The role of calcium precipitation in the sulfoglycolithocholate-induced cholestasis of the bile fistula hamster

Sulfate glycolithocholic acid (SGLC) has been shown to be highly cholestatic in the rat. This study was performed in order to gain understanding of the mechanisms of SGLC-induced cholestasis and the aim of the investigation was to explore the hypothesis that SGLC could cause a precipitation of calcium in bile. We studied the effects of intravenously administrated SGLC on bile flow, biliary lipids secretion and calcium excretion in the female bile fistula hamster. We also performed in-vitro studies with a Ca2(+)-selective electrode in order to measure the calcium binding capacity of SGLC. The results showed that after 1 h of infusion of 8 mumol/100 g body weight [14C]SGLC bile flow dropped to zero. During the infusion period a fine white sludge was visible in the test tube used for bile collection. TLC and HPLC analysis of both the supernatant and the precipitate showed that unchanged SGLC was excreted into bile. Up to 20% of biliary SGLC and more than 50% of the total Ca2+ present in bile was precipitated. The SGLC/Ca2+ molar ratio in the precipitate was 1.12 +/- 0.3 (mean +/- S.D. of four experiments). Light and electron microscopy of the liver did not show any specific abnormalities. The Ca2+ binding activity of SGLC in vitro, was highest among the bile acids tested at a concentration of 0.1 mM, when almost 100% of bile acids are in the monomeric (non-micellar) form. This suggests that among the bile acids, SGLC exerts the strongest binding activity on free calcium ions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bile acid concentrations in systemic and portal serum in presumably normal man and in cholestatic and cirrhotic conditions

Total bile acid concentration was determined in systemic and portal serum and in liver tissue from patients with presumably normal liver function, and from patients with extrahepatic cholestasis. Systemic and portal serum bile acids were also determined in patients with alcoholic liver cirrhosis. In 5 patients, in whom a portal catheter was inserted through the umbilical vein, the diurnal variation in systemic and portal serum bile acid concentration was studied. In patients with presumably normal liver function the fasting systemic serum bile acid concentration was 4.8+/-0.5 mumol times 1(-1), and the portal concentration was 12.9+/-1.5 mumol times 1(-1). In cholestasis and liver cirrhosis the systemic and portal bile acid concentration was substantially elevated. The bile acid concentration gradient between systemic serum, portal serum, liver tissue, and hepatic bile was 1:3:80:2600 in the patients with normal liver function. In both the cholestatic and cirrhotic condition the systemic and portal serum bile acid concentration was equilibrated. Postprandially both the systemic and portal bile acid concentration increased, but the gradient between these concentrations was unchanged. The results are compatible with the hypothesis that portal and systemic serum bile acid concentrations are determined by the intestinal absorption rate in subjects with normal liver function and by the hepatic and renal clearance capacity in cholestatic and cirrhotic conditions.     

Ileal dysfunction in Crohn's disease assessed by the postprandial serum bile acid response.

We assessed ileal functional integrity in 20 consecutive patients with Crohn's disease by sequential measurement of the postprandial serum bile acid concentration. In all 14 patients with active Crohn's disease involving the terminal ileum, the mean (+/- SEM) peak response in the cholylglycine (0.4 +/- 0.04 mumol/l, n = 14) as well as in the total serum bile acid concentration (2.0 +/- 0.4 mumol/l, n = 10) was similar to that seen in a group of children who had undergone ileal resection. A significantly greater increase in the cholylglycine (1.8 +/- 0.18 mumol/l, n = 16, P less than 0.01) and in the total serum bile acid concentration (9.8 +/- 2.4 mumol/l, n = 11, P less than 0.025) was noted in normal children. In five of the six remaining patients (three with Crohn's disease shown not to involve the ileum and two of three with asymptomatic, treated Crohn's ileitis) and in seven patients with ulcerative colitis, the meal stimulated responses were normal. These preliminary results suggest that measurement of the serum bile concentration after a meal stimulus may provide a valuable index of ileal inflammation in patients with Crohn's disease.     

Vitamin E deficiency and its clinical significance in adults with primary biliary cirrhosis and other forms of chronic liver disease

The vitamin E status of 146 adults with chronic liver disease was assessed by estimating both their serum vitamin E concentration and the ratio of serum vitamin E to serum cholesterol concentration. Low levels of vitamin E occurred most frequently in patients with primary biliary cirrhosis and other forms of chronic cholestatic liver disease. When a serum vitamin E concentration of 12.3 mumol/l (mean-2 SD of a control population) was taken as the lower limit of normal, 44% of patients with primary biliary cirrhosis and 32% with other chronic cholestatic liver disease had a reduced concentration, indicating a biochemical deficiency of vitamin E. If a vitamin E/total cholesterol ratio of 2.35 mumol/mmol was taken as the lower limit of normal, then 64% and 43% of patients with primary biliary cirrhosis and other chronic cholestatic liver disease, respectively, had a biochemical deficiency of vitamin E. Of the patients with chronic cholestasis and a serum bilirubin concentration greater than 100 mumol/l, 91% had a reduced vitamin E/cholesterol ratio. Twelve patients with primary biliary cirrhosis and severe vitamin E deficiency (serum vitamin E less than 5.0 mumol/l and a vitamin E/cholesterol ratio less than 1.0 mumol/mmol) underwent extensive neurological investigation. Five had a mild mixed sensorimotor peripheral neuropathy, which was not, however, typical of the neurological syndrome associated with vitamin E deficiency. In patients with severe biochemical deficiency of vitamin E (less than 5 mumol/l and less than 1 mumol/mmol total cholesterol), administration of large oral doses of vitamin E only increased serum concentrations to within the normal range in one patient; in the others even weekly parenteral administration over a 3-month period did not correct deficiency. In patients with less severe biochemical deficiency, the serum vitamin E concentration and vitamin E/total cholesterol ratio were restored to normal by oral or intramuscular supplements of the vitamin.     

Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis

We have prospectively studied changes in serum postprandial cholylglycine (CG) concentration during 297 pregnancies. We found an increase in CG concentration from 0.3 mumol/L at 15 weeks' pregnancy to 0.6 mumol/L at 40 weeks' pregnancy. Although this increase was statistically significant (p less than 0.005), median concentrations of CG remained well within the normal range (0-1.5 mumol/L). However, 10% of the group showed markedly elevated serum CG concentrations at 30 weeks' pregnancy, and the CG level in this group continued to rise during the third trimester. Pruritus was significantly more common in the group with elevated CG concentrations (48%) than in the group with normal CG levels (20%) (p less than 0.005). Serum CG was a much more sensitive predictor of pruritus during pregnancy than other biochemical liver tests. Elevated CG levels were found more commonly in Mediterranean and Asian patients than patients of other ethnic origins (p less than 0.025). No statistically significant associations were found between elevated CG concentrations and maternal age, number of previous pregnancies, pruritus during previous pregnancies, contraceptive-induced cholestasis, and fetal maturity. We conclude that obstetric cholestasis is probably much more common than previously suspected and that consideration should be given to the measurement of serum bile acids in all pregnant individuals with unexplained pruritus.     

Erythrocyte lipid alterations in pediatric cholestatic liver disease: relationship to serum bile acids

Chronic pediatric cholestatic liver disease is accompanied by an elevated erythrocyte membrane cholesterol/phospholipid molar ratio. Since bile acids are known to affect erythrocyte membrane integrity, we sought to determine what relationship existed between serum bile acid concentrations and the observed alterations in erythrocyte membrane lipids. Ten children with chronic cholestasis (2 months-3 1/2 yrs) were evaluated a total of twenty-two times. For all studies a reliable correlation between erythrocyte membrane cholesterol and phospholipid was noted (r = 0.88, p less than 0.001). When total serum bile acids exceeding 100 mumol/L were excluded, a strong relationship between serum bile acids and erythrocyte cholesterol/phospholipid molar ratio was noted (r = 0.61, p less than 0.03). The results suggest that with mild to moderate cholestasis changes in serum bile acids influence erythrocyte membrane lipid composition with parallel increases in cholesterol and phospholipid.     

Serum cystatin C measurement in differential diagnosis of intra and extrahepatic cholestatic diseases

Objective. Cystatin C is a very potent inhibitor of cysteine proteinases and, it has been clinically applied as a sensitive marker in monitoring of renal and liver functions. The aim of this study was to reveal whether cystatin C may be a useful marker for distinguishing intra-versus extrahepatic cholestasis.Materials and methods. Serum cystatin C concentrations were determined by nephelometric immunoassay using N latex cystatin C kit in 53 patients with cholestatic disorder that included 18 patients with intrahepatic cholestasis, 17 patients with malignant extrahepatic cholestasis, 18 patients with benign extrahepatic cholestasis. Serum cystatin C concentration was also determined in 20 healthy volunteers.Results. Mean serum cystatin C concentration was 2.82 ± 0.24 mg/l (SD) in patients with intrahepatic cholestasis, 2.05 ± 0.15 mg/l in patients with extrahepatic malignant cholestasis, 1.37 ± 0.13 mg/l in extrahepatic benign cholestatic patients and 0.93 ± 0.24 mg/l in control group. Serum cystatin C concentrations in patients with cholestatic disease were significantly higher than those in the healthy controls (p < 0.001). Moreover, mean serum cystatin C concentration in patients with intrahepatic cholestasis was higher than those in extrahepatic cholestasis groups (p < 0.001). Serum cystatin C concentrations were significantly higher in patients with malignant extrahepatic cholestasis than in patients with benign extrahepatic cholestasis (p < 0.001). There were no correlations patients among serum cystatin C concentrations and serum levels of AST, ALT, ALP, GGT, total and conjugated bilirubin.Conclusion. Our results suggested that serum cystatin C level may be a potential biochemical marker both to point out an intrahepatic origin by excluding an extrahepatic source of cholestasis in patients with jaundice and to possibly differentiate bening and malignant extrahepatic cholestatic disorders.     

Serum bile acids in primary biliary cirrhosis

Serum bile acid classes have been studied in 15 patients with primary biliary cirrhosis in five patients with cholestasis, and in five patients who had cirrhosis without cholestatic features. Conjugated monohydroxy bile acids (12-35% serum total bile acids) were found in eight of 11 sera from patients with primary biliary cirrhosis, in sera from four patients with cholestasis but not in any of the five patients with cirrhosis. The glycine conjugates/taurine conjugates (G/T) ratio in eight of 11 patients with primary biliary cirrhosis and two of four patients with cholestasis was <1.0.Bile acid concentrations in seven patients with primary biliary cirrhosis were measured before and during cholestyramine therapy. Decreases in serum total bile acid concentrations were observed which were accompanied by small increases in the trihydroxy/dihydroxy ratio and also in the G/T ratio in six of the seven patients. No association was found between the concentration of any particular conjugated or free bile acid and the presence or absence of pruritus.     

Benign recurrent intrahepatic cholestasis: a long-term follow-up study of two patients

Two brothers with benign recurrent intrahepatic cholestasis were studied over a period of 6 years. During this period, 11 episodes of cholestasis were observed, with a mean duration of 2.6 months (range: 2 weeks to 6 months). Once, both brothers developed cholestasis simultaneously. There was a prevalence for episodes of cholestasis in wintertime. The postprandial rise in serum sulfated glycolithocholic acid was increased in the patients, and the bile acid pool was enriched with secondary bile acids. In periods prior to cholestasis, the urinary 3 alpha OH-bile acid concentration was often elevated (greater than 50 mumoles per liter) without a clear correlation with the clinical prodromata. However, it could not be used as a predictor of cholestasis. In contrast, the postprandial rise in serum 3 alpha OH-bile acids was always grossly elevated in periods just before cholestasis. An increase both in fecal bile acid excretion as well as secondary bile acids in the bile acid pool indicated an increased spillover of bile acids into the large bowel. Cholestyramine administered directly after the first signs of cholestasis appeared to shorten an episode of cholestasis. On the other hand, withdrawal of cholestyramine in a cholestasis-free period may have resulted in an episode of cholestasis. Neither taurine supplementation for 3 and 7 weeks nor calcium phosphate, which binds sulfated bile acids in vitro, for 3 weeks could prevent an episode of cholestasis, although the latter normalized the bile acid pool composition. There is a rationale for a fat-restricted diet and cholestyramine therapy only as maintenance treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Formation of iso-ursodeoxycholic acid during administration of ursodeoxycholic acid in man

The appearance of iso-ursodeoxycholic acid (isoUDCA; 3 beta,7 beta-dihydroxy-5 beta-cholan-24-oic acid) in serum of patients with chronic cholestatic liver disease and of healthy subjects during administration of ursodeoxycholic acid (UDCA) is reported. Comparison of the mass spectrum of the newly appearing bile acid with that of authentic 3 beta,7 beta-dihydroxy-5 beta-cholan-24-oic acid revealed its identity as the 3 beta-epimer of UDCA. The appearance of 13C-isoUDCA in serum after ingestion of 13C-UDCA proved its product precursor relationship with UDCA. The putative intermediate in the epimerization of UDCA to isoUDCA, 3-oxo-7 beta-hydroxy-5 beta-cholan-24-oic acid, was identified in serum of patients with cholestatic liver disease during treatment with UDCA. Serum concentrations of isoUDCA after 4 weeks of UDCA treatment were 1.37 +/- 0.79 mumol/l (mean +/- S.D.) in eight patients with primary biliary cirrhosis (PBC), 1.25 +/- 0.91 mumol/l in six patients with primary sclerosing cholangitis (PSC) and 3.87 +/- 0.44 mumol/l in four healthy controls. The intestinal bacterial flora as well as microsomal enzymes of the liver may be involved in the epimerization of UDCA to isoUDCA as indicated by decreased serum levels of isoUDCA under antibiotic treatment with doxycycline (100 mg/day) in healthy subjects and a correlation (r = 0.873, p less than 0.001) between the hepatic microsomal function measured by the 14C-aminopyrine breath test and the fractional conversion of applied UDCA to isoUDCA (isoUDCA/UDCA + isoUDCA) in patients with PBC or PSC. Future studies of bile acid metabolism under UDCA treatment should include measurement of isoUDCA to further elucidate its biological role.     

Benign recurrent intrahepatic cholestasis: studies of bilirubin kinetics, bile acids, and cholangiography.

Three patients with benign recurrent intrahepatic cholestasis are described. They had had between five and 16 attacks of cholestasis. Between attacks the liver function tests, including serum bile acids, were normal. Serial serum bilirubin and bile acid estimations during the cholestasis in one patient revealed a consistent discrepancy between the serum bilirubin and bile acid concentrations during three consecutive attacks. In the other two patients the serum concentrations of bile acids and bilirubin varied in parallel. Analysis of the individual serum bile acids did not reveal high concentrations of any 'toxic' bile acid. In one patient, plasma bromsulphthalein (BSP) curves were obtained during both remission and cholestatic periods. The 45 minute retention was slightly increased (10.8%) during remission. During the cholestasis, the 45 minute retention (25%) and the fractional extraction coefficient (Ke=0.069 min-1) were markedly abnormal. The hepatic clearance of unconjugated radiobilirubin was normal at all times in this patient, although during cholestasis, conjugated bilirubin reflexed from the liver to the plasma and was then cleared slowly with a half life of approximately 12 hours. Treatment with corticosteroids, cholestyramine, and phenobarbitone was unsatisfactory.     

Urinary excretion of bile acid glucosides and glucuronides in extrahepatic cholestasis

Recently the formation of bile acid glucosides has been described as a novel conjugation mechanism in vitro and in vivo. In 10 patients with extrahepatic cholestasis caused by carcinoma of the head of the pancreas we investigated excretion rates and profiles of urinary bile acid glucosides. Urinary bile acid glucosides and, for comparison, bile acid glucuronides were extracted and characterized according to established methods. In controls total urinary bile acid glucoside excretion was 0.22 +/- 0.03 mumol/24 hr (mean +/- S.E.M.)-in the range of bile acid glucuronide excretion (0.41 +/- 0.06 mumol/24 hr; mean +/- S.E.M.). A gas chromatography-mass spectrometry-characterized trihydroxy bile acid glucoside of still-unknown hydroxyl positions accounted for 65% of total urinary bile acid glucosides. In extrahepatic cholestasis total urinary bile acid glucoside excretion was 0.52 +/- 0.13 mumol/24 hr (mean +/- SEM), yet significantly lower than bile acid glucuronide excretion (1.53 +/- 0.13 mumol/24 hr; mean +/- SEM; p less than 0.001). In cholestasis the primary bile acid derivatives cholic and chenodeoxycholic acid glucosides amounted to 90%, whereas the trihydroxy bile acid glucoside had decreased to 5% of total bile acid glucoside excretion, indicating its alteration during enterohepatic circulation. The data establish the composition and quantity of urinary bile acid glucosides in healthy controls and cholestasis and constitute a quantitative comparison with another glycosidic conjugation reaction, bile acid glucuronidation.     

The influence of prolonged physical stress on gastric juice components in healthy man

Eight healthy men were exposed to 5 days of continuous heavy exercise combined with caloric deficiency and sleep deprivation. Immediately after the stress period the fasting and postprandial intragastric bile acid concentration, pepsin concentration, and gastric juice acidity were measured. Compared with a control experiment performed 8 weeks later, the results from the stress period showed a sevenfold increase in the fasting concentration of intragastic bile acids (from 35 mumol/l to 256 mumol/l; p less than 0.02), there was a tendency towards an increase in the fasting intragastric pepsin concentration, and there was an increase (p less than 0.05) in the intragastric pH level throughout the 3rd postprandial hour. It appears that physical stress induces changes in the intragastric milieu that might dispose for mucosal lesions.     

Intestinal involvement in progressive systemic sclerosis detected by increased unconjugated serum bile acids.

In patients with progressive systemic sclerosis, impaired motor function of the small intestine may lead to bacterial overgrowth causing diarrhoea, steatorrhoea and malabsorption. As unconjugated serum bile acids have been proposed as markers for small bowel bacterial overgrowth, we studied individual unconjugated serum bile acids in 36 patients with progressive systemic sclerosis. These patients had significantly higher serum concentrations of unconjugated cholic acid (median 0.18; range 0.05-30.75 v 0.09; 0.01-0.19 mumol/l, p less than 0.001) and chenodeoxycholic acid (0.10; 0.01-6.83 v 0.04; 0.01-0.39 mumol/l, p less than 0.025) than healthy controls (n = 16). This difference was mainly due to patients with diarrhoea (n = 10), who had significantly higher concentrations of unconjugated serum bile acids than patients with normal bowel habit (cholic acid median 0.55 v 0.16 mumol/l, p less than 0.001; chenodeoxycholic acid 0.75 v 0.07 mumol/l; p less than 0.005). All patients with raised unconjugated serum bile acids had oesophageal motility disorders. These results confirm a relationship between motility disorders and bacterial overgrowth in patients with progressive systemic sclerosis.     

Sulphated and unsulphated bile acids in serum, bile, and urine of patients with cholestasis.

Samples of serum, bile, and urine were collected simultaneously from patients with cholestasis of varying aetiology and from patients with cirrhosis; their bile acid composition was determined by gas/liquid chromatography and mass spectrometry. In cholestasis, the patterns in all three body fluids differed consistently and strikingly. In serum, cholic acid was the major bile acid and most bile acids (greater than 93%) were unsulphated, whereas, in urine, chenodeoxycholic was the major bile acid, and the majority of bile acids (greater than 60%) were sulphated. Secondary bile acids were virtually absent in bile, serum, and urine. The total amount of bile acids excreted for 24 hours correlated highly with the concentration of serum bile acids; in patients with complete obstruction, urinary excretion averaged 71-6 mg/24 h. In cirrhotic patients, serum bile acids were less raised, and chenodeoxycholic acid was the predominant acid. In healthy controls, serum bile acids were consistently richer in chenodeoxycholic acid than biliary bile acids, and no bile acids were present in urine. No unusual monohydroxy bile acids were present in patients with primary biliary cirrhosis, but, in several patients, there was a considerable amount of hyocholic acid present in the urinary bile acids. The analyses of individual bile acids in serum and urine did not appear to provide helpful information in the differential diagnosis of cholestasis. Thus, in cholestasis, conjugation of chenodeoxycholic acid with sulphate becomes a major biochemical pathway, urine becomes a major route of bile acid excretion, and abnormal bile acids are formed.     

Serum bile acids in the diagnosis of hepatobiliary disease.

The value of serum bile acids (SBA) in the diagnosis of hepatobiliary disease has been investigated. A modified GLC method was used, with an overall coefficient of variation of +/- 11% in the control range. Serum was obtained after a 12 hour fast, and two hours after a fatty meal from 73 patients and 14 control subjects. In controls the total fasting SBA of 2.17 +/- 0.86 mumol/l increased significantly (p less than 0.001) to 3.81 +/- 1.14 mumol/l after a meal. All icteric patients had raised SBA, but in 23 anicteric patients there was no significant difference in the detection of chronic liver disease by fasting SBA, postprandial SBA, AST, or gamma GTP. Compared with controls, serum in patients contained proportionately less deoxycholic acid (p less than 0.001), there was proportionately more cholic acid in extrahepatic obstruction (p less than 0.001), and proportionately more chenodeoxycholic acid in patients with cirrhosis, viral hepatitis, and neoplasia (p less than 0.001). In control subjects, the fasting cholic:chenodeoxycholic acid ratio ranged from 0.5-1.0, and differed significantly (p less than 0.001) from patients with extrahepatic obstruction 0.96-3.6, and cirrhosis 0.1-0.5. It is concluded that serum bile acids measured by sensitive methods can provide useful diagnostic information.     

Concentrations of glycine- and taurine-conjugated bile acids in portal and systemic venous serum in man

Concentrations of glycine and taurine conjugates of cholic, chenodeoxycholic, and deoxycholic acid in portal and systemic venous serum and in bile were measured in eight subjects undergoing elective cholecystectomy. Mean concentrations in systemic serum ranged from 0.07 to 0.17 mumol/l, in portal serum from 0.49 to 2.09 mumol/l, and in bile from 2.72 to 17.2 mmol/l. The percentage content of trihydroxy-bile acid conjugates in bile (49%) and in portal serum (51%) was higher than in systemic serum (35%) (P less than 0.001). The estimated hepatic fractional uptake of glycocholic acid (mean, 83%) and of taurocholic acid (83%) was higher than the uptakes of the dihydroxy-bile acid conjugates (60-68%). The percentage contents of glycine-conjugated bile acids in systemic serum (mean, 66%), portal serum (62%), and bile (65%) were not significantly different.     

Increased intercellular adhesion molecule-1 serum concentration in cholestasis

Background/Aims: Increase of serum levels of the soluble intercellular adhesion molecules in patients with the cholestatic liver diseases primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are known and have been thought to indicate activation of the immune system and the grade of the inflammatory process. In hepatitis and cholestatic diseases, expression of adhesion molecules was found on the surface of bile duct epithelia and hepatocytes.Materials and Methods: Serum levels of sICAM-1 in patients with intrahepatic cholestasis in PBC (n=42) and extrahepatic cholestasis (n=18) due to choledocholithiasis were investigated. sICAM-1 levels and “classical” cholestasis parameters as alkaline phosphatase (ALP), γ-glutamyl-transpeptidase (γ-GTP) and bilirubin levels were compared. Furthermore, sICAM-1 concentrations and “classical” cholestasis parameters were analysed before and after therapy with ursodeoxycholic acid (UDCA). In addition, sICAM-1 was detected in serum and bile fluid of four patients with cholestasis due to choledocholithiasis. Soluble ICAM-1 levels in sera and, if accessible, in bile fluids were determined using a commercially available ELISA system. Statistics were done by Wilcoxon's signed rank exact test and Spearman's rank correlation test. Sensitivity and specificity of cholestasis parameters and sICAM-1 concentrations was analysed by receiver operating characteristic (ROC) curves.Results: Increased sICAM-1 serum concentrations in a similar range were found in patients with PBC (range 251–2620 μg/l; median 966 μg/l) as well as in patients with extrahepatic cholestasis (257–2961 μg/l; median 760 μg/l) compared to healthy controls (n=12; 220–500 gmg/l; median 318 μg/l). sICAM-1 levels correlated significantly to histological stage I to IV (p<0.001), ALP (range 107–1877 U/l; median 545 U/l; r=0.496, p=0.0008), bilirubin (range 0.3–26 mg/dl; median 0.8 mg/dl; r=0.52; p<0.0004) and γ-GTP levels (range 43–705 U/l; median 221 U/l; r=0.36; p=0.02) in PBC patients. In PBC patients a histological stage III or IV (n=21) could be predicted with high sensitivity (95%) and specificity (85%) if sICAM-1 levels were above 840 μg/l. After treatment of PBC patients with UDCA, sICAM-1 levels decreased significantly with decline of other “classical” cholestasis parameters. Increased sICAM-1 levels (range 257–2961, median 745 μg/l) in extrahepatic cholestasis correlated also significantly with serum concentrations of bilirubin (r=0.8; p<0.01; range 0.3–19.7, median 1.6 mg/dl), γ-GTP (r=0.55; p=0.03; range 33–1401, median 179 U/l) and ALP (r=0.61; p=0.1; range 110–1378, median 562 U/l). sICAM-1 2as detectable in bile fluid (264–919 μg/l) of four patients with extrahepatic cholestasis and nose-biliary catheterisation.Conclusions: sICAM-1 concentrations were found to discriminate between histological stage I/II and stage III/IV of PBC with higher sensitivity and specificity than “classical” cholestasis parameters. Increased serum concentrations for sICAM-1 in intra- and in extrahepatic cholestasis and detection of sICAM-1 in the bile may indicate that sICAM-1 is eliminated through the bile. In other words, not only increased synthesis but also decreased elimination may be responsible for increased sICAM-1 serum levels in patients with cholestatic liver diseases.     

Failure of ursodeoxycholic acid to prevent a cholestatic episode in a patient with benign recurrent intrahepatic cholestasis: a study of bile acid metabolism

Ursodeoxycholic acid was administered to a patient with benign recurrent intrahepatic cholestasis to prevent cholestatic episodes. A detailed study of bile acid metabolism in this patient was carried out in the anicteric and icteric phases before and after ursodeoxycholic acid (750 mg/day) administration. Urinary, biliary and serum bile acids were measured by gas chromatography-mass spectrometry and by high-performance liquid chromatography techniques. During the anicteric phase the daily urinary excretion and serum concentrations of bile acids were within normal ranges, indicating normal hepatic uptake and secretion of bile acids during the cholestasis-free period. Only slight qualitative differences from normal individuals were observed; the relative proportions of deoxycholic acid in the bile and serum were higher, and 12-oxo-lithocholic acid was the predominant urinary bile acid. During the icteric phase a marked increase in the urinary excretion of primary bile acids and C-1, C-2, C-4 and C-6 hydroxylated metabolites was found. Serum bile acid concentrations increased before the rise in bilirubin, suggesting an acute disturbance in bile acid transport at the onset of the cholestatic attack. After ursodeoxycholic acid administration in the anicteric phase, bile became enriched with the exogenous bile acid, but little qualitative change was found in the other metabolites present in the urine, serum or bile during the anicteric or icteric phases. Prolonged administration of ursodeoxycholic acid failed to prevent recurrence of a cholestatic episode, suggesting that in benign recurrent intrahepatic cholestasis, oral ursodeoxycholic acid may be of little benefit in the treatment or prevention of cholestasis despite marked enrichment of the bile acid pool with this hydrophilic bile acid.     

Tauroursodeoxycholate prevents taurolithocholate-induced cholestasis and toxicity in rat liver

Ursodeoxycholate has been advocated for the treatment of cholestatic liver diseases. The coinfusion of tauroursodeoxycholate with taurolithocholate in the perfused rat liver completely prevented the decrease of bile flow and the increase of oxygen uptake found with taurolithocholate only. Bile flow and bile salt secretion were increased with the coinfusion of both bile acids as compared with the infusion of tauroursodeoxycholate only (+4.30 microliters/g liver per 30 min) with 16 and 32 mumol/l tauroursodeoxycholate (+1.55 microliters/g liver per 30 min with 80 and 160 mumol/l). Morphological examination revealed a 50% decrease of the number of necrotic cells in the periportal area. Tauroursodeoxycholate did not inhibit the uptake of taurolithocholate, but increased its transcellular passage and biotransformation. Thus, tauroursodeoxycholate prevents taurolithocholate-induced cholestasis and liver cell toxicity probably by an intracellular mechanism.