Plasma Amino Acid Concentrations Predict Mortality in Patients with End-Stage Liver Disease

<div><p>Background</p><p>The liver plays a key role in amino acid metabolism. In former studies, a ratio between branched-chain and aromatic amino acids (Fischer’s ratio) revealed associations with hepatic encephalopathy. Furthermore, low concentrations of branched-chain amino acids were linked to sarcopenia in literature. Encephalopathy and sarcopenia are known to dramatically worsen the prognosis. Aim of this study was to investigate a complex panel of plasma amino acids in the context of mortality in patients with end-stage liver disease.</p><p>Methods</p><p>166 patients evaluated for orthotopic liver transplantation were included. 19 amino acids were measured from citrated plasma samples using mass spectrometry. We performed survival analysis for plasma amino acid constellations and examined the relationship to established mortality predictors.</p><p>Results</p><p>33/166 (19.9%) patients died during follow-up. Lower values of valine (p<0.001), Fischer’s ratio (p<0.001) and valine to phenylalanine ratio (p<0.001) and higher values of phenylalanine (p<0.05) and tyrosine (p<0.05) were significantly associated with mortality. When divided in three groups, the tertiles discriminated cumulative survival for valine (p = 0.016), phenylalanine (p = 0.024) and in particular for valine to phenylalanine ratio (p = 0.003) and Fischer’s ratio (p = 0.005). Parameters were also significantly correlated with MELD and MELD-Na score.</p><p>Conclusions</p><p>Amino acids in plasma are valuable biomarkers to determine increased risk of mortality in patients with end-stage liver disease. In particular, valine concentrations and constellations composed of branched-chain and aromatic amino acids were strongly associated with prognosis. Due to their pathophysiological importance, the identified amino acids could be used to examine individual dietary recommendations to serve as potential therapeutic targets.</p></div

Description of liver disease etiologies, comorbidities and Child-Pugh-Turcotte classification in numbers and percentage in the analyzed population (N = 166).

<p>Description of liver disease etiologies, comorbidities and Child-Pugh-Turcotte classification in numbers and percentage in the analyzed population (N = 166).</p

Correlation diagrams for chosen metabolites versus unrounded MELD scores (N = 166).

<p>LTx: liver transplantation.</p> <p>roh: Spearman’s roh coefficient.</p> <p>#: Patient who received Fresubin^® Hepa before blood taking at Intensive Care Unit.</p

Baseline characteristics in the analyzed population.

<p>Baseline characteristics in the analyzed population.</p

Comparison of distributions between the deceased and surviving patients was performed using Mann-Whitney-U-Test.

<p>Patients receiving an OLT during follow-up time were excluded in this analysis (N = 18). Values in the table are medians. Significant results are written in bold and asterisked (**, ***). Essential amino acids are printed in italics.</p

Cumulative survival according to Kaplan-Meier for chosen variables (N = 166).

<p>Presented p-values are from global Log-Rank tests. Maximum follow-up was 24 months.</p> <p>T1 (blue): group below the 33rd percentile.</p> <p>T2 (green): group within the 33rd and 67th percentile.</p> <p>T3 (yellow): group above the 67th percentile.</p> <p>BCAA: Branched-chain amino acids, sum of valine, leucine and isoleucine.</p> <p>AAA: Aromatic amino acids, sum of phenylalanine, tyrosine and tryptophan.</p

Data of the measured metabolite panel (N = 166).

<p>Survival analysis was performed by an univariate cox-regression model. Significant results are written in bold and asterisked (*, **, ***). Essential amino acids are printed in italics.</p

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

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