Prognostic value of albumin‐related ratios in HBV‐associated decompensated cirrhosis

Abstract Background Identification of effective and accurate prognostic biomarkers for hepatitis B virus‐associated decompensated cirrhosis (HBV‐DeCi) is challenging. This study was designed to determine and compare the prognostic value of albumin‐related ratios (blood urea nitrogen‐to‐albumin ratio [BAR], C‐reactive protein‐to‐albumin ratio [CAR], prothrombin time‐international normalized ratio‐to‐albumin ratio [PTAR], neutrophil count‐to‐albumin ratio [NAR], and D‐dimer‐to‐albumin ratio [DAR]) in HBV‐DeCi patients. Methods We retrospectively recruited 161 HBV‐DeCi patients. Receiver operating characteristic curve, DeLong test, and Cox regression analyses were used to estimate and compare the predictive value of these five albumin‐related ratios and Model for End‐Stage Liver Disease (MELD) score. Results A total of 29 (18.0%) patients had died 30 days after admission. The prognostic roles of CAR, DAR, PTAR, NAR, and BAR in HBV‐DeCi were different. CAR, PTAR, NAR, and BAR were significantly higher in non‐survivors compared with survivors. However, DAR did not differ between the two groups. The predictive power of BAR was superior to that of the other four albumin‐related biomarkers and similar to that of MELD score. On multivariate analysis, BAR and MELD score were identified as independent prognostic factors, and the combination of BAR and MELD score may improve the prognostic accuracy in HBV‐DeCi. Conclusion The present findings suggest that BAR may be a simple and useful prognostic tool to predict mortality in HBV‐DeCi patients.

as an independent risk predictor for prognosis. However, the score requires complex calculations and is inconvenient for routine practice.
Furthermore, the score is affected by diuretics, bleeding, and ascites, and thus its prediction accuracy is limited and unsatisfactory. 6 In clinical practice, the prognosis of HBV-DeCi patients is difficult to predict because it is affected by many unstable factors, including inflammation, complications, and therapeutic options. These factors may be associated with the complex pathophysiological mechanism of HBV-DeCi. Consequently, it is necessary to combine relevant parameters and construct models that can effectively predict the prognosis of HBV-DeCi patients.
Serum albumin is considered a biomarker of malnutritioninflammation syndrome, and there is emerging data that hypoalbuminemia is related to worse survival in intensive care unit patients. [7][8][9] Albumin has multiple functions and plays important roles in liver disease severity, progression, and prognosis. First, albumin is a negative acute-phase reactant and decreases in response to inflammation, thereby serving as an inflammation marker. Second, albumin is synthesized in the liver and can reflect the liver synthetic function, an important indicator for assessment of hepatic function. Third, albumin is a marker that reflects nutritional status, and low albumin is often associated with malnutrition. Decreased albumin is a common complication in cirrhotic patients that can lead to ascites and hepatic encephalopathy, and even a tendency toward spontaneous bacterial peritonitis, and has a negative impact on prognosis. 10,11 Recently, the clinical usefulness of albumin-related biomarkers available from routine testing has been reported in various diseases, including liver diseases, such as C-reactive protein-to-albumin ratio (CAR), [12][13][14] D-dimer-to-albumin ratio (DAR), 15 prothrombin time-international normalized ratio-to-albumin ratio (PTAR), [16][17][18] neutrophil countto-albumin (NAR), [19][20][21] and blood urea nitrogen-to-albumin ratio (BAR). [22][23][24][25] However, no studies have investigated the differences in prognostic value of these albumin-related ratios in HBV-DeCi patients. Therefore, we conducted this retrospective study to determine and compare the prognostic value of these albumin-related ratios and their clinical utility in HBV-DeCi patients in China. (2) malignant tumors; (3) underlying liver disease (e.g., other viral hepatitis and alcohol-or drug-related liver diseases); and (4) complication with cardiac diseases or blood-system diseases. All patients received antiviral therapy from the start date. The primary outcome was 30-day survival.

| Clinical data collection
Demographic and clinical parameters, including gender, age, laboratory variables (total bilirubin, total protein, albumin, blood urea In the study population, the 30-day mortality rate was 18.0% (29/161). The cause of death was hepatic failure (n = 8), gastrointestinal bleeding (n = 8), encephalopathy (n = 7), hepatorenal syndrome (n = 5), and unknown (n = 1). The patients were divided into non-survivors (n = 29) and survivors (n = 132). Table 1 shows the baseline characteristics in the two groups. Significant differences in total bilirubin, creatinine, INR, total protein, hemoglobin, CAR, PTAR, NAR, BAR, and MELD score were found between the two groups (all p < 0.05). Compared with survivors, non-survivors were more likely to have ascites, hepatorenal syndrome, or encephalopathy (all p < 0.05). Table 2 lists the relationships between the albumin-related ratios, MELD score, WBC, CRP, and mortality. In univariate analyses, high MELD score, high CAR, high PTAR, high NAR, high BAR, high WBC, and high CRP were associated with mortality. In multivariate analyses, only high BAR and high MELD score were identified as independent factors for worse survival. Next, ROC curves were used to assess the discrimination ability of the factors for mortality ( Figure 3). The AUCs for CAR and DAR for the prediction of mortality F I G U R E 1 Flow diagram of the patients enrolled in this study and the reasons for exclusion    Note: Data are expressed as n or median (interquartile range).

TA B L E 2 Univariate and multivariate analyses of risk factors associated with mortality in HBV-DeCi patients
were not significant (both p > 0.05

| DISCUSS ION
Patients with HBV-DeCi have a very high risk of mortality, and determining the prognosis of HBV-DeCi is challenging. Current research has mainly focused on the prognostic value of albumin-related biomarkers in these patients. To our knowledge, this is the first study to date that determines and compares the five albumin-related ratios for poor survival prediction in HBV-DeCi patients. We found that the prognostic roles of CAR, DAR, PTAR, NAR, and BAR in HBV-DeCi patients were different. The major findings of the study are summarized below.
First, there is considerable evidence that inflammation is common in advanced cirrhotic patients and associated with adverse outcomes. 27,28 Neutrophil count and CRP are universal inflammatory markers, and the prognostic role of values based on these two inflammatory factors in HBV-associated liver disease has been explored, including NAR (ratio of neutrophil count to albumin) 19 and CAR (ratio of CRP to albumin). 12 For example, Han et al. 19 proposed that high NAR was linked to poor survival in HBV-DeCi patients, while Huang et al. 12 found that CAR was related to the prognosis of HBV-DeCi patients and was better than MELD score for predicting HBV-DeCi mortality. However, NAR and CAR were not identified as predictors of poor outcomes in the present multivariate analyses. This may be due to differences in the risk factors included in the regression analyses in the three studies. Notably, the AUC for CAR to predict mortality was not significant compared with the reference line (p = 0.054) in the present study. This may arise because CRP is influenced by multiple factors such as body mass index, weight loss, and smoking, 29 meaning that it cannot effectively reflect the inflammatory F I G U R E 3 ROC curve analyses for albumin-related ratios and MELD score for prediction of 30-day mortality in HBV-DeCi patients  Second, coagulopathy and hemorrhage risk are commonly seen in severe liver cirrhosis patients, because of decreased production of blood pro-and anti-coagulant proteins in the liver and/or portal hypertension. 30,31 Recently, PTAR was reported as a novel method for liver function assessment in hepatocellular carcinoma. 17 In addition, Gao et al. 18 24 and pancreatitis. 25 Furthermore, Yu et al. 35 identified BUN and age as predictive factors for poor prognosis in advanced liver diseases using machine learning. Kidney dysfunction is a common comorbid condition in liver disease, and several reports have indicated that kidney dysfunction is linked to mortality in cirrhotic patients. 36 Among the 161 patients in the present cohort, 22 (14.0%) suffered from hepatorenal syndrome. In addition, gastrointestinal bleeding has a high incidence in cirrhotic patients and carries a high risk of death and decreased hemoglobin in these patients. 37 In the present study,

| CON CLUS IONS
In summary, we evaluated five albumin-related ratios (CAR, DAR, PTAR, NAR, and BAR) for the prediction of mortality in HBV-DeCi patients. Our study suggests that BAR can be a simple, effective, and useful prognostic tool to predict poor outcomes in HBV-DeCi patients and that use of a combination of BAR and MELD score can improve the prognostic accuracy. However, because this was a retrospective study, further prospective clinical trials are warranted to validate the present results.

ACK N OWLED G M ENTS
The authors thank Alison Sherwin, PhD, from Liwen Bianji (Edanz) (www.liwen bianji.cn/) for editing the English text of a draft of this article.

CO N FLI C T O F I NTE R E S T
None of the authors have any commercial or other association that might pose a conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data are available upon reasonable request.