Long-Term Ursodeoxycholic Acid Therapy Does Not Alter Lithocholic Acid Levels in Patients with Cystic Fibrosis with Associated Liver Disease.

OBJECTIVE: To evaluate the fasting and postprandial serum bile acid composition in patients with cystic fibrosis-associated liver disease (CFLD) after chronic administration of ursodeoxycholic acid (UDCA) (20 mg/kg/day). The aim was to specifically focus on the extent of biotransformation of UDCA to its hepatotoxic metabolite, lithocholic acid, because of recent concerns regarding the safety of long-term, high-dose UDCA treatment for CFLD. STUDY DESIGN: Twenty patients with CFLD (median age 16 years, range: 2.4-35.0) prescribed UDCA therapy for at least 2 years were studied. Total and individual serum bile acids were measured by stable-isotope dilution mass spectrometry, in fasting and 2-hour postprandial samples taken during chronic UDCA (20 mg/kg/day) administration. RESULTS: During chronic UDCA administration (median duration 8 years, IQR: 6-16), UDCA became the predominant serum bile acid in all patients (median, IQR: 3.17, 1.25-5.56 µmol/L) and chenodeoxycholic acid concentrations were greater than cholic acid (1.86, 1.00-4.70 µmol/L vs 0.40, 0.24-2.71 µmol/L). The secondary bile acids, deoxycholate and lithocholate, were present in very low concentrations in fasted serum (<0.05 µmol/L). After UDCA administration, 2-hour postprandial concentrations of both UDCA and chenodeoxycholic acid significantly increased (P < .01), but no significant changes in serum lithocholic acid concentrations were observed. CONCLUSION: These data do not support recent suggestions that enhanced biotransformation of UDCA to the hepatotoxic secondary bile acid lithocholic occurs when patients with CFLD are treated with relatively high doses of UDCA.

Bile acid profiles by capillary electrophoresis in intrahepatic cholestasis of pregnancy.

ICP (intrahepatic cholestasis of pregnancy) is characterized by pruritus and biochemical cholestasis, including raised SBAs (serum bile acids) and, usually, elevated aminotransferases levels. However, AHP (asymptomatic hypercholanaemia of pregnancy) is defined as the presence of total SBA levels above the cut-off value (11 microM) in healthy pregnant women, thus elevation of total SBAs do not necessarily reflect an ICP condition. The aim of the present study was to describe clinical, obstetric, perinatal and biochemical findings, as well as the SBA profile, in pregnant women studied in the third trimester of pregnancy in order to define characteristic patterns of individual bile acids that enable women with ICP to be distinguished from AHP and healthy pregnancies. Free and conjugated ursodeoxycholic (UDCA), cholic (CA), lithocholic (LCA), deoxycholic (DCA) and chenodeoxycholic (CDCA) acids were evaluated by CE (capillary electrophoresis) in 41 patients (15 of them simultaneously by HPLC), in 30 healthy pregnant women and in 10 non-pregnant women. A highly significant correlation between CE and HPLC for total SBAs (r=0.990) and for individual SBAs was found. Normal pregnant women had higher total SBA levels than non-pregnant women (due to an increase in taurine-conjugated dihydroxy SBAs). Women with ICP had higher levels of total SBAs, the free/conjugated ratio, LCA, CA, CDCA and DCA than normal pregnant women. Newborns from women with ICP had lower birth weight and gestational age. Women with AHP had higher levels of conjugated dihydroxy SBAs than normocholanaemic patients, without any evidence of a clinical difference. In conclusion, the present study has shown a clear difference in SBA profiles between ICP and normal pregnancies (including AHP), involving a shift towards a characteristic hydrophobic composition in women with ICP.

[Determination of cholic and sulfolithocholic acids in various hepatopathies]. / Determinación de los ácidos cólico y sulfolitoglicocólico en diferentes hepatopatías.

The conjugated cholic acid (glycocholic acid) (GC) in the serum and the conjugated sulfolithocholic acid (sulfolithoglycocholic acid (SLGC) in 35 aggressive chronic hepatitis (HCA), 22 cirrhosis, 11 primary biliary cirrhosis (CBP), 11 pruritus of pregnancy and in 20 normal controls were determined. The control group revealed a mean value of GC of 21 micrograms % with a dispersion of +/- 14 micrograms % and for SLGC of 36 micrograms % with a dispersion of +/- 9 micrograms %. The frequency of the alteration of GC and SLGC in the cases of chronic hepatitis was low (14% and 9%) as well as in the cirrhosis (23% and 14%). In the pruritus of pregnancy the values reached 64% and 45%. On the other hand, the values were significantly elevated in CBP (100% and 90%) (p.001 and p.006). The absolute values in the various pathologies revealed mean values which were different but with a very wide dispersion that prevented us from seeing any relation between those absolute values and the different diseases. The alteration in the metabolism of biliary acids in the hepatic pathology was manifested by the postprandial determination of GC and SLGC in 20 HCA in whom the frequency of abnormal values rose from 14% and 9% on fasting to 60% and 45% prandially.

Pathologic versus physiologic cholestasis: elevated serum concentration of a secondary bile acid in the presence of hepatobiliary disease.

Serum levels of the primary bile acids cholic and chenodeoxycholic acid are transiently elevated in normal neonates and infants; this represents a state of "physiologic cholestasis." In this study we determined, using specific radioimmunoassay, the concentration of a secondary bile acid, sulfated lithocholate, in serum obtained from healthy infants and from those with various hepatobiliary diseases. The serum levels of sulfated lithocholate were low in 69 neonates (less than 5 days of age: mean +/- SEM = 0.45 +/- 0.05 mumoles/L) and in 78 normal infants (less than one year of age: 0.49 +/- 0.02); there was no postprandial rise. These values were similar to those seen in 95 older children (0.56 +/- 0.03) and in maternal (0.49 +/- 0.04) and cord blood (0.44 +/- 0.03) of the neonates. In contrast, in patients with neonatal cholestasis of any nature there was a consistent marked rise in serum concentrations of sulfated lithocholate (mean = 4.46 +/- 0.39, P less than 0.001). In infants monitored during the course of parenteral nutrition, elevated values of sulfated lithocholate often occurred in the presence of normal results of other liver function tests. Serum sulfated lithocholate concentration is an accurate index of neonatal hepatobiliary disease; the sensitivity and specificity of this test remain to be further defined.