Effects of ursodeoxycholic acid on conjugated bile acids and progesterone metabolites in serum and urine of patients with intrahepatic cholestasis of pregnancy

This study examined the effect of ambient temperature and feeding on brown adipose tissue (BAT) function and thermoregulation in lambs born either vaginally at term or by Caesarean section close to term. Immediately after birth lambs were placed in a warm (30 degrees C) or cool (15 degrees C) ambient temperature and measurements of colonic temperature and heat production recorded for 6 h. Lambs were fed 50 ml of colostrum when 5 h old. The amount of uncoupling protein and level of guanosine 5'diphosphate (GDP) binding in BAT was higher in vaginally delivered lambs than in lambs delivered by Caesarean section. For each delivery group, GDP binding was greater in lambs maintained at 30 degrees C than in lambs maintained at 15 degrees C. O2 consumption, CO2 production and colonic temperature only increased after feeding in lambs born by Caesarean section and maintained at 30 degrees C, a response that was accompanied by a decreased incidence of shivering. Irrespective of delivery temperature, plasma thyroid hormone concentrations and noradrenaline content of BAT were lower in lambs born by Caesarean section than in those born vaginally. Plasma cortisol concentrations were higher in lambs delivered by Caesarean section, as was adrenaline content of BAT in these lambs maintained at 30 degrees C. It is concluded that the thermoregulatory response to feeding in terms of changes in both recruitment of shivering and colonic temperature were observed only in lambs delivered by Caesarean section.     

Elevated levels of bile acids in colostrum of patients with cholestasis of pregnancy are decreased following ursodeoxycholic acid therapy [see comemnts

BACKGROUND/AIMS: Intrahepatic cholestasis of pregnancy is characterised by increased levels of serum bile acids. Ursodeoxycholic acid therapy corrects the serum bile acid profile. The aims of this study were: (i) to investigate bile acid excretion into colostrum of women with intrahepatic cholestasis of pregnancy; (ii) to compare concentrations of bile acids in serum and colostrum of non-treated and ursodeoxycholic acid-treated patients; and (iii) to clarify whether ursodeoxycholic acid is eliminated into colostrum following treatment. METHODS: Bile acids were assessed by gas chromatography and high-performance liquid chromatography in serum collected at delivery, and in colostrum obtained at 2+/-1 days after labour, from patients with intrahepatic cholestasis of pregnancy, non-treated (n=9) and treated (n=7) with ursodeoxycholic acid (14 mg/kg bw per day, for 14+/-7 days) until parturition. RESULTS: The concentration of total bile acids in colostrum from patients with intrahepatic cholestasis of pregnancy was higher than in normals (23.3+/-14.8 micromol/l vs. 0.7+/-0.2 micromol/l, p<0.01) and cholic acid was a major species (19.0+/-13.1 micromol/l), reflecting the elevated concentrations in maternal serum (48.9+/-21.0 micromol/l, total bile acids; 33.9+/-16.7 micromol/l, cholic acid. Following ursodeoxycholic acid administration, total bile acids and cholic acid levels in colostrum diminished to 5.7+/-2.5 micromol/l and 3.6+/-1.5 micromol/l, respectively; the proportion of cholic acid decreased (60.6+/-8.0% vs. 76.8+/-5.0%, p<0.05). The ursodeoxycholic acid concentration in colostrum was maintained following treatment; its increased percentage (9.4+/-3.2% vs. 1.0+/-0.2%, p<0.01) was still lower than in maternal serum (20.8+/-3.6%, p<0.05). Only a small proportion (<1%) of lithocholic acid was found in colostrum following therapy. CONCLUSIONS: Bile acid concentrations are elevated and cholic acid is the major species accumulating in colostrum, reflecting serum bile acid profiles in intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid therapy decreases endogenous bile acid levels in colostrum.     

Serum bile acids in cholestasis of pregnancy

Using routine liver function tests, cholestasis of pregnancy was diagnosed in 86 pregnant women with pruritus. Serum aminotransferase levels were elevated in all cases, ASAT in 99%, and ALAT in 100%. In these patients serum concentrations of cholic, chenodeoxycholic, and deoxycholic acid were determined using a gas chromatographic method and were compared with those in a group of 40 uncomplicated pregnancies. Of these bile acids, cholic acid levels were most frequently elevated, ie, in 92% of the patients. The frequency of elevation of serum levels of alkaline phosphatase, and total and conjugated bilirubin was lower. Thus, it appears that in addition to serum aminotransferase levels the serum cholic acid concentration is a sensitive indicator of cholestasis of pregnancy. The cholestasis series was divided into 3 subgroups of increasing severity of cholestasis as assessed by maternal serum cholic acid levels, and the occurrence of signs of fetal distress was compared between these subgroups. The only intrauterine fetal loss in the series belonged to the severe cholestasis group. The incidence of meconium-stained amniotic fluid also increased significantly in this group, and 21 of the 24 cases with other signs of fetal distress were in the groups of moderate and severe cholestasis.     

Relationship between biliary and serum bile acids and response to ursodeoxycholic acid in patients with primary biliary cirrhosis

OBJECTIVE: Ursodeoxycholic acid (UDCA) improves liver biochemistries and enriches the bile with UDCA in patients with primary biliary cirrhosis. The aim of this study was to determine whether the degree of enrichment of bile correlated with that of serum and whether either of these measures correlated with improvement in measures of liver disease. METHODS: In a randomized study, biliary and serum bile acid analyses were performed at entry and after 2 yr of UDCA or placebo. RESULTS: The percentage of ursodeoxycholic acid in bile increased by 42% in the UDCA group (n = 61) compared with 8% in the placebo group (n = 57) (p < 0.0001). Measurement of serum bile acids in 32 patients (18 ursodeoxycholic acid, 14 placebo) indicated that at 2 yr, ursodeoxycholic acid comprised 65% of serum bile acids in the treated group and 7% in the placebo group. Agreement between bile and serum was fair (r = 0.75, p < or = 0.00002) because in some patients, plasma but not biliary bile acids were enriched with UDCA. Changes in biliary ursodeoxycholic acid correlated significantly but weakly with the changes in serum alkaline phosphatase, AST, bilirubin, and in Mayo risk score. Correlations between changes in serum bile acid composition and biochemical measures of disease activity were even weaker. CONCLUSION: The measurement of biliary bile acids is superior to that of serum bile acids for assessing the compliance and changes in the circulating bile acids in patients receiving ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Furthermore, measures to further increase the proportion of ursodeoxycholic acid in circulating bile acids should be explored.     

Evaluation of total serum bile acids concentration and bile acid profiles in healthy cats after oral administration of ursodeoxycholic acid

Ursodeoxycholic acid (UDCA; 10 mg/kg of body weight) was administered orally to 5 healthy cats for 3 months. Signs of illness were not apparent in any cat during treatment with UDCA. Results of monthly CBC, serum biochemical analysis, and urinalysis were unchanged during drug administration. There was a decrease in serum cholesterol concentration in 4 cats. Total postprandial serum bile acids (PPSBA) concentration was significantly (P = 0.0003) increased over total preprandial serum bile acids (PRSBA) concentration at all sample collection periods. The PRSBA and PPSBA concentrations were significantly (P < 0.05) increased at all sample collection periods after administration of UDCA, compared with baseline values. Ursodeoxycholic and tauroursodeoxycholic acids were not detected in serum prior to initiating administration of UDCA. Both bile acids were detected in the serum of all cats 1 and 2 months after UDCA administration and were detected in the serum of 2 cats 3 months after initiating UCDA administration. Hepatic ultrasonographic findings were normal before and after completion of UDCA administration. A mild, focal lymphocytic infiltrate was observed in 3 cats 3 months after initiating UDCA administration. Results of the study indicate that UDCA is absorbed into the systemic circulation of cats after oral administration, undergoes hepatic conjugation, and appears to be safe.     

Serum bile acids and ursodeoxycholic acid treatment in cystic fibrosis-related liver disease

Increased circulating levels of hepatotoxic bile acids may contribute to the cholestasis characteristic of cystic fibrosis-related liver disease. The aims of this study were to compare serum bile acid profiles in patients with cystic fibrosis with and without liver disease, and to evaluate the effect of treatment with ursodeoxycholic acid, a non-hepatotoxic bile acid, on liver biochemistry and serum bile acids in patients with cystic fibrosis-related liver disease. Fasting and postprandial serum bile acid levels were analysed in 15 patients (nine males; median age 18 years) with cystic fibrosis-related liver disease and compared with serum bile acid levels in 18 cystic fibrosis patients (12 males; median age 22 years) without liver disease and 10 control subjects. Fasting and postprandial serum levels of primary and secondary serum bile acids were analysed using high-performance liquid chromatography. Liver biochemistry and serum bile acids were measured in six cystic fibrosis patients with liver disease before and 6 months after treatment with ursodeoxycholic acid 20 mg/kg/day and compared with six control patients with cystic fibrosis-related liver disease. Total fasting and postprandial serum bile acid levels were significantly (P < 0.01) elevated in patients with liver disease compared to those without liver disease and controls. The fasting glycine conjugates of cholic acid, chenodeoxycholic acid and deoxycholic acid, and the fasting and postprandial taurine conjugates of cholic acid and chenodeoxycholic acid were significantly (P < 0.05) elevated in liver disease patients compared to patients without liver disease and controls. After 6 months' treatment with ursodeoxycholic acid, although the serum was significantly saturated with ursodeoxycholic acid and significant improvements in liver biochemistry were observed in the treatment group, there was no significant reduction in the levels of individual serum bile acids. Although circulating levels of potentially hepatotoxic serum bile acids are elevated in patients with cystic fibrosis-related liver disease, improvements in liver biochemistry associated with ursodeoxycholic acid treatment cannot be attributed solely to alterations in levels of endogenous bile acids.     

Inheritance of intrahepatic cholestasis of pregnancy in one kindred

We report three sisters with intrahepatic cholestasis of pregnancy (ICP) and the pedigree of the family, including six generations. ICP was observed in five successive generations; most of the patients also had cholelithiasis. The uniform expression, the complete penetrance of the trait and the direct parent-to-child transmission support the Mendelian dominant mode of inheritance. Determination of HLA A, B and C haplotype was made in five ICP patients, without any findings of HLA type common to everyone. X-linked inheritance cannot be excluded in this study.     

Diagnosis and therapy of blood coagulation disorders in intrahepatic cholestasis

The reduction of prothrombin level below 5% in a patient with intrahepatic cholestasis of pregnancy is reported. The necessity of controlling the Quick level or better factors II, VII, IX and X is discussed. A well-timed Vitamin K therapy in all cases with impaired secretion of bile during pregnancy is recommended.     

Increased urinary excretion of 3-oxo-delta4 bile acids in Japanese patients with idiopathic neonatal cholestasis

This report examines the reliability of nighttime blood pressure dipping. Twenty-one individuals were studied twice with ambulatory blood pressure monitoring. On one occasion they were studied as outpatients, and on the other as inpatients on a clinical research ward. Blood pressure monitoring revealed the expected dip in blood pressure at nighttime. However, there was little test-retest reliability across the two settings. The test-retest correlations for the dip in blood pressure across the two settings were nonsignificant for systolic, diastolic, and mean arterial blood pressure. Caution is advised before diagnosing dipping or nondipping on the basis of one 24-h ambulatory blood pressure recording.     

The changes of lipid metabolism and hemorrheology in intrahepatic cholestasis during pregnancy

OBJECTIVE: To identify the influence of the increased level of serum cholyglycine (CG) on lipid metabolism and hemorrheology in patients with intrahepatic cholestasis during pregnancy (ICP). METHODS: The concentrations of serum CG, total cholesterol (CH), triglycerides (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), high shear and low shear of blood specific viscosity (HS and LS), plasma specific viscosity (PV) and hematocrit (HCT) were measured in 68 cases of primiparas with single pregnancy and 30 healthy nonpregnant women respectively. The group of ICP was composed of 35 cases with CG > 6 mumol/L, the group of normal pregnancy, 33 cases with CG < 6 mumol/L. RESULTS: The means of CG and the lipidic parameters in the two pregnant groups were significantly higher than those in the non-pregnancy group (P < 0.02-0.001) except the means of HDL-C between the groups of ICP and non-pregnancy. The levels of LDL-C, LDL-C/HDL-C, LS, PV and HCT in the ICP were significantly higher than those in the normal pregnancy group (P < 0.02-0.001). CONCLUSIONS: There are significant changes of lipid metabolism and hemorrheology in patients with ICP. However, these changes could be corrected after pregnancy termination, when the level of serum CG returned to normal. The results suggest that the pathophysiologic changes of ICP are associated with increased level of serum CG.     

Small bile duct abnormalities and chronic intrahepatic cholestasis in Beh?et's syndrome

A 42-year-old man with Beh?et's disease of the intestinal type and a chronic cholestatic profile is presented. He had oral aphthea, genital ulcer, erythema nodosum, thrombophlebitis and central retinitis during the clinical course. Deep ileal ulcers recurred with massive bleeding and perforation. Cholestatic laboratory findings were also noted in the clinical course. A biopsied liver specimen, taken at the second operation for the ileal ulcer, showed chronic portal inflammation associated with ductopenia and epithelial degeneration of the small interlobular bile ducts, but periductal concentric fibrosis was not found. The patient died of sepsis 7 months after the last laparotomy. Although there was no significant abnormality in the large biliary tract at autopsy, pericholangitis in the small portal tracts and cholestasis were pronounced. Sclerosing cholangitis is one of well-known complications of ulcerative colitis or Crohn's disease. We report herein another rare association of small bile duct damage resembling sclerosing cholangitis with enteritis in Beh?et's disease.     

Effects of ursodeoxycholic acid therapy on in vitro gallbladder contractility in patients with cholesterol gallstones

PURPOSE: Ethambutol is an essential medication in the management of tuberculosis. However, it can cause an optic neuropathy of uncertain etiology. Ethambutol toxicity was therefore studied in rodent retinal cells, and agents that might block its toxicity were considered. METHODS: The toxicity of ethambutol and related agents was evaluated in rodent retinal dissociated cell preparations and whole eyes. Calcium fluxes and mitochondrial function were evaluated by fluorescent and staining techniques. For in vivo assays, adult rats were administered oral ethambutol over a 3-month period. Cell survival was assessed by stereology. RESULTS: Ethambutol is specifically toxic to retinal ganglion cells in vitro and in vivo. Endogenous glutamate is necessary for the full expression of ethambutol toxicity, and glutamate antagonists prevent ethambutol-mediated cell loss. Ethambutol causes a decrease in cytosolic calcium, an increase in mitochondrial calcium, and an increase in the mitochondrial membrane potential. CONCLUSIONS: The visual loss associated with ethambutol may be mediated through an excitotoxic pathway, inasmuch as ganglion cells are rendered sensitive to normally tolerated levels of extracellular glutamate. Ethambutol perturbs mitochondrial function. Its toxicity may depend on decreased ATPase activity and mitochondrial energy homeostasis. Glutamate antagonists may be useful in limiting the side effects seen with ethambutol.     

Effect of administration of ursodeoxycholic acid at bedtime on cholesterol saturation of hepatic bile in Japanese patients with gallstone

The administration of a single, daily 600 mg dose of ursodeoxycholic acid (UDCA) at bedtime and 3-200 mg doses per day at mealtime was conducted for 6 patients with gallstone and choledocholithiasis who were undergoing biliary drainage for the purpose of improving jaundice. Hepatic bile was collected from a drainage tube after a lapse of time in order to compare the bile acid compositions and cholesterol saturation index (SI) in bile for the 2 protocols. A significant increase in UDCA levels in hepatic bile was observed after both UDCA administration at bedtime and mealtime, but the effect of bedtime administration was significantly greater than that of mealtime administration. Whereas levels of cholic acid and chenodeoxycholic acid (CDCA) decreased for the case of bedtime administration, this was not detected for mealtime administration, although no significant differences among the mean interval values were observed. A significant in difference decreased SI was observed during UDCA bedtime administration, but not during mealtime administration, compared to the SI before administration. This suggests a decreased cholesterol excretion into the bile. Based on these findings and from the point of view of compliance, bedtime administration of UDCA appears to be an effective method.     

Treatment of non-extractable common bile duct stones with combination ursodeoxycholic acid plus endoprostheses

To assess the effect of timing of human chorionic gonadotrophin (HCG) administration in ovarian stimulation cycles, the serum oestradiol concentration and follicle profile were compared with the clinical pregnancy rate in 582 ovarian stimulation-intra-uterine insemination (OS-IUI) cycles and 3917 in-vitro fertilization-embryo transfer (IVF-ET) cycles. The pregnancy rates increased exponentially with increasing oestradiol in both OS-IUI and IVF-ET cycles (R2 = 0.720, P < 0.001) but then decreased in OS-IUI cycles when the oestradiol concentration exceeded 5000 pmol/l (R2 = 0.936, P < 0.004) at HCG administration. In OS-IUI cycles the percentages of cycles with three or more mature follicles (> or = 18 mm diameter) increased up to an oestradiol concentration of 5000 pmol/l then declined, mirroring the pregnancy rate (R2 = 0.900, P = 0.01). The exponential increase in pregnancy rate with increasing oestradiol concentration in IVF-ET cycles suggests that high oestradiol concentration does not have a deleterious effect on endometrial receptivity. The decrease in pregnancy rate in OS-IUI cycles when oestradiol concentration exceeded 5000 pmol/l reflected fewer mature follicles, resulting from premature administration of HCG to avoid severe ovarian hyperstimulation syndrome (OHSS). We recommend that HCG administration be delayed until multiple follicles have reached maturity, and reducing the risk of severe OHSS by converting high risk OS-IUI cycles to IVF-ET, or if funds or facilities are unavailable, transvaginally draining all but four or five mature follicles.     

Effect of ursodeoxycholic acid on hypertransaminasaemia and bile acid composition in patients undergoing bone marrow transplantation--a double-blind randomized control study

A dimensionless number, the reduced mobility, mu i, of separand, i, defined by mu i = ueff,i/(Ueff,i + Ueo) (with the specific effective mobility, Ueff,i, and the unspecific electroosmotic mobility, Ueo), permits expressing the effect of the electroosmotic flow (EOF) in capillary zone electrophoresis (CZE) on all relevant separation parameters, such as selectivity, efficiency, and resolution. A detailed discussion is given for the extent of the effect of the EOF on both cations and anions. The gain and loss of separation performance by application of an EOF is described quantitatively by expressions consisting solely of the reduced mobility.     

Methylprednisolone-hemisuccinate and its metabolites in serum, urine and bile from two patients with acute graft rejection

A cross-sectional assessment of differences in social class and other sociodemographic variables at hospital admission for patients with psychotic disorders was carried out through a systematic survey of psychotic patients admitted to greater Baltimore psychiatric facilities between 1983 and 1989. Female patients, first-admission patients, and patients with bipolar disorder or other, nonschizophrenic psychosis were more likely to have been admitted to community, university, and private hospitals than to state hospitals. Patients in medium and higher social class categories were 1.29 to 2.57 times more likely to be admitted to community, university, and private hospitals than to state hospitals.     

Hepatic cholesterol and bile acid metabolism in subjects with gallstones: comparative effects of short erm feeding of chenodeoxycholic and ursodeoxycholic acid

The activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and 7alpha-hydroxylase, the enzymes controlling the rate of hepatic synthesis, respectively, of cholesterol and bile acids, and the microsomal cholesterol content were evaluated in 25 patients with cholesterol gallstones and 17 subjects without gallstones. The same quantities were estimated in 16 additional patients with gallstones given chenodeoxycholic (CDCA) or ursodeoxycholic acid (UDCA) at a dose of 15 mg/kg per day in order to investigate the comparative effect of a short term (7 days) administration of the two bile acids on the hepatic sterol metabolism. As compared to the controls, subjects with gallstones exhibited a 36% decrease of 7alpha-hydroxylase (26.8 +/- 6.2 versus 41.7 +/- 4.2 pmol/min per mg protein) and a 24% increase of the microsomal cholesterol (78.7 +/- 15.3 versus 63.1 +/- 18.1 nmol/mg protein). Although higher in the gallstone patients, the activity of HMG-CoA reductase did not differ significantly in the two groups of subjects. Administration of CDCA and UDCA changed the bile acid pool composition so that the fed bile acid predominated in the bile (mean CDCA 73% and mean UDCA 54%). Bile lipid composition did not appreciably change. In the eight subjects treated with CDCA the activity of HMG-CoA reductase was reduced to 45% of the value of untreated subjects (27.9 +/- 14.5 versus 63.5 +/- 25.3 pmol/min per mg protein) whereas in the eight subjects treated with UDCA the same enzyme showed a twofold increase (123.5 +/- 20.9). In the treated groups 7alpha-hydroxylase activity was somewhat decreased but the values did not differ significantly from those of the untreated subjects. Microsomal cholesterol content decreased with CDCA (64.8 +/- 11.6 nmol/mg protein) as well as with UDCA (59.1 +/- 10.1) treatment; however in the latter the difference attained statistical significance (P < 0.05). Altogether the results would suggest that in the liver of patients with gallstones the conversion of cholesterol to bile acids is somewhat reduced, and that changing the bile acid pool composition, by exogenous bile acid feeding, has disparate effects on hepatic cholesterol synthesis. The findings could represent the acute changes produced by bile acid feeding, however they could imply that the effects of two bile acids in dissolving cholesterol gallstones might not be related only to the changes in hepatic sterol metabolism.-Carulli, N., M. Ponz De Leon, F. Zironi, A. Pinetti, A. Smerieri, R. Iori, and P. Loria. Hepatic cholesterol and bile acid metabolism in subjects with gallstones: comparative effects of short term feeding of chenodeoxycholic and ursodeoxycholic acid.     

Direct spectrophotometry of total bile acids in serum

In this simple and direct method for determining total bile acids in serum, the serum was mixed with sodium pyruvate, a lactate dehydrogenase blocker, and bile acids were then measured spectrophotometrically after the following enzyme reaction. Bile acids are converted to 3-oxo bile acids with 3 alpha-hydroxysteroid dehydrogenase (EC 1.1.1.50) with concomitant reduction of NAD+ to NADH. The hydrogen in the NADH generated is transferred by diaphorase (EC 1.6.4.3) to nitrotetrazolium blue to yield diformazan 540 nm). Analytical recovery of the various bile acids in serum averaged 96.2%. The CV for the day-to-day variation was 4.3%. Normal values are less than 7 mumol/L. Total serum bile acids were estimated by this method in 118 fasting patients with various liver diseases. This determination is clearly shown to be useful as a liver-function test.     

Increased serum IgM class anti-lipid A antibody and therapeutic effect of ursodeoxycholic acid in primary biliary cirrhosis

BACKGROUND/AIMS: There is as yet no explanation for the increased serum IgM level observed in patients with primary biliary cirrhosis. METHODOLOGY: The serum IgM class anti-lipid A antibody was determined in patients with primary biliary cirrhosis using Elisa and Western blot techniques. RESULTS: Using enzyme-linked immunosorbent assay, we found the concentration of serum IgM class anti-lipid A antibody was the highest in 21 patients with PBC as compared to 29 patients with other liver diseases and 19 controls. Using western blotting, IgM class anti-lipid A antibody was detected as a clear band in patients with primary biliary cirrhosis. The level of this antibody correlated significantly (p < 0.005) with that of total IgM. Treatment with ursodeoxycholic acid improved not only the routine biochemical profile but also the level of IgM class anti-lipid A antibody (p < 0.005). CONCLUSIONS: Since the lipid A plays a primary role in the biological activities of lipopolysaccharide (a component of gram-negative bacteria), bacterial antigen may participate in the elevation of serum IgM levels in patients with primary biliary cirrhosis. Ursodeoxycholic acid treatment may improve the cholestasis, and this may have altered the response to stimulation by gut derived bacterial antigens.