantly associated with prognosis in end-stage liver disease. This association is independent of the stage of liver disease. Further studies should be performed to investigate S1P, its role in the pathophysiology of liver diseases and its potential for therapeutic interventions.</p></div

Correlation between concentrations of S1P, SA1P and SPH with the MELD score.

<p>Correlation between concentrations of S1P, SA1P and SPH with the MELD score.</p

Baseline characteristics of the analyzed study population (N = 95).

<p>Baseline characteristics of the analyzed study population (N = 95).</p

Kaplan Meier log rank tests for tertiles of S1P (A), SA1P (B) and SPH (C) for one-year survival.

<p>Censored cases are represented by a vertical line on each survival rate curve.</p

Baseline characteristics stratified by survival at three-months and one-year.

<p>Baseline characteristics stratified by survival at three-months and one-year.</p

Summary of spearman rank coefficients of correlation between S1P levels and liver and lipid related parameters.

<p>Summary of spearman rank coefficients of correlation between S1P levels and liver and lipid related parameters.</p