Bile acid indices as biomarkers for liver diseases II: The bile acid score survival prognostic model

Abstract

BACKGROUND Cholestatic liver diseases are characterized by an accumulation of toxic bile acids (BA) in the liver, blood and other tissues which lead to progressive liver injury and poor prognosis in patients. AIM To discover and validate prognostic biomarkers of cholestatic liver diseases based on the urinary BA profile. METHODS We analyzed urine samples by liquid chromatography-tandem mass spectrometry and investigated the use of the urinary BA profile to develop survival models that can predict the prognosis of hepatobiliary diseases. The urinary BA profile, a set of non-BA parameters, and the adverse events of liver transplant and/or death were monitored in 257 patients with cholestatic liver diseases for up to 7 years. The BA profile was characterized by calculating BA indices, which quantify the composition, metabolism, hydrophilicity, formation of secondary BA, and toxicity of the BA profile. We have developed and validated the bile-acid score (BAS) model (a survival model based on BA indices) to predict the prognosis of cholestatic liver diseases. RESULTS We have developed and validated a survival model based on BA (the BAS model) indices to predict the prognosis of cholestatic liver diseases. Our results demonstrate that the BAS model is more accurate and results in higher true-positive and true-negative prediction of death compared to both non-BAS and model for end-stage liver disease (MELD) models. Both 5- and 3-year survival probabilities markedly decreased as a function of BAS. Moreover, patients with high BAS had a 4-fold higher rate of death and lived for an average of 11 mo shorter than subjects with low BAS. The increased risk of death with high vs low BAS was also 2-4-fold higher and the shortening of lifespan was 6-7-mo lower compared to MELD or non-BAS. Similarly, we have shown the use of BAS to predict the survival of patients with and without liver transplant (LT). Therefore, BAS could be used to define the most seriously ill patients, who need earlier intervention such as LT. This will help provide guidance for timely care for liver patients. CONCLUSION The BAS model is more accurate than MELD and non-BAS models in predicting the prognosis of cholestatic liver diseases.

Urinary BA Indices as Prognostic Biomarkers for Complications Associated with Liver Diseases

“…The study population was described in details previously (cite our most recent paper [ 1 , 32 , 46 , 48 ]. Briefly, patients with hepatobiliary conditions were diagnosed by University of Nebraska Medical Center's (UNMC) hepatology Clinic (Omaha, NE, USA).…”

“…BA concentrations were quantified by LC-MS/MS, as described previously [ 1 , 32 , 46 , 48 ]. Briefly, a Waters ACQUITY ultraperformance liquid chromatography (UPLC) system (Waters, Milford, MA, USA) coupled to an Applied Biosystem 4000 Q TRAP® quadrupole linear ion trap hybrid mass spectrometer with an electrospray ionization (ESI) source (Applied Biosystems, MDS Sciex, Foster City, CA, USA) was used to perform the LC-MS/MS analysis.…”

“…The BA profile in urine was characterized using BA “indices,” as we have described previously [ 1 , 32 , 46 , 48 ]. Table 1 shows a summary of the BA indices used in the current study.…”

“…Furthermore, we have demonstrated that urinary BA indices outperformed the currently used blood liver enzymes as biomarkers for cholestatic liver diseases [ 1 , 32 , 47 ]. In addition, we have recently developed a BA-based survival model (the BA score (BAS) model) to predict the prognosis of cholestatic liver diseases [ 48 ]. BAS had a higher true-positive and true-negative prediction of 5- and 3-year death and liver transplant than other non-BA models including MELD.…”