Circulating levels of 3-hydroxymyristate, a direct quantification of endotoxaemia in noninfected cirrhotic patients.

BACKGROUND & AIMS: The quantification of lipopolysaccharide (LPS) in biological fluids is challenging. We aimed to measure plasma LPS concentration using a new method of direct quantification of 3-hydroxymyristate (3-HM), a lipid component of LPS, and to evaluate correlations between 3-HM and markers of liver function, endothelial activation, portal hypertension and enterocyte damage. METHODS: Plasma from 90 noninfected cirrhotic patients (30 Child-Pugh [CP]-A, 30 CP-B, 30 CP-C) was prospectively collected. The concentration of 3-HM was determined by high-performance liquid chromatography coupled with mass spectrometry. RESULTS: 3-HM levels were higher in CP-C patients (CP-A/CP-B/CP-C: 68/70/103 ng/mL, P = 0.005). Patients with severe acute alcoholic hepatitis (n = 16; 113 vs 74 ng/mL, P = 0.012), diabetic patients (n = 22; 99 vs 70 ng/mL, P = 0.028) and those not receiving beta blockers (n = 44; 98 vs 72 ng/mL, P = 0.034) had higher levels of 3-HM. We observed a trend towards higher baseline levels of 3-HM in patients with hepatic encephalopathy (n = 7; 144 vs 76 ng/mL, P = 0.45) or SIRS (n = 10; 106 vs 75 ng/mL, P = 0.114). In multivariate analysis, high levels of 3-HM were associated with CP (OR = 4.39; 95%CI = 1.79-10.76) or MELD (OR = 8.24; 95%CI = 3.19-21.32) scores. Patients dying from liver insufficiency (n = 6) during a 12-month follow-up had higher baseline levels of 3-HM (106 vs 75 ng/mL, P = 0.089). CONCLUSIONS: In noninfected cirrhotic patients, 3-HM arises more frequently with impairment of liver function, heavy alcohol consumption, diabetic status, nonuse of beta blockers and a trend towards poorer outcome is also observed. The direct mass measurement of LPS using 3-HM appears reliable to detect transient endotoxaemia and promising to manage the follow-up of cirrhotic patients.

Accuracy of calprotectin using the Quantum Blue Reader for the diagnosis of spontaneous bacterial peritonitis in liver cirrhosis.

AIM: We aimed to evaluate the accuracy of the dosage of calprotectin in ascitic fluid (AF) using the Quantum Blue assay, for the prompt diagnosis of spontaneous bacterial peritonitis (SBP). METHODS: We prospectively collected 236 AF samples from 119 cirrhotic patients hospitalized in two French centers between May 2016 and May 2017. Bloody and chylous/cloudy AF, and secondary peritonitis were excluded. SBP was diagnosed if neutrophils in AF were >250/mm3 using standard cytology. The Quantum Blue Reader selectively measured the calprotectin antigen (MRP8/14) in 12 min within the measurable range from 0.18 to 1.80 µg/mL; values outside this range were registered as 0.17 and 1.81 µg/mL. RESULTS: A total of 36 AF were considered as SBP (15.2%). SBP had higher median levels of calprotectin than non-SBP (1.81 vs. 0.25 µg/mL, P < 0.001). Calprotectin levels were positively correlated with neutrophils in AF (r = 0.57, P < 0.001) and C-reactive protein (r = 0.43, P < 0.001), but not with the Child-Pugh and Model for End-Stage Liver Disease scores. The optimal threshold of calprotectin to diagnose SBP was set at 1.51 µg/mL (80th percentile of calprotectin), yielding sensitivity, specificity, and positive and negative predictive values of 86.1%, 92.0%, 65.9%, and 97.3%, respectively. Only one asymptomatic patient with SBP had a low calprotectin level, but a high serum C-reactive protein level that strongly suggested an ongoing infection. We also showed that intraclass correlation coefficients for inter- and intra-observer agreement were excellent, with 0.95 and 0.89, respectively. CONCLUSIONS: The dosage of calprotectin in AF using the Quantum Blue assay is a rapid and reliable method of ruling out SBP in hospitalized cirrhotic patients.

Copeptin is an independent prognostic factor for transplant-free survival in cirrhosis.

BACKGROUND & AIMS: Copeptin is a stable cleavage product of the arginine vasopressin (AVP) precursor and is equimolarly secreted with AVP. Copeptin is currently considered a reliable prognostic marker in a wide variety of diseases other than cirrhosis. We aimed to investigate the association between severity of cirrhosis and copeptin concentrations and to confirm whether copeptin is of prognostic significance in cirrhosis. METHODS: One hundred and eighty-four cirrhotic patients hospitalized in two tertiary referral centres were studied. Serum copeptin was measured in samples obtained at hospital admission. Differences in serum copeptin between Child-Pugh classes were evaluated using the Kruskal-Wallis test. Cox proportional hazard regression and Kaplan-Meier analyses were performed to evaluate associations of copeptin and other possible prognostic factors with 6- and 12-month mortality. RESULTS: Median serum copeptin (interquartile range) increased significantly through Child-Pugh classes A [5.4 (3.1-10.7) pmol/L], B [9.6 (6.0-17.3) pmol/L] and C [13.8 (5.8-34.1) pmol/L, P < 0.01]. Patients with serum copeptin >12.3 pmol/L displayed significantly higher mortality rates at 6 and 12 months as compared to those with serum copeptin ≤12.3 pmol/L (Log-rank test: P < 0.01). Serum copeptin >12.3 pmol/L was significantly associated with mortality, particularly at 6 months, independently of age, clinical parameters and Model for End stage Liver Disease (MELD), MELD-sodium and Child-Pugh score. CONCLUSIONS: Serum copeptin concentration increases significantly along with the severity of cirrhosis as defined by the Child-Pugh classification. A high serum copeptin concentration predicts survival, particularly at 6 months, independently of liver-specific scoring systems in a heterogeneous population of hospitalized cirrhotic patients.

Prognostic value of C-reactive protein levels in patients with cirrhosis.

I dentifying cirrhosis with a poor short-term prognosis remains crucial for improving the allocation of liver grafts. The purpose of this study was to assess the prognostic value of a model combining the variation of C-reactive protein (CRP) levels within 15 days, the Model for End-Stage Liver Disease (MELD) score, and the presence of comorbidities in patients with decompensated cirrhosis with a Child-Pugh score > B7 and to test the relevance of this model in patients with compensated cirrhosis. We collected data for cirrhotic patients without hepatocellular carcinoma, extrahepatic malignancy, human immunodeficiency virus infection, organ transplantation, seen between January 2010 and December 2011. Multivariate analyses of predictors of 3-month mortality used Cox models adjusted with the age-adjusted Charlson comorbidity index. The prognostic performance [area under receiver operating characteristic curves (AUROCs)] of the 3-variable model was compared to that of the MELD score. The 241 patients who met the inclusion criteria included 109 patients with a Child-Pugh score > B7 who were hospitalized for decompensation. In these patients with severe cases, the 3-month mortality was independently predicted by the MELD score [hazard ratio (HR), 1.10; 95% confidence interval (CI), 1.05-1.14; P < 0.001] and a CRP level > 32 mg/L at the baseline and on day 15 (HR, 2.21; 95% CI, 1.03-4.76; P = 0.042). This model was better than MELD alone (AUROC, 0.789 versus 0.734; P = 0.043). In the whole population with cirrhosis, the 3-month mortality was also predicted by high MELD scores (HR, 1.11; 95% CI, 1.07-1.16; P < 0.001) and a CRP level > 10 mg/L at the baseline and on day 15 (HR, 2.89; 95% CI, 1.29-6.48; P < 0.001), but the AUROCs of the 3-variable model and the MELD score alone were no longer significantly different (0.89 versus 0.88, not significant). In conclusion, prognostic models incorporating variations in CRP predict 3-month mortality in patients with cirrhosis. Such models are particularly relevant for patients with decompensated cirrhosis but provide a limited increase in prediction in comparison with the MELD score in the whole population with cirrhosis.

Granulocyte colony stimulating factor in decompensated cirrhosis, acute alcoholic hepatitis, and acute-on-chronic liver failure: A comprehensive meta-analysis of randomized controlled trials.

BACKGROUND: GCSF may improve the prognosis of severe liver disease by promoting liver regeneration and immune restoration. Our Aim was to investigate its controversial efficacy in decompensated cirrhosis, acute alcoholic hepatitis (AAH), or acute-on-chronic liver failure (ACLF) through meta-analysis. METHODS: Meta-analysis of proportions (random effect model) including 19 RCTs (1287 patients from 16 Asian and 3 European studies including 487 ACLF, 231 AAH and 569 cirrhotic patients) evaluating survival at day-28, day-90, 6 months, one year, and/or occurrence of sepsis as major outcomes. RESULTS: In patients with decompensated cirrhosis, G-CSF administration was associated with a reduction in the weight-adjusted risk of mortality of 9% at day-90 (OR=0.33; 95%CI: 0.18-0.58; p = 0.0002), 16% at 6 months (OR=0.31; 95%CI: 0.15-0.62; p = 0.0009), 26% at one year (OR=0.21; 95%CI:0.12-0.38, p<0.0001) and a weight-adjusted 28% risk reduction for sepsis (OR=0.28; 95%CI: 0.16-0.49; p<0.0001). Only Asian studies were positive. In AAH, G-CSF was associated with an 18% reduction in weight-adjusted mortality risk at day-28 (OR=0.31; 95%CI:0.11-0.83, p = 0.021), 32% at day-90 (OR=0.20; 95%CI:0.09-0.46, p<0.0001) and a weight-adjusted 42% risk reduction for sepsis (OR=0.17; 95%CI: 0.08-0.38; p<0.0001). Only Asian studies, in which corticosteroids were not given systematically in case of severe AAH, were positive. In patients with ACLF, the results on mortality at day-28 were heterogeneous, and GCSF had no beneficial effect on sepsis or survival at day-90. CONCLUSION: G-CSF may be effective in patients with decompensated cirrhosis or AAH by reducing the occurrence of sepsis and mortality. Further meta-analyses of individual data, or new, powerful and methodologically flawless therapeutic trials, are warranted to confirm these results, which harbor wide divergences between Asian and European RCTs.

Left gastric vein embolization during TIPS placement for acute variceal bleeding has no effect on bleeding recurrence: Results of a multicenter study.

PURPOSE: The purpose of this study was to evaluate whether concomitant left gastric vein embolization (LGVE) during transjugular intrahepatic portosystemic shunt (TIPS) for acute variceal hemorrhage could reduce the risk of bleeding recurrence. MATERIAL AND METHOD: A national multicenter observational study was conducted in 14 centers between January 2019 and December 2020. All cirrhotic patients who underwent TIPS placement for acute variceal bleeding were included. During TIPS procedure, size of left gastric vein (LGV), performance of LGVE, material used for LGVE and portosystemic pressure gradient (PPG) before and after TIPS placement were collected. A propensity score for the occurrence of LGVE was calculated to assess effect of LGVE on rebleeding recurrence at six weeks and one year. RESULTS: A total of 356 patients were included (mean age 57.3 ± 10.8 [standard deviation] years; 283/356 [79%] men). Median follow-up was 11.2 months [interquartile range: 1.2, 13.3]. The main indication for TIPS was pre-emptive TIPS (162/356; 46%), rebleeding despite secondary prophylaxis (105/356; 29%), and salvage TIPS (89/356; 25%). Overall, 128/356 (36%) patients underwent LGVE during TIPS procedure. At six weeks and one year, rebleeding-free survival did not differ significantly between patients who underwent LGVE and those who did not (6/128 [5%] vs. 15/228 [7%] at six weeks, and 11/128 [5%] vs. 22/228 [7%] at one year, P = 0.622 and P = 0.889 respectively). A total of 55 pairs of patients were retained after propensity score matching. In patients without LGVE, the rebleeding rate was not different from those with LGVE (3/55 [5%] vs. 4/55 [7%], P > 0.99, and 5/55 [9%] vs. 6/55[11%], P > 0.99, at six weeks and one year respectively). Multivariable analysis identified PPG after TIPS placement as the only predictor of bleeding recurrence (hazard ratio = 1.09; 95% confidence interval: 1.02-1.18; P = 0.012). CONCLUSION: In this multicenter national real-life study, we did not observe any benefit of concomitant LGVE during TIPS placement for acute variceal bleeding on bleeding recurrence rate.