Bile acid indices as biomarkers for liver diseases I: Diagnostic markers

Abstract

BACKGROUND Hepatobiliary diseases result in the accumulation of toxic bile acids (BA) in the liver, blood, and other tissues which may contribute to an unfavorable prognosis. AIM To discover and validate diagnostic biomarkers of cholestatic liver diseases based on the urinary BA profile. METHODS We analyzed urine samples by liquid chromatography-tandem mass spectrometry and compared the urinary BA profile between 300 patients with hepatobiliary diseases vs 103 healthy controls by statistical analysis. The BA profile was characterized using BA indices, which quantifies the composition, metabolism, hydrophilicity, and toxicity of the BA profile. BA indices have much lower inter- and intra-individual variability compared to absolute concentrations of BA. In addition, BA indices demonstrate high area under the receiver operating characteristic curves, and changes of BA indices are associated with the risk of having a liver disease, which demonstrates their use as diagnostic biomarkers for cholestatic liver diseases. RESULTS Total and individual BA concentrations were higher in all patients. The percentage of secondary BA (lithocholic acid and deoxycholic acid) was significantly lower, while the percentage of primary BA (chenodeoxycholic acid, cholic acid, and hyocholic acid) was markedly higher in patients compared to controls. In addition, the percentage of taurine-amidation was higher in patients than controls. The increase in the non-12α-OH BA was more profound than 12α-OH BA (cholic acid and deoxycholic acid) causing a decrease in the 12α-OH/ non-12α-OH ratio in patients. This trend was stronger in patients with more advanced liver diseases as reflected by the model for end-stage liver disease score and the presence of hepatic decompensation. The percentage of sulfation was also higher in patients with more severe forms of liver diseases. CONCLUSION BA indices have much lower inter- and intra-individual variability compared to absolute BA concentrations and changes of BA indices are associated with the risk of developing liver diseases.

A Current Understanding of Bile Acids in Chronic Liver Disease

“…The increase in total urinary CA and CDCA was highest in PSC and lowest in HBV infection. The total urinary primary/secondary BA ratio was high in most cases of CLD and low only in PBC 38 . In another study, including patients with alcoholic or non-alcoholic cirrhosis, serum conjugated primary BAs such as GCA, GCDCA, TCA, TCDCA, and TUDCA were higher in Child-Turcotte-Pugh (CTP) B and C than in CTP A while secondary BAs showed a decreasing trend with advancing J o u r n a l P r e -p r o o f cirrhosis 39 .…”

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.…”

“…To address these limitations, we have established the concept of “BA idices.” BA indices are ratios calculated from the absolute individual BA concentration and their metabolites [ 1 , 32 , 45 , 46 ]. BA indices have markedly low inter- and intraindividual variability and are more resistant to the above-mentioned cofactors than absolute BA concentrations.…”