Glycodeoxycholic Acid Levels as Prognostic Biomarker in Acetaminophen-Induced Acute Liver Failure Patients

Abstract

Acetaminophen (APAP)-induced acute liver failure (ALF) remains a major clinical problem. Although a majority of patients recovers after severe liver injury, a subpopulation of patients proceeds to ALF. Bile acids are generated in the liver and accumulate in blood during liver injury, and as such, have been proposed as biomarkers for liver injury and dysfunction. The goal of this study was to determine whether individual bile acid levels could determine outcome in patients with APAP-induced ALF (AALF). Serum bile acid levels were measured in AALF patients using mass spectrometry. Bile acid levels were elevated 5-80-fold above control values in injured patients on day 1 after the overdose and decreased over the course of hospital stay. Interestingly, glycodeoxycholic acid (GDCA) was significantly increased in non-surviving AALF patients compared with survivors. GDCA values obtained at peak alanine aminotransferase (ALT) and from day 1 of admission indicated GDCA could predict survival in these patients by receiver-operating characteristic analysis (AUC = 0.70 for day 1, AUC = 0.68 for peak ALT). Of note, AALF patients also had significantly higher levels of serum bile acids than patients with active cholestatic liver injury. These data suggest measurements of GDCA in this patient cohort modestly predicted outcome and may serve as a prognostic biomarker. Furthermore, accumulation of bile acids in serum or plasma may be a result of liver cell dysfunction and not cholestasis, suggesting elevation of circulating bile acid levels may be a consequence and not a cause of liver injury.

Screening for biomarkers of liver injury induced by Polygonum multiflorum: a targeted metabolomic study

“…GDCA in bile, as well as HDCA in serum were significant decrease and were selected as potential biomarkers for HSW induced liver injury. GDCA has been selected as biomarker in acetaminophen-induced acute liver failure in clinical study (Woolbright et al, 2014), Dietary HDCA exerted hypolipidemic effects by reducing farnesoid X receptor antagonist bile acids in mouse enterohepatic tissues (Watanabe and Fujita, 2014). Bile acids was synthesized in liver, and transported from hepatocytes into the biliary tracts by canalicular transporters, this process was sensitive to perturbation (Jaeschke et al, 2002; Yamazaki et al, 2013), which further confirmed that bile acids were highly sensitive markers for liver injury.…”

Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis

“…Bile acid measurements were performed as previously described in detail (Woolbright et al, 2014a). In brief, bile samples were first diluted 1:50 in water, whereas serum samples were used as is.…”

Acetaminophen hepatotoxicity: an updated review

“…In 2012, a small retrospective study found that the Sequential Organ Failure Assessment (SOFA), evaluating multisystem dysfunction, is a better predictor than the King's College Criteria for identifying patients that will ultimately require transplantation, but again, further investigation is needed (Cholongitas et al 2012). Additional areas of promise for determining prognosis in acetaminophen-related ALF include individual bile acids such as glycodeoxycholic acid, markers of apoptosis such as M30, and indocyanine green (ICG) clearance (Milesi-Halle et al 2011;Rutherford et al 2012;Woolbright et al 2014). ICG clearance is a measure of the functional capacity of the liver and has shown positive correlation with extent of hepatic necrosis in murine models of acetaminophen hepatotoxicity (MilesiHalle et al 2011).…”