Bile acid profiles in urine of patients with liver diseases

Abstract

Abstract. Quantitative gas chromatography‐mass spectrometry was used to study the metabolic profiles of unconjugated, conjugated and sulphated bile acids in urine of patients with intermittent intrahepatic cholestasis of unknown aetiology, cirrhosis of the liver, primary biliary cirrhosis, viral and toxic hepatitis and extrahepatic cholestasis. A large number of bile acids was present which can broadly be classified into four groups: cholic and chenodeoxycholic acids constituted between 49·4% and 77·9% of the total bile acids (mean values of the groups); deoxycholic and other 3,12‐disubstituted bile acids between 1·3% and 12·3%, monohydroxy bile acids between 6·7% and 14·4% and bile acids hydroxylated at C‐1 or C‐6 between 4·6% and 14·6%. The high proportion of bile acids from the latter group, and the presence of tetrahydroxylated bile acids, clearly distinguished hepatic disease from the normal state. The metabolic profiles were very variable and there were few consistent differences between the groups of diseases studied. Norcholic acid constituted a significantly higher percentage of the total bile acids in cirrhotic patients (6·2 ± 6·8%) than in non‐cirrhotic patients (1·3±1·8%, P<0·001). With this exception, no profile was specific for any type of intra‐ or extra‐hepatic cholestasis. The excretion rates of the major l‐hydroxylated bile acids were positively correlated to each other. The same was true for the major 6‐hydroxylated bile acids. This may indicate that cholic, chenodeoxycholic and deoxycholic acids act as substrates for common 1‐ and 6‐hydroxylating enzymes. Possibly the taurine conjugates are preferred substrates since 1‐hydroxylated bile acids and hyocholic acid were found mainly in this fraction. A positive correlation between the excretion of sulphated 3β‐hydroxy‐5‐cholenoic acid and 3β,12α‐dihydroxy‐5‐cholenoic acid indicates a direct metabolic relationship between these compounds. Confirming previous data, a high proportion of bile acids was sulphated. The degree of sulphation increased with decreasing number of hydroxyl groups, reaching 100% for the monohydroxy and most of the dihydroxy acids. Tetrahydroxycholanoates were not sulphated, and sulphation of trihydroxycholanoates was positively correlated to the renal bile acid excretion rate. Bile from patients with intermittent intrahepatic cholestasis did not contain the tetrahydroxylated bile acids present in urine. Hyocholic acid was a very minor, mainly taurine conjugated, bile acid. Monohydroxy bile acids were usually below the detection limit. These data do not support the hypothesis that lithocholic acid participates in the initiation or perpetuation of intermittent intrahepatic cholestasis of unknown aetiology.

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

“…Notably, urine from patients suffering from cholestasis contains elevated levels of 6-hydroxylated bile acids (including the LCA metabolite hyodeoxycholic acid), which are products of CYP3A4 (16,37). These findings suggest that increased 6-hydroxylation is a relevant mechanism for reducing the levels of toxic bile acids in humans.…”

A two-year prospective study of the effect of ursodeoxycholic acid on urinary bile acid excretion and liver morphology in cystic fibrosis-associated liver disease

“…We have no explanation for this finding, but high amounts of UDCA have been reported previously in cases with severe liver disease. 32,33 The UDCA metabolites increased in all patients during treatment and did not show any difference between the biochemical responders and nonresponders.…”

CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice

“…In cholestatic liver disease in humans, hydroxylation of bile acids is already spontaneously observed, which renders bile acids more hydrophilic and thus less toxic. 6,31 Functionally, CAR and PXR stimulation was followed by a shift from primary cholic acid and muricholic acids (triols) to polyhydroxylated bile acids (pentols) in serum in CBDL mice. In urine, the less toxic and better water-soluble tetrols dominated in all studied groups.…”

“…In addition, detoxification of accumulating biliary compounds via phase I hydroxylation and phase II conjugation may counteract cholestatic liver damage by rendering hydrophobic substrates less toxic and better soluble for biliary and urinary excretion. 5,6 However, intrinsic hepatocellular adaptive induction of transporters and enzymes in cholestasis is too weak to prevent ongoing liver injury. 4,7 In addition to the classical bile acid receptor, farnesoid X receptor (FXR), also the xenobiotic receptors, constitutive androstane receptor (CAR) and pregnane X receptor (PXR), critically participate in the regulation of genes involved in the detoxification and transport of bile acids and bilirubin.…”