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HDL-related biomarkers are robust predictors of survival in patients with chronic liver failure

Open AccessPublished:February 13, 2020DOI:https://doi.org/10.1016/j.jhep.2020.01.026

      Highlights

      • HDL levels are profoundly decreased in chronic liver failure.
      • HDL-related biomarkers (HDL-C, apoA-I) are robust predictors of disease progression and survival.
      • The prognostic value of single HDL-related biomarkers is very similar to that of the composite scores.
      • HDL-related biomarkers correlated inversely with markers of inflammation.

      Background & Aims

      High-density lipoprotein cholesterol (HDL-C) levels are reduced in patients with chronic liver disease and inversely correlate with disease severity. During acute conditions such as sepsis, HDL-C levels decrease rapidly and HDL particles undergo profound changes in their composition and function. We aimed to determine whether indices of HDL quantity and quality associate with progression and survival in patients with advanced liver disease.

      Methods

      HDL-related biomarkers were studied in 508 patients with compensated or decompensated cirrhosis (including acute-on-chronic liver failure [ACLF]) and 40 age- and gender-matched controls. Specifically, we studied levels of HDL-C, its subclasses HDL2-C and HDL3-C, and apolipoprotein A1 (apoA-I), as well as HDL cholesterol efflux capacity as a metric of HDL functionality.

      Results

      Baseline levels of HDL-C and apoA-I were significantly lower in patients with stable cirrhosis compared to controls and were further decreased in patients with acute decompensation (AD) and ACLF. In stable cirrhosis (n = 228), both HDL-C and apoA-I predicted the development of liver-related complications independently of model for end-stage liver disease (MELD) score. In patients with AD, with or without ACLF (n = 280), both HDL-C and apoA-I were MELD-independent predictors of 90-day mortality. On ROC analysis, both HDL-C and apoA-I had high diagnostic accuracy for 90-day mortality in patients with AD (AUROCs of 0.79 and 0.80, respectively, similar to that of MELD 0.81). On Kaplan-Meier analysis, HDL-C <17 mg/dl and apoA-I <50 mg/dl indicated poor short-term survival. The prognostic accuracy of HDL-C was validated in a large external validation cohort of 985 patients with portal hypertension due to advanced chronic liver disease (AUROCs HDL-C: 0.81 vs. MELD: 0.77).

      Conclusion

      HDL-related biomarkers are robust predictors of disease progression and survival in chronic liver failure.

      Lay summary

      People who suffer from cirrhosis (scarring of the liver) have low levels of cholesterol carried by high-density lipoproteins (HDL-C). These alterations are connected to inflammation, which is a problem in severe liver disease. Herein, we show that reduced levels of HDL-C and apolipoprotein A-I (apoA-I, the main protein carried by HDL) are closely linked to the severity of liver failure, its complications and survival. Both HDL-C and apoA-I can be easily measured in clinical laboratories and are as good as currently used prognostic scores calculated from several laboratory values by complex formulas.

      Graphical abstract

      Keywords

      Linked Article

      • Reply to: “Prognostic value of HDL-related biomarkers in patients with HBV-related ACLF”
        Journal of HepatologyVol. 75Issue 1
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          We thank Wen et al.1 for their interest in our study on the prognostic value of HDL-related biomarkers in chronic liver failure.
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      • Prognostic value of HDL-related biomarkers in patients with HBV-related ACLF
        Journal of HepatologyVol. 75Issue 1
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          We read with great interest the article by Trieb and Rainer et al.1 The authors suggested a very similar prognostic value of HDL-C and ApoA1 to the traditional model for end-stage liver disease (MELD) score, in their cohort mainly composed of patients with HCV- or alcohol-related cirrhosis. Currently, chronic HBV infection remains a major cause of chronic liver disease. It has been reported previously that liver and coagulation failures were the most common types of organ failure in patients with chronic HBV infection-related acute-on-chronic liver failure (HBV-ACLF), whereas kidney and cerebral failures were more frequently observed in patients with non-HBV-ACLF.
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      Introduction

      Chronic liver disease is a growing public health problem across Europe and the United States.
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      raising the possibility that HDL particles play a critical role in the pathophysiology of chronic liver failure. HDL consists of 2 large subclasses, namely large, buoyant HDL2 particles and small, dense HDL3 particles. Recent studies provided evidence that the anti-inflammatory properties of HDL3 are superior to those of HDL2.
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      Small, dense high-density lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, anti-inflammatory, and antiapoptotic functionalities.
      HDL3 effectively mobilizes cholesterol from cholesterol-rich microdomains, which serve as signal platforms for Toll-like receptors and thus attenuate the inflammatory response.
      • Fessler M.B.
      • Parks J.S.
      Intracellular lipid flux and membrane microdomains as organizing principles in inflammatory cell signaling.
      This may increase susceptibility of patients with cirrhosis to bacterial infections, which are the most common triggers of acute-on-chronic liver failure (ACLF).
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      • Pappas G.
      • Falagas M.E.
      Bacterial infection-related morbidity and mortality in cirrhosis.
      We have recently shown that cirrhosis alters HDL composition and function and that HDL cholesterol efflux capacity (CEC) predicted 12-month mortality in patients with cirrhosis.
      • Trieb M.
      • Horvath A.
      • Birner-Gruenberger R.
      • Spindelboeck W.
      • Stadlbauer V.
      • Taschler U.
      • et al.
      Liver disease alters high-density lipoprotein composition, metabolism and function.
      However, the measurement of CEC is very demanding and currently unsuitable as a routine clinical test. In the present study, we investigated the prognostic value of several HDL-related biomarkers that can be easily integrated into routine clinical testing, i.e. HDL-C, apoA-I, and the HDL subclasses HDL2-C and HDL3-C in a large cohort of patients with compensated and decompensated advanced chronic liver disease (ACLD), including ACLF. In addition, we assessed CEC as a metric of HDL function.

      Patients and methods

      Patients

      The patient population of this explorative cross-sectional study included 508 patients with cirrhosis from 2 different cohorts: (i) 228 consecutive patients with stable cirrhosis recruited between 2011 and 2016 at the Medical University of Graz (outpatient clinic or gastrointestinal ward including stable patients undergoing evaluation for liver transplantation) and (ii) 280 patients with decompensated cirrhosis with or without ACLF who were investigated between February and September 2011 in the multicenter CANONIC study in 12 European countries (for further details, see Moreau et al.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ). In both studies, the diagnosis of cirrhosis was based on liver histology or a combination of clinical, biochemical and imaging signs. Patients with prior solid organ transplantation or the presence of hepatocellular carcinoma were excluded. Due to the impact of cholestasis on lipid profiles, patients with cholestatic liver diseases were excluded.
      • Vodnala D.
      • Rubenfire M.
      • Brook R.D.
      Secondary causes of dyslipidemia.
      Hospitalized patients with cirrhosis were examined for the presence of acute decompensation (AD) or ACLF as defined by Moreau et al.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      Besides baseline data (history, physical examination, and laboratory measurements), information on liver transplantation and mortality at 90 days and 12 months following enrollment were recorded. In addition, data regarding the occurrence of complications of cirrhosis were obtained in patients with stable cirrhosis at baseline. Complications of cirrhosis were defined as follows: development of new-onset ascites in a patient without ascites at baseline, development of new-onset hepatic encephalopathy, development of spontaneous bacterial peritonitis, hepatorenal syndrome, new-onset jaundice (clinically detectable or bilirubin >3 mg/dl), upper gastrointestinal bleeding due to portal hypertension (variceal bleeding or bleeding from portal hypertensive gastropathy), occurrence of portal vein thrombosis, or death from liver disease. Besides, occurrence of severe infection requiring antibiotic therapy within 12 months was assessed in patients with stable cirrhosis.
      Furthermore, 40 age- and sex-matched healthy controls who did not meet the following exclusion criteria were included: any history of cardiovascular disease, pregnancy, obesity, dyslipidemia, liver disease, renal disease, diabetes or clinical signs of inflammation. Control participants did not take lipid-lowering medication or anti-inflammatory drugs. Blood was sampled at baseline from patients and healthy controls.
      In addition, HDL-C was investigated in an external validation cohort composed of 985 consecutive patients who underwent hepatic venous pressure gradient (HVPG) measurement between 2004 and 2018 at the Vienna Hepatic Hemodynamic Lab at the Medical University of Vienna (“HVPG cohort”). Patients with a normal HVPG (≤5 mm Hg), porto-sinusoidal vascular disease, cholestatic liver disease, transjugular intrahepatic portosystemic shunt, a history of liver transplantation, or missing information on HDL-C were excluded.
      All 3 studies had been approved by the local Institutional Review Boards (IRBs) in accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient unless the requirement had been waived by the local IRB.

      Lipid and cytokine assays

      Levels of total cholesterol were measured enzymatically (Diasys, Holzheim, Germany). The levels of total HDL-C and HDL3-C were determined using homogeneous assays from Denka Seiken Co., Ltd. (Tokyo, Japan).
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      • Satoh N.
      • Ishii T.
      • Kumakura J.
      • Hirano T.
      Development of a homogeneous assay for measurement of high-density lipoprotein-subclass cholesterol.
      HDL2-C was estimated by subtracting HDL3-C from total HDL-C. ApoA-I was determined by immunoturbidimetry as described.
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      • Schilcher G.
      • Curcic S.
      • Trieb M.
      • Ljubojevic S.
      • Stojakovic T.
      • et al.
      Dialysis modalities and HDL composition and function.
      Analyses were performed on an Olympus AU680 analyzer (Beckman Coulter, Brea, USA). Cytokines (interleukin [IL]-6, IL-8, tumor necrosis factor-α [TNF-α]) were quantified using a multiplexed bead-based immunoassay.

      Preparation of apoB-depleted serum

      ApoB-depleted serum was prepared by addition of 40 μl of polyethyleneglycol (20% in 200 mmol/L glycine buffer) to 100 μl of serum.
      • Trieb M.
      • Horvath A.
      • Birner-Gruenberger R.
      • Spindelboeck W.
      • Stadlbauer V.
      • Taschler U.
      • et al.
      Liver disease alters high-density lipoprotein composition, metabolism and function.
      Serum was incubated at room temperature for 20 min and the supernatant recovered after centrifugation (10,000 rpm, 20 min, 4°C).

      HDL cholesterol efflux capacity

      CEC was assessed using an established assay.
      • Trieb M.
      • Kornej J.
      • Knuplez E.
      • Hindricks G.
      • Thiele H.
      • Sommer P.
      • et al.
      Atrial fibrillation is associated with alterations in HDL function, metabolism, and particle number.
      ,
      • Untersteller K.
      • Meissl S.
      • Trieb M.
      • Emrich I.E.
      • Zawada A.M.
      • Holzer M.
      • et al.
      HDL functionality and cardiovascular outcome among nondialysis chronic kidney disease patients.
      J774 macrophages, maintained in DMEM with 10% fetal bovine serum were plated on 48-well plates (300,000 cells/well). Cells were labeled for 24 h with 1 μCi/ml [3H]-cholesterol (Perkin Elmer, Boston, MA, USA). [3H]-cholesterol-labeled J774 macrophages were incubated in the presence of 0.3 mmol/L 8-(4-chlorophenylthio)-cAMP to stimulate ATP-binding cassette transporter A1 (ABCA1) expression. After labeling, cells were washed twice with serum-free DMEM and subsequently equilibrated in serum-free DMEM containing 0.2% BSA for 2 h. After 2 additional washing steps, [3H]-cholesterol efflux was determined by incubating cells for 3 h with serum-free DMEM containing 2.8% apoB-depleted serum. Cholesterol efflux was expressed as the radioactivity in the medium relative to total radioactivity in medium and cells. A control serum was used on each plate to decrease inter-plate variability. All steps were performed in the presence of 2 μg/ml of the acyl coenzyme A cholesterol acyltransferase inhibitor Sandoz 58-035 (Sigma, Darmstadt, Germany).

      Composite prognostic scores

      The prognostic value of HDL-related biomarkers (as single prognostic parameters) was compared with established composite prognostic scores as appropriate: (i) with the model for end-stage liver disease (MELD) score in all patient groups, (ii) with the Chronic Liver Failure Consortium (CLIF-C) AD score
      • Jalan R.
      • Pavesi M.
      • Saliba F.
      • Amoros A.
      • Fernandez J.
      • Holland-Fischer P.
      • et al.
      The CLIF consortium acute decompensation score (CLIF-C ADs) for prognosis of hospitalised cirrhotic patients without acute-on-chronic liver failure.
      in patients with AD, and (iii) with CLIF-C ACLF score
      • Jalan R.
      • Saliba F.
      • Pavesi M.
      • Amoros A.
      • Moreau R.
      • Gines P.
      • et al.
      Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.
      in patients with ACLF.

      Statistical analysis

      Continuous variables are reported by median (Q1–Q3) whereas categorical data are presented as frequencies and percentages. Non-normally distributed variables were compared non-parametrically with Kruskal-Wallis tests using Bonferroni correction for multiple comparisons. Correlations were analyzed by Pearson product-moment estimates. Statistical analyses were performed using GraphPad Prism (Version 4.0, GraphPad Software) or SPSS Statistics Version 26 (SPSS Inc., Chicago, IL, USA). Univariate binary logistic regression analysis was used to evaluate prognostic variables for development of complications. Odds ratios estimated from logistic regression are reported with corresponding 95% CIs. Nagelkerke's Pseudo-R2 is given for each model as a measure of goodness-of-fit. Variables identified as potential covariates (p <0.10) from univariate analyses were then tested in multivariable logistic regression models. Competing risk analysis was performed to assess the prognostic value of HDL-related biomarkers for 90-day and 12-month mortality. Either HDL or apoA-I was added to MELD and analyzed by multivariable competing risk analysis with death as the event and liver transplantation as a competing risk, using SAS version 9.4. In addition, the performance of prognostic variables was tested by ROC analysis. AUROCs were compared by the method of DeLong et al.
      • DeLong E.R.
      • DeLong D.M.
      • Clarke-Pearson D.L.
      Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.
      using MedCalc version 14.10.2 (MedCalc Software, Ostend, Belgium). The effect of prognostic variables on mortality was analyzed by the Kaplan-Meier method and compared by log-rank test. The results of the study are reported following the TRIPOD (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) statement recommendations.
      • Collins G.S.
      • Reitsma J.B.
      • Altman D.G.
      • Moons K.G.
      Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement.

      Results

      Patient characteristics

      In total, 508 patients were enrolled in 2 cohorts, 228 patients with stable cirrhosis in the Austrian single-center and 280 patients with AD in the European multicenter cohort. Among patients with stable cirrhosis, 131 patients (57.5%) were classified as Child-Pugh class A, 74 patients (32.5%) Child-Pugh class B and 23 patients (10%) class C. Among the 280 patients with AD, 107 were diagnosed with ACLF. Further details on characteristics of patients (including mortality data) and of controls are given in Table 1. Patients who were transplanted during follow-up were censored for ROC analyses. Nine patients with stable cirrhosis (4%) were taking lipid-lowering drugs while this information was not available for patients with AD. Due to the small number of cases in the stable cirrhosis cohort and presumably low lipid-lowering medication in patients with AD, no further analyses with respect to lipid-lowering medication were performed. Patient characteristics of the external validation cohort from Vienna (HVPG cohort) are given in Table S1.
      Table 1Characteristics of study participants.
      ControlsStable cirrhosisADACLF
      N40228173107
      Age [years]57 (48–64)58 (51–63)58 (51–67)55 (48–64)
      Gender (% male)60%75%64%64%
      Etiology of cirrhosis
       Alcohol58%53%57%
       HCV17%31%28%
       Other25%16%15%
      Child-Pugh score6 (5–8)9 (8–11)11 (10–13)
      MELD12 (9–16)16 (12–20)27 (22–33)
      CLIF-C AD scoren.a.52 (46–57)n.a.
      CLIF-C ACLF scoren.a.n.a.49 (43–56)
      WBC [109/L]6.0 (5.1–6.7)5.1 (3.9–6.5)5.7 (4.1–8.2)8.4 (5.3–12.3)
      PLT [109/L]249 (218–270)111 (79–150)97 (59–141)67 (42–114)
      Bilirubin [mg/dl]0.5 (0.4–0.7)1.4 (0.8–2.8)2.8 (1.4–5.6)7.4 (2.3–18.7)
      Creatinine [mg/dl]0.8 (0.7–0.9)0.8 (0.7–1.0)0.9 (0.7–1.2)1.9 (0.9–3.2)
      INR1.01 (0.98–1.04)1.28 (1.16–1.48)1.46 (1.27–1.75)1.88 (1.40–2.52)
      Sodium [mmol/L]140 (139–141)139 (136–141)136 (133–139)134 (128–137)
      Albumin [g/dl]4.4 (4.3–4.6)4.0 (3.3–4.4)2.9 (2.6–3.2)3.0 (2.3–3.4)
      90-day mortality4%15%42%
      12-month mortality7%27%56%
      ACLF, acute-on-chronic liver failure; AD, acute decompensation; CLIF-C, Chronic Liver Failure Consortium; INR, international normalized ratio; MELD, model for end-stage liver disease; PLT, platelet count; WBC, white blood cell count. Data are shown as median (Q1–Q3). n.a., not applicable.

      HDL-related biomarkers correlate with liver disease severity

      We assessed HDL-C and apoA-I in all 508 patients and 40 age- and gender-matched controls. Furthermore, the major HDL subclasses HDL2-C and HDL3-C as well as CEC were determined in a subset of 333 patients (228 patients with stable cirrhosis and 105 patients with AD). Median levels of total cholesterol and HDL-related biomarkers, including HDL-C, HDL3-C, apoA-I, and CEC, were significantly lower in patients with cirrhosis compared to healthy controls and gradually decreased with increasing severity of disease (Table 2, Fig. 1).
      Table 2HDL-related biomarkers.
      ControlsStable cirrhosisADACLF
      N40228173107
      Cholesterol [mg/dl]231 (199–285)149 (120–181)95 (73–126)71 (42–100)
      HDL-C [mg/dl]63 (52–83)47 (36–60)22 (11–30)11 (5–20)
      HDL2-C [mg/dl]30 (23–48)28 (19–38)13 (7–20)5 (0–10)
      HDL3-C [mg/dl]32 (27–41)18 (13–23)11 (7–15)6 (4–10)
      ApoA-I [mg/dl]178 (152–210)122 (90–149)69 (43–89)33 (18–67)
      CEC12.2 (10.6–14.3)9.7 (7.3–11.9)5.8 (4.4–7.6)4.6 (3.8–7.2)
      AD, acute decompensation; ACLF, acute-on-chronic liver failure; apoA-I, apolipoprotein A1; CEC, cholesterol efflux capacity; HDL-C, high-density lipoprotein cholesterol. Data are shown as median (Q1–Q3).
      Figure thumbnail gr1
      Fig. 1HDL-related biomarkers are associated with severity of chronic liver failure.
      Plasma samples of healthy controls (n = 40) and patients with SC (n = 228), AD (n = 173) and ACLF (n = 107) were examined for levels of (A) HDL-C and (B) apoA-I. ∗p <0.05, ∗∗p <0.01, ∗∗∗p <0.001 vs. control; ###p <0.001 vs. SC; §p <0.05, §§§p <0.001 vs. AD (Kruskal-Wallis test with Bonferroni correction). ACLF, acute-on-chronic liver failure; AD, acute decompensation; ApoA-I, apolipoprotein A1; HDL-C, high-density lipoprotein cholesterol; SC, stable cirrhosis.

      HDL-related biomarkers correlate with inflammatory markers

      The pathophysiology of chronic liver failure is determined by several factors, including systemic inflammation.
      • Arroyo V.
      • Garcia-Martinez R.
      • Salvatella X.
      Human serum albumin, systemic inflammation, and cirrhosis.
      ,
      • Claria J.
      • Stauber R.E.
      • Coenraad M.J.
      • Moreau R.
      • Jalan R.
      • Pavesi M.
      • et al.
      Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure.
      Therefore, we determined the concentrations of various inflammatory markers in subsets of our cohort of patients with cirrhosis. Compared to patients without ACLF, patients with ACLF showed significantly higher numbers of white blood cells (Fig. S1A) and higher C-reactive protein (CRP) levels (Fig. S1B), IL-6 (Fig. S1C) and TNF-α (Fig. S1E), while IL-8 remained unchanged (Fig. S1D). Levels of CRP increased progressively with stage of cirrhosis (Fig. S1B). Since HDL shows anti-inflammatory activity, we next investigated whether HDL-related biomarkers are associated with indices or mediators of inflammation in these subsets. Interestingly, we found strong negative associations of total cholesterol and all HDL-related biomarkers (HDL-C, HDL2-C, HDL3-C, apoA-I, and CEC) with white blood cell count, CRP, IL-6, IL-8, and TNF-α (Table S2).

      HDL-related biomarkers predict complications and mortality

      Complications of cirrhosis and mortality in patients with stable cirrhosis

      The predictive values of HDL-related biomarkers regarding occurrence of complications within 12 months were assessed in patients with stable cirrhosis at baseline (n = 228). 27 patients had to be excluded due to insufficient follow-up (n = 8) or insufficient data with respect to complications (n = 19). In total, 201 patients were included for analysis. Overall, complications occurred in 77 of 201 patients (38%); usually more than 1 complication per patient was recorded (Table S3). In univariate analysis, total cholesterol, HDL-C, HDL2-C, HDL3-C, apoA-I, CEC, international normalized ratio, bilirubin, Child-Pugh and MELD scores were associated with development of complications (data not shown). In order to avoid multicollinearity, only 1 lipid-related biomarker and MELD score were included in multivariate analyses. Multivariable logistic regression yielded both HDL-C and apoA-I as independent predictors of complications (Table 3). On ROC analysis, HDL-C and apoA-I showed high diagnostic accuracy for 12-month mortality (Fig. 2A) and for development of complications within 12 months (Fig. 2B), with AUROCs very similar to those of MELD. Interestingly, HDL-C and apoA-I levels were significantly lower in patients who developed severe infections requiring antibiotic therapy within 12 months (HDL-C: 30 (20–48) mg/dl vs. 52 (42–65) mg/dl, p <0.001; apoA-I: 75 (49–114) mg/dl vs. 132 (107–153) mg/dl, p <0.001).
      Table 3Independent predictive factors with respect to development of complications in stable cirrhosis (n = 228).
      HR95% CIp valueR2
      Univariate
       HDL-C0.960.94–0.98<0.0010.163
       ApoA-I0.970.96–0.98<0.0010.315
       MELD1.301.19–1.41<0.0010.334
      Add to MELD
       HDL-C0.980.96–1.000.061
       MELD1.261.15–1.37<0.001
       Combined0.346
       ApoA-I0.980.97–0.990.001
       MELD1.191.08–1.31<0.001
       Combined0.387
      Multivariable logistic regression. ApoA-I, apolipoprotein A1; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MELD, model for end-stage liver disease; R2, Nagelkerke’s R2.
      Figure thumbnail gr2
      Fig. 2HDL-related biomarkers predict complications and mortality.
      ROC curves illustrating the prognostic value of HDL-C, apoA-I and MELD score. (A) 12-month mortality in stable cirrhosis; (B) development of complications within 12 months in stable cirrhosis; (C) 90-day mortality in AD/ACLF cohort; (D) 90-day mortality in external validation set (HVPG cohort). ACLF, acute-on-chronic liver failure; AD, acute decompensation; ApoA-I, apolipoprotein A1; HDL-C, high-density lipoprotein cholesterol; HVPG, hepatic venous pressure gradient; MELD, model for end-stage liver disease.

      Mortality in patients with AD

      The impact of HDL-related biomarkers on mortality was assessed in patients with AD with or without ACLF (n = 280) using competing risk analysis. Both HDL-C and apoA-I showed high predictive value for the outcomes of interest, i.e. 90-day and 12-month mortality, on univariate analysis and remained independent prognostic variables on multivariable analysis when added to MELD (Table 4). On ROC analysis, HDL-related biomarkers showed high diagnostic accuracy for 90-day mortality (Fig. 2C). When our AD cohort was split into the first (n = 105) and second (n = 175) dataset of CANONIC patients, ROC analysis yielded very similar results (Fig. S2A-B). Furthermore, the prognostic value of HDL-related biomarkers was compared with the CLIF-C AD score for patients with AD and with the CLIF-C ACLF score for patients with ACLF, again with similar results for HDL-related biomarkers and the respective composite scores (Fig. S3A-B). Of note, in all ROC analyses diagnostic accuracies of HDL-C and apoA-I were very similar to that of MELD (Table 5). Calculation of Youden index identified optimal cut-offs of <17 mg/dl for HDL-C and of <50 mg/dl for apoA-I for prediction of 90-day mortality. On Kaplan-Meier analysis, baseline HDL-C or apoA-I values below these cut-offs were associated with markedly lower 90-day survival (Fig. 3A,B) and showed very similar prognostic value as a baseline MELD of ≥22 points (Fig. 3C).
      Table 4Independent predictive factors of 90-day and 12-month mortality in CANONIC patients (AD+ACLF, n = 280).
      HR95% CIp value
      90-day mortality
      Univariate
       HDL-C0.910.89–0.94<0.001
       ApoA-I0.970.96–0.98<0.001
      Add to MELD
       HDL-C0.940.92–0.97<0.001
       MELD1.091.05–1.13<0.001
       ApoA-I0.980.97–0.99<0.001
       MELD1.081.04–1.12<0.001
      12-month mortality
      Univariate
       HDL-C0.940.93–0.96<0.001
       ApoA-I0.980.97–0.99<0.001
      Add to MELD
       HDL-C0.970.95–0.990.004
       MELD1.071.04–1.11<0.001
       ApoA-I0.990.98–0.990.019
       MELD1.071.04–1.11<0.001
      Competing risk analysis with death as event and liver transplantation as competing risk. ACLF, acute-on-chronic liver failure; AD, acute decompensation; ApoA-I, apolipoprotein A1; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; MELD, model for end-stage liver disease.
      Table 5Predictive discrimination of 90-day mortality by HDL-related biomarkers compared to composite prognostic scores.
      AD/ACLF n = 280AD n = 173ACLF n = 107HVPG cohort n = 985
      AUROC (95% CI)
      HDL-C0.79 (0.73–0.85)0.82 (0.74–0.89)0.75 (0.64–0.85)0.81 (0.76–0.87)
      ApoA-I0.80 (0.74–0.86)0.82 (0.74 0.91)0.73 (0.62–0.84)
      MELD0.81 (0.75–0.87)0.81 (0.70–0.91)0.72 (0.61–0.83)0.77 (0.70–0.84)
      CLIF-C AD score0.72 (0.62–0.82)
      CLIF-C ACLF score0.75 (0.65–0.85)
      ACLF, acute-on-chronic liver failure; AD, acute decompensation; ApoA-I, apolipoprotein A1; CLIF-C, Chronic Liver Failure Consortium; HDL-C, high-density lipoprotein cholesterol; HVPG, hepatic venous pressure gradient; MELD, model for end-stage liver disease.
      Figure thumbnail gr3
      Fig. 3Kaplan-Meier plots of survival probability in patients with acute decompensation of cirrhosis.
      (A) Mortality was significantly higher in patients with HDL-C <17 mg/dl (p <0.001 by log-rank test). (B) Mortality was significantly higher in patients with apoA-I <50 mg/dl (p <0.001 by log-rank test). (C) Mortality was significantly higher in patients with MELD ≥22 (p <0.001 by log-rank test). ApoA-I, apolipoprotein A1; HDL-C, high-density lipoprotein cholesterol; HVPG, hepatic venous pressure gradient; MELD, model for end-stage liver disease.

      Mortality in external validation cohort

      In the external validation cohort from Vienna, including 985 patients with ACLD and portal hypertension (HVPG cohort), 54 patients died within 90 days. Again, HDL-C was an excellent predictor of 90-day mortality (AUROC HDL-C: 0.81 vs. MELD: 0.77, p = 0.24 by DeLong test) (Table 5, Fig. 2D).

      Discussion

      In this explorative cross-sectional study, we show that HDL-related biomarkers are robust predictors of disease progression and survival, respectively, in the setting of stable cirrhosis and/or AD. The prognostic values of HDL-C and apoA-I as single and readily available parameters were very similar to those of the composite scores MELD, CLIF-C AD and CLIF-C ACLF. Furthermore, the prognostic value of HDL-C was confirmed in a large external validation cohort of patients with ACLD and portal hypertension.
      Several laboratory markers and functional scores have been studied as predictors of mortality in patients with cirrhosis. The Child-Pugh score comprises serum levels of bilirubin and albumin, prothrombin time, degree of ascites and severity of hepatic encephalopathy and was originally introduced to predict mortality in patients with cirrhosis undergoing surgery.
      • Pugh R.N.
      • Murray-Lyon I.M.
      • Dawson J.L.
      • Pietroni M.C.
      • Williams R.
      Transection of the oesophagus for bleeding oesophageal varices.
      The MELD score was initially developed to predict mortality of patients undergoing transjugular intrahepatic portosystemic shunt insertions and employs serum levels of creatinine and bilirubin and the international normalized ratio.
      • Malinchoc M.
      • Kamath P.S.
      • Gordon F.D.
      • Peine C.J.
      • Rank J.
      • ter Borg P.C.
      A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts.
      We recently showed that HDL maturation, metabolism and function is significantly altered in patients with liver disease.
      • Trieb M.
      • Horvath A.
      • Birner-Gruenberger R.
      • Spindelboeck W.
      • Stadlbauer V.
      • Taschler U.
      • et al.
      Liver disease alters high-density lipoprotein composition, metabolism and function.
      The results of the present study suggest that HDL-related biomarkers, such as HDL-C, HDL3-C, apoA-I and CEC, reflect deterioration in liver function and reliably predict disease progression, development of complications and survival in patients with cirrhosis. HDL-C and apoA-I can be easily measured in routine clinical laboratories and – as single parameters – show excellent diagnostic accuracies for 90-day and 12-month mortality which are very similar to those of composite scores such as Child-Pugh and MELD. In particular, HDL-C and apoA-I decrease with increasing severity of the disease regardless of the etiology of cirrhosis. Of note, baseline HDL-C <17 mg/dl and apoA-I <50 mg/dl are associated with dismal prognosis (90-day survival approx. 50%) and those prove useful as single biomarkers of short-term survival. Our findings are consistent with an earlier study by Poynard et al. that investigated 581 patients with alcohol-related liver disease and reported reduced 1-year survival of patients with cirrhosis and apoA-I <100 mg/dl.
      • Poynard T.
      • Abella A.
      • Pignon J.P.
      • Naveau S.
      • Leluc R.
      • Chaput J.C.
      Apolipoprotein AI and alcoholic liver disease.
      Bacterial infections are common in cirrhosis and account for significant mortality.
      • Arvaniti V.
      • D'Amico G.
      • Fede G.
      • Manousou P.
      • Tsochatzis E.
      • Pleguezuelo M.
      • et al.
      Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis.
      They are facilitated by immune dysfunction that worsens with liver disease progression and frequently results in ACLF.
      • Tandon P.
      • Garcia-Tsao G.
      Bacterial infections, sepsis, and multiorgan failure in cirrhosis.
      ,
      • Gustot T.
      • Durand F.
      • Lebrec D.
      • Vincent J.L.
      • Moreau R.
      Severe sepsis in cirrhosis.
      The risk of individuals with cirrhosis becoming septic is more than doubled compared to the general population and their clinical outcomes are dismal despite intensive care.
      • Foreman M.G.
      • Mannino D.M.
      • Moss M.
      Cirrhosis as a risk factor for sepsis and death: analysis of the national hospital discharge survey.
      • Arabi Y.
      • Ahmed Q.A.
      • Haddad S.
      • Aljumah A.
      • Al-Shimemeri A.
      Outcome predictors of cirrhosis patients admitted to the intensive care unit.
      • Mackle I.J.
      • Swann D.G.
      • Cook B.
      One year outcome of intensive care patients with decompensated alcoholic liver disease.
      HDL regulates the cholesterol levels of cell membranes through its ability to remove cholesterol and other lipid species from cells, thereby reducing inflammatory receptor signaling.
      • Fessler M.B.
      • Parks J.S.
      Intracellular lipid flux and membrane microdomains as organizing principles in inflammatory cell signaling.
      ,
      • Iqbal A.J.
      • Barrett T.J.
      • Taylor L.
      • McNeill E.
      • Manmadhan A.
      • Recio C.
      • et al.
      Acute exposure to apolipoprotein A1 inhibits macrophage chemotaxis in vitro and monocyte recruitment in vivo.
      HDL particles bind LPS and reduce cytokine production and mortality in various animal models.
      • Levine D.M.
      • Parker T.S.
      • Donnelly T.M.
      • Walsh A.
      • Rubin A.L.
      In vivo protection against endotoxin by plasma high density lipoprotein.
      • Hubsch A.P.
      • Casas A.T.
      • Doran J.E.
      Protective effects of reconstituted high-density lipoprotein in rabbit gram-negative bacteremia models.
      • McDonald M.C.
      • Dhadly P.
      • Cockerill G.W.
      • Cuzzocrea S.
      • Mota-Filipe H.
      • Hinds C.J.
      • et al.
      Reconstituted high-density lipoprotein attenuates organ injury and adhesion molecule expression in a rodent model of endotoxic shock.
      Accordingly, the susceptibility to LPS-induced liver damage is higher in rats with cirrhosis than in healthy animals
      • Tazi K.A.
      • Bieche I.
      • Paradis V.
      • Guichard C.
      • Laurendeau I.
      • Dargere D.
      • et al.
      In vivo altered unfolded protein response and apoptosis in livers from lipopolysaccharide-challenged cirrhotic rats.
      and decreases with HDL administration.
      • Thabut D.
      • Tazi K.A.
      • Bonnefont-Rousselot D.
      • Aller M.
      • Farges O.
      • Guimont M.C.
      • et al.
      High-density lipoprotein administration attenuates liver proinflammatory response, restores liver endothelial nitric oxide synthase activity, and lowers portal pressure in cirrhotic rats.
      ,
      • Ramirez M.J.
      • Ibanez A.
      • Navasa M.
      • Casals E.
      • Morales-Ruiz M.
      • Jimenez W.
      • et al.
      High-density lipoproteins reduce the effect of endotoxin on cytokine production and systemic hemodynamics in cirrhotic rats with ascites.
      In a previous study, we observed that cirrhosis significantly impaired the ability of HDL to suppress LPS-induced activation of the proinflammatory transcription factor NF-κB in monocytes and subsequent IL-6 and TNF-α production.
      • Trieb M.
      • Horvath A.
      • Birner-Gruenberger R.
      • Spindelboeck W.
      • Stadlbauer V.
      • Taschler U.
      • et al.
      Liver disease alters high-density lipoprotein composition, metabolism and function.
      In the present study, we report a robust inverse association of HDL-related biomarkers with white blood cell count, CRP, IL-6, IL-8, and TNF-α. Furthermore, patients with subsequent infection showed significantly lower levels of HDL-related biomarkers. In the context of chronic liver failure, the immunomodulatory function of HDL is of particular interest. Reduced HDL quantity and function may play an important role in the pathophysiology of systemic inflammation that drives the development of ACLF.
      • Claria J.
      • Stauber R.E.
      • Coenraad M.J.
      • Moreau R.
      • Jalan R.
      • Pavesi M.
      • et al.
      Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure.
      In line with this concept, an ex vivo study in patients with advanced chronic liver failure has shown that the restoration of HDL function by addition of reconstituted HDL reduces the LPS-induced inflammatory response.
      • Galbois A.
      • Thabut D.
      • Tazi K.A.
      • Rudler M.
      • Mohammadi M.S.
      • Bonnefont-Rousselot D.
      • et al.
      Ex vivo effects of high-density lipoprotein exposure on the lipopolysaccharide-induced inflammatory response in patients with severe cirrhosis.
      It should be noted that a similar therapeutic approach with reconstituted apoA-I (CSL112) infusions has already been attempted in patients with myocardial infarction and was found safe in a recent phase II study.
      • Michael Gibson C.
      • Korjian S.
      • Tricoci P.
      • Daaboul Y.
      • Yee M.
      • Jain P.
      • et al.
      Safety and tolerability of CSL112, a reconstituted, infusible, plasma-derived apolipoprotein A-I, after acute myocardial infarction: the AEGIS-I trial (ApoA-I event reducing in ischemic syndromes I).
      This study has some limitations: our results, albeit robust, are observational, do not prove causality and may be subject to unmeasured confounders. Strengths of our study include the large number of patients (n = 508) representing the whole spectrum of chronic liver failure, separate analysis of individual outcome parameters in patients with stable cirrhosis vs. AD, long-term follow-up of the study cohort for at least 1 year, the detailed assessment of multiple HDL-related biomarkers focusing on readily available parameters (HDL-C, apoA-I), and the confirmation of the prognostic value of HDL-C in a large external validation cohort comprising 985 patients.
      In conclusion, we report for the first time that HDL-related biomarkers predict the development of complications in stable cirrhosis, as well as predicting short-term mortality in the setting of AD. The prognostic value of HDL-C and apoA-I as single biomarkers was similar to currently used composite scores. Both HDL-C and apoA-I provided incremental prognostic information when added to MELD. Further research is needed to validate HDL-related biomarkers as predictors of the development of ACLF in cirrhosis.

      Abbreviations

      Apo, apolipoprotein; ACLF, acute-on-chronic liver failure; AD, acute decompensation; CEC, cholesterol efflux capacity; CLIF-C, Chronic Liver Failure Consortium; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; HVPG, hepatic venous pressure gradient; IL, interleukin; INR, international normalized ratio; LPS, lipopolysaccharide; MELD, model for end-stage liver disease; PLT, platelet count; SC, stable cirrhosis; TNF-α, tumor necrosis factor-α; WBC, white blood cell count.

      Financial support

      This study was supported by the Austrian Science Fund FWF (FWF W1241, DK-MOLIN, P22976-B18 to G.M. and P24362 to VS).

      Authors' contributions

      MT, FR, VS, AH1, JC, RES, GM: study design, data evaluation, manuscript writing and final review; MT, AT, EK, HS, TS: lipid assay; CP, AA: data management, statistical analysis; FR, VS, PD, AH3,5, LB, MM, RP, TR, AG, PC, CA, RM, RES: patient recruitment, data collection and final manuscript review.

      Conflicts of interest

      Alexander Gerbes received personal fees from CSL Behring, GRIFOLS, and Falk. All other authors declare that they have no conflicts of interest related to the study.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      The authors wish to thank Lusik Balayan, Sabine Paulitsch, Andreas Posch and Andrea Streit for excellent technical assistance.

      Supplementary data

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