Pregnancy course in patients with intrahepatic cholestasis of pregnancy treated with very low doses of ursodeoxycholic acid

Objective. Ursodeoxycholic acid (UDCA) has been proposed as the optimal pharmacological treatment for intrahepatic cholestasis of pregnancy (ICP). The lowest effective dosage of UDCA in women with ICP has not been established. The objective is to determine the risk of adverse pregnancy outcomes resulting from ICP and to measure changes in liver function parameters and pruritus severity in ICP patients treated with low doses of UDCA. Material and methods. ICP was diagnosed in 203 patients on the basis of pruritus and elevated liver biochemical parameters. Patients with total bile acids (TBA) ≥10 μmol/l (n = 157) received UDCA (300–450 mg/day; 4–6 mg/kg/day) until delivery. Maternal and fetal outcomes of women with ICP were compared with 100 patients without cholestasis. Patients with ICP were hospitalized for treatment and fetal surveillance. Results. There was no correlation between fetal and neonatal complication rates in ICP patients and biochemical markers of cholestasis. Significant declines in serum TBA (p = 0.003), bilirubin concentration (p = 0.026) and aminotransferase activity (p < 0.001) were observed during treatment with low doses of UDCA. Moreover, severity of pruritus was ameliorated during the 2 weeks of therapy (p = 0.037). A total of 17 patients (10.9%) did not respond to treatment. Conclusions. UDCA at low doses improved biochemical markers and clinical symptoms in almost 90% of ICP patients.     

Intrahepatic cholestasis of pregnancy: Amelioration of pruritus by UDCA is associated with decreased progesterone disulphates in urine

Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus, elevated bile acids, and, specifically, elevated disulphated progesterone metabolites. We aimed to study changes in these parameters during treatment with dexamethasone or ursodeoxycholic acid (UDCA) in 40 out of 130 women included in the Swedish ICP intervention trial (26 randomized to placebo or UDCA, 14 randomized to dexamethasone). Serum bile acid profiles and urinary steroid hormone metabolites were analyzed using isotope-dilution gas chromatography-mass spectrometry and electrospray-mass spectrometry. We found that all patients displayed ICP-typical serum bile acid profiles with >50% cholic acid at baseline but almost 80% UDCA upon treatment with this bile acid. In UDCA-treated patients, relative amounts of disulphated progesterone metabolites in urine decreased by 34%, 48% (P < 0.05), and 55% (P < 0.05) after 1, 2, and 3 weeks of treatment, respectively, which was significantly correlated to improvements of pruritus scores but not to serum bile acid levels. In contrast, in patients randomized to dexamethasone or placebo, no changes in steroid metabolites or pruritus scores were observed. Conclusion: UDCA treatment in ICP decreased urinary excretion of disulphated progesterone metabolites, suggesting that amelioration of pruritus is connected to stimulation of hepatobiliary excretion of progesterone disulphates.     

Effect of ursodeoxycholic acid administration on bile duct proliferation and cholestasis in bile duct ligated rat

The origin, mechanism, and significance of the bile duct proliferation (BDP) associated with cholestasis remain unexplained. This study examined the effect of oral administration of ursodeoxycholic acid (UDCA) on both BDP and cholestasis in the rat. After bile duct ligation, male Sprague-Dawley rats were treated for 30 days with either UDCA (5 mg/day) (group A) or saline solution (group B). Animals were sacrificed at day 30. The serum activity of aminotransferase (ALT, AST), alkaline phosphatase, and -glutamyltransferase (GGT) was significantly lower (P<0.01) in the UDCA-treated rats. Total serum bilirubin and total serum bile acids were lower (P<0.001) in group A. Moreover, the control of BA in bile was reduced also (P<0.02). Conversely, serum cholesterol levels were not different between the two groups. Histological examination showed that the number of ductular cells in the portal areas was significantly (P<0.001) reduced in UDCA-treated as compared to saline-treated rats. The replication activity, assessed as the number of bromodeoxyuridine-positive cells, was also significantly lower in treated animals (33±11 vs 64±22 per 1000 cells;P<0.001). Lobular bile ductules were three times larger in group B, and extrahepatic duct measurements confirmed this increase in size of the larger biliary ducts (P<0.001). These findings demonstrate that UDCA reduces BDP in response to BD ligation. Although the mechanism(s) of this effect is still hypothetical, UDCA may reduce the level of irritating bile salts such as chenodeoxycholic acid and lithocolate and increase periductular bile acid recirculation. These data support the beneficial effect of UDCA treatment in chronic cholestatic disease.     

Urinary bile acid sulfate levels in patients with primary biliary cirrhosis

Aim: Urinary bile acids are mainly conjugated with sulfuric acid. In a previous work, we demonstrated that the levels of urinary sulfated bile acids (USBA) and serum total bile acids (TBA) were correlated very well and also that USBA was considered to be a more useful indicator of hepatic fibrosis than TBA in patients with hepatitis C virus (HCV)‐related liver diseases. In the current study we aimed to confirm these finding in patients with primary biliary cirrhosis (PBC), a prototypic cholestatic liver disease. Methods: Urinary sulfated bile acids were measured using an automatic assay kit in 50 patients with PBC, of whom 11 were diagnosed as having cirrhosis. We obtained specimens before ursodeoxycholic acid (UDCA) administration in four patients, and during UDCA in 46 patients. The correlations between USBA and various laboratory tests were studied. Results: The median USBA level was 67.9 µmol/g creatinine in PBC; 27.7 without cirrhosis and 210.3 with cirrhosis (P = 0.001). The number of PBC patients with elevated USBA was significantly higher than those with elevated TBA (82% vs. 56%). This significance was remarkable especially in early stages, non‐cirrhotic patients (77% vs. 49%). USBA level was well correlated with TBA (r_s = 0.72), and negatively correlated with platelet (r_s = ?0.34) and albumin (r_s = ?0.31). Conclusion: Urinary sulfated bile acids and TBA are well correlated, and together with the findings that USBA is not affected by meals, USBA is considered to be more beneficial and convenient than TBA for earlier detection of fibrosis in PBC.     

Diagnosis and therapy of intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is characterized by the occurrence of pruritus mostly in the third trimenon. Diagnosis is based on the presence of pruritus and elevated levels of serum bile acids in the absence of pruritic skin diseases. There is strong evidence of a genetic predisposition for ICP. Numerous studies have investigated the association of known cholestasis genes such as ABCB4 (also designated MDR3), ABCB11 ( BSEP) and ATP8B1 ( FIC1) with ICP. The results of these studies implicate a heterogeneous etiology of this syndrome. ICP increases the risk of preterm delivery and fetal loss. Furthermore, intense pruritus may necessitate premature induction of labor with its known higher frequency of complications for mother and child. Therefore, ICP pregnancies should be managed as high-risk pregnancies. Pharmaceuticals to alleviate pruritus or improve cholestasis like antihistamines, phenobarbital, anion exchange resins, dexamethasone or S-adenosylmethionine are not widely accepted because of questionable efficacy or side effects. Recent randomized studies have shown beneficial effects of ursodeoxycholic acid (UDCA) on laboratory data and pruritus in patients with ICP. Improved knowledge about the diagnostic classification of different types and pathophysiological mechanisms of ICP may allow for a more targeted treatment of this disease in future.     

Randomized Trial of Interferon-Alpha plus Ursodeoxycholic Acid versus Interferon plus Placebo in Patients with Chronic Hepatitis C Resistant to Interferon

Background: Ursodeoxycholic acid (UDCA) could potentiate the effect of interferon (IFN) in patients with chronic hepatitis C resistant to IFN. We compared the efficacy of IFN with that of a combination of IFN and UDCA. Methods: Patients were randomized to receive UDCA (13-15 mg/kg/day) (n = 47) or placebo (n = 44) plus interferon (3 MU three times weekly) for 6 months and were then followed up for 6 additional months. Results: At entry 30% of patients had cirrhosis, and 70% had HCV genotype 1. Five and four patients withdrew from the combination and the monotherapy groups, respectively. At 6 months alanine aminotransferase (ALAT) and gamma-glutamyl transferase (GGT) activities were significantly lower (P &lt; 0.001) in the combination group than in the monotherapy group; the differences were no longer significant at 1 year. At 6 months ALAT activities normalized in 10 and 8 patients in the combination and the monotherapy groups, respectively (P = 0.67). In 10 of them (5 in each group) HCV RNA levels became undetectable. At 1 year four versus one patient had a sustained normalization of ALAT, and in one patient the HCV RNA became negative. There was no difference in the histologic progression. In this setting, in contrast to chronic cholestasis, UDCA administration induced an increase in total serum bile acids and did not change primary bile acids. Conclusions: An IFN plus UDCA combination is more effective than IFN alone in terms of ALAT but not in terms of the virologic response. These results favor the hypothesis that UDCA has an effect on the biochemical indices of cellular injury independent of a change in primary bile acids.     

A combination therapy of vitamin K1 and bile acid on hemorrhagic diathesis in patients with decompensated liver cirrhosis

This paper presents a study of treatment involving vitamin K₁ (VK₁) accompanied by bile acids for hemorrhagic diathesis that was applied 42 times in 35 patients with decompensated liver cirrhosis. The hepaplastin test (HPT) value showed no change during the administration of VK₁ alone. The HPT value elevated significantly, however, after the administration of VK₁ with bile acid, expecially when using ursodeoxycholic acid (UDCA). The HPT value in patients treated with VK₁ in addition to UDCA before treatment with 53.2% ± 10.2% (mean ± SD) and after that for 2.1 ± 1.1 months (mean ± SD) with 74.7 ± 16.8% showed a significant difference (p< 0.001). On the other hand, no significant difference was noted between the HPT value of 57.2 ± 13.6% before and that of 62.9 ± 13.9% after the treatment in patients treated using VK₁ in conjunction with chenodeoxycholic acid (CDCA). These results indicate that the therapy incorporating VK₁ and bile acid, especially UDCA, is useful for reducing the hemorrhagic tendency in patients with decompensated liver cirrhosis who show no improvement using VK₁ alone.     

Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid

Intrahepatic cholestasis of pregnancy (ICP) is characterized by troublesome maternal pruritus, elevated serum bile acids (> or =10 micromol/L) and increased fetal risk. Recently we determined a cutoff level of serum bile acids, > or =40 micromol/L, to be associated with impaired fetal outcome. We have now studied the effects of ursodeoxycholic acid (UDCA) and dexamethasone on pruritus, biochemical markers of cholestasis, and fetal complication rates in a double-blind, placebo-controlled trial. For this purpose, 130 women with ICP were randomly allocated to UDCA (1 g/day for three weeks), or dexamethasone (12 mg/day for 1 week and placebo during weeks 2 and 3), or placebo for 3 weeks. Pruritus and biochemical markers of cholestasis were analyzed at inclusion and after 3 weeks of treatment. Fetal complications (spontaneous preterm delivery; asphyxial events; and meconium staining of amniotic fluid, placenta, and membranes) were registered at delivery. An intention-to-treat analysis showed significant reduction of alanine aminotransferase (ALT) (P = .01) and bilirubin (P = .002) in the UDCA group only. In a subgroup analysis of ICP women with serum bile acids > or =40 micromol/L at inclusion (n = 34), UDCA had significant effects on pruritus (-75%), bile acids (-79%), ALT (-80%), and bilirubin (-50%) as well, but not on fetal complication rates. Dexamethasone yielded no alleviation of pruritus or reduction of ALT and was less effective than UDCA at reducing bile acids and bilirubin. In conclusion, 3 weeks of UDCA treatment improved some biochemical markers of ICP irrespective of disease severity, whereas significant relief from pruritus and marked reduction of serum bile acids were only found in patients with severe ICP.     

Inhibition of glucose production and stimulation of bile flow by R (+)‐α‐lipoic acid enantiomer in rat liver

Abstract: Aims/Background: R (+)‐α‐lipoic acid (RLA) has been suggested for the treatment of liver diseases, but has also been shown to improve glucose utilization in diabetic patients. Because detailed information of RLA action on carbohydrate metabolism in intact liver is lacking, we examined concentration‐dependent effects of RLA on hepatic glucose production. Methods: RLA (10^?6?10^?3 mol L^?1) or buffer (control) was infused in isolated livers of fasted rats during recirculating perfusion for 90 min (n = 4–6/group). Hepatic glucose and lactate fluxes and bile secretion were continuously monitored. Results: RLA reduced lactate (10 mmol L^?1)‐dependent glucose production in concentration‐dependent fashion (R = ? 0.780, P < 0.001) by up to 67% compared with control (0.36 ± 0.02 µmol min^?1 g^?1). In parallel, RLA dose dependently decreased lactate uptake (R = ? 0.592, P < 0.001) also by up to 67% (control: 0.58 ± 0.08 µmol min^?1 g^?1). RLA (10^?4 mol L^?1 and 10^?3 mol L^?1) stimulated bile flow by ～ 20 and ～ 50%, respectively (P < 0.02 vs. control). After 10^?3 mol L^?1 RLA infusion, liver glycogen was ～ 3 fold higher (5.2 ± 1.1 vs. control: 1.8 ± 0.2 µmol g^?1, P < 0.002). Also at low lactate concentrations (1 mmol L^?1), 10^?3 mol L^?1 RLA reduced glucose production by ～ 53% and lactate uptake by ～ 60%, but stimulated bile secretion by ～ 50% (P < 0.05). Conclusion: RLA reduces hepatic glucose release by inhibiting lactate‐dependent glucose production in a concentration‐dependent fashion.     

Relationship between pruritus and autotaxin in intrahepatic cholestasis of pregnancy

ObjectiveIntrahepatic cholestasis of pregnancy is a temporary, pregnancy-specific disease that resolves with delivery, characterized by itching (pruritus), as well as high transaminase and serum bile acid levels in the third trimester of pregnancy. Due to the effects of Autotaxin on the physiology of pregnancy, we aimed to investigate Autotaxin activity in patients with intrahepatic cholestasis of pregnancy.Patients and methodsSixty-nine patients diagnosed with intrahepatic cholestasis of pregnancy and 20 healthy pregnant women were enrolled in the study. Fasting serum bile acid, pruritus intensity, serum parameters, gestational week of the patients at the time of diagnosis were recorded, and birth week and birth weight were monitored. Autotaxin serum level was measured enzymatically.ResultsThe mean serum bile acid level (n = 69; 38.74 ± 35.92 μmol/L) in patients with intrahepatic cholestasis of pregnancy (n = 69) was detected to be higher than healthy pregnant women (n = 20; 5.05 ± 1.88 μmol/L) (p < 0.001). Weak correlation was detected between serum bile acid level and itch intensity (p = 0.014, r = 0.295), while no relation was detected between Autotaxin and itch intensity (p = 0.446, r = 0.09). Although mean Autotaxin (intrahepatic cholestasis of pregnancy: 678.10 ± 424.42 pg/mL, control: 535.16 ± 256.47 pg/mL) levels were high in patients with intrahepatic cholestasis of pregnancy, it was not statistically significant (p = 0.157).ConclusionIn our study, we observed that the serum Autotaxin level did not make a significant difference in patients with intrahepatic cholestasis of pregnancy compared to healthy pregnant women. These findings suggest that larger clinical studies are required to reveal the physio-pathological effects of Autotaxin on pregnancy.     

Ursodeoxycholic acid therapy in intrahepatic cholestasis of pregnancy: Results in real-world conditions and factors predictive of response to treatment

BackgroundUrsodeoxycholic acid (UDCA) therapy is commonly used in intrahepatic cholestasis of pregnancy (ICP).AimTo evaluate the efficacy and tolerance of UDCA in real-world conditions and to search for factors predictive of response to treatment.MethodsThis observational study included 98 consecutive patients suffering from pruritus during pregnancy associated with increased ALT levels or total bile acid (TBA) concentrations, without other causes of cholestasis. The entire ABCB4 gene coding sequence was analyzed by DNA sequencing.ResultsUDCA was prescribed until delivery in all patients (mean dose 14.0 mg/kg/day; mean duration 30.4 days). Pruritus improved in 75/98 (76.5%) patients, and totally disappeared before delivery in 25/98 (25.5%). After 2–3 weeks of treatment, ALT levels decreased by more than 50% of base line in 67/86 (77.9%) patients and normalized in 34/86 (39.5%), and TBA concentrations decreased in 28/81 (34.6%). Only one patient stopped the treatment before delivery. On multivariate analysis, ALT >175 IU/l before treatment was associated with improvement of pruritus (OR 2.97, 95% CI 1.12–7.89, P = 0.029) and with decreased ALT (OR 18.61, 95% CI 3.94–87.99, P = 0.0002). ABCB4 gene mutation was not associated with response to treatment.ConclusionThis study supports the use of UDCA as first line therapy in ICP.     

Changes in Bile Acid Composition and Effect on Cytolytic Activity of Fecal Water by Ursodeoxycholic Acid Administration: a Placebo-Controlled Cross-over Intervention Trial in Healthy Volunteers

Background: Ursodeoxycholic acid (UDCA) has been shown to affect membrane-damaging effects of bile acids in vitro and fecal bile acid composition in rats. This study evaluates the effect of UDCA on fecal bile acid composition and on cytolytic activity of fecal water in man to clarify the potential chemopreventive role of UDCA for colorectal cancer. Methods: In this placebo-controlled crossover intervention trial, the effect of 900 mg/day UDCA orally in 15 healthy volunteers was studied. At the end of each 4-week period, 72 h feces were collected. Total and individual bile acids in feces were determined by gas chromatography and soluble bile acids were analyzed by high-performance liquid chromatography. Cytolytic activity of fecal water was measured using an erythrocyte lysis assay. Results: In feces, the percentages of primary bile acids--cholic acid (CA) and chenodeoxycholic acid (CDCA)--and of secondary bile acid--deoxycholic acid (DCA)--decreased after supplementation with UDCA, whereas those of UDCA and LCA increased from 2.7 ± 0.4% to 23.7 ± 2.6%, P < 0.0001 and from 26.2 ± 1.2% to 49.4 ± 1.8%, P < 0.0001 respectively. The concentrations of these two bile acids in fecal water also increased after UDCA administration from 7.8 ± 1.9 μmol/l to 47.0 ± 6.7 μmol/l (UDCA), P < 0.0001 and from 2.5 ± 0.6 μmol/l to 18.3 ± 4.1 μmol/l (LCA), P < 0.002, respectively. Cytolytic activity of fecal water was not affected by UDCA. Conclusion: These results do not support a protective effect of UDCA supplementation against colorectal cancer in man.     

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.     

Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy. A 12-year experience.

OBJECTIVE: To assess the efficacy of ursodeoxycholic acid (UDCA) in patients with intrahepatic cholestasis of pregnancy (ICP) and in the outcome of pregnancy. METHODS: Retrospective analysis of our 12-year experience treating ICP patients with UDCA. Thirty-two patients with pruritus starting before week 34 of pregnancy and with increased serum bile salts (BS) and alanine aminotransferase (ALT) received UDCA (15 mg/kg/day) for at least 3 weeks before delivery. They were compared with 16 historical controls who did not receive UDCA. All patients were followed up until delivery and in puerperium. Newborns were followed up during 3 months. RESULTS: UDCA treatment attenuated pruritus (P < 0.05), serum bilirubin and ALT decreased (P < 0.05) and BS declined. Delivery at term (> or = 37 weeks) occurred in 65.7% of UDCA-treated patients compared with only 12.5% in controls (P < 0.01). Infants born to mothers treated with UDCA weighed a mean of 500 g more than the controls (2882+/-582 vs 2385+/-582; P < 0.01). At 3 months, all infants developed normally. Twenty-six children whose mothers received UDCA were re-examined after 1-12 years and they and their mothers were healthy. CONCLUSIONS: UDCA improved pruritus and biochemical cholestasis, and facilitated deliveries at term in ICP patients, with a higher birthweight compared with historical controls. The drug was well tolerated and no adverse effects were detected in their infants.     

Effect of ursodeoxycholic acid administration on biliary lipid secretion in primary biliary cirrhosis

Ursodeoxycholic acid (UDCA) has been reported to improve liver function tests when administered to patients with cholestatic liver diseases, such as primary biliary cirrhosis (PBC). However, its effects on biliary lipid metabolism in patients with PBC are still unknown. In this study we report the effect that UDCA (600 mg/day, for four weeks) had on biliary cholesterol saturation index, biliary bile acid pattern and pool size, and biliary lipid output in seven female patients (ages 34–58 years) with PBC, stages I to III. A significant improvement of liver function tests was observed after four weeks of treatment. Saturation index was significantly decreased from 1.23±0.1 to 0.7±0.08 (P<0.02); this effect was due to the significant decrease of biliary cholesterol concentration from 6.7±0.36 to 3.6±0.37 percent molar (P<0.02). A significant decrease of cholesterol output (from 88±9 to 55±10 μmol/hr, P<0.02) was also observed. The amount of cholic acid, the predominant bile acid in bile, significantly decreased (from 47.3±3.5 to 35.4±2.6 percent molar, P<0.02), as did amounts of chenodeoxycholic and deoxycholic acids, while the amount of UDCA rose from 1.6±1.0 to 34.0±1.3 percent molar (P<0.02). Total bile acid pool size was not affected by UDCA, but the evaluation of individual bile acid pool sizes showed an increased proportion of UDCA relative to the endogenous bile acids. The results of the study confirm the beneficial effect of UDCA on liver function tests in PBC patients and support the hypothesis that the improvement of these measurements may be due to replacement of toxic endogenous bile acids with UDCA.     

The multiple facets of ABCB4 (MDR3) deficiency

Opinion statement ABCB4 (MDR3), a lipid translocator, moves phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane. Genetic mutations of ABCB4 lead to three distinct but related hepatobiliary diseases. Progressive familial intrahepatic cholestasis (PFIC) type 3 is a chronic cholestatic syndrome characterized by a markedly elevated γ-glutamyltranspeptidase. Patients present with jaundice, pruritus, and hepatosplenomegaly. Periportal inflammation progresses to biliary cirrhosis and causes portal hypertension. Ursodeoxycholic acid (UDCA) normalizes liver function tests in approximately one half of treated PFIC type 3 patients. Partial responders or nonresponders eventually will require liver transplantation. Gallstone patients with ABCB4 mutations may have low phospholipid-associated cholelithiasis syndrome, characterized by cholesterol gallstones and intrahepatic microlithiasis, along with recurrent biliary symptoms, despite cholecystectomy. Patients with ABCB4 mutations also may develop intrahepatic brown pigment stones. UDCA may improve biliary symptoms even before the dissolution of stones occurs. Additional therapies such as farnesoid X receptor ligands/agonists and benzfibrates show future therapeutic promise. Intrahepatic cholestasis of pregnancy affects pregnant women with abnormal ABCB4. These women suffer from disabling pruritus and also may experience steatorrhea. Fetuses are at high risk for prematurity and stillbirths. The definitive treatment is delivery of the baby. In the interim, limited fat intake, fat-soluble vitamin supplementation, and UDCA with or without S-adenosylmethionine can provide symptomatic relief. Additional hepatobiliary diseases related to ABCB4 mutations are likely to be identified. This may result in the discovery of additional therapies for PFIC type 3, gallstones, and intrahepatic cholestasis of pregnancy.     

Efficacy of ursodeoxycholic acid in the treatment of patients with chronic hepatitis C

A case-control study was conducted to evaluate the efficacy of ursodeoxycholic acid (UDCA) in the treatment of Chinese patients with chronic hepatitis C. Patients who failed to have sustained responses to interferon (IFN) therapy, refused to take IFN or were unsuitable for IFN treatment were enrolled into this study. The treatment group had 15 patients and they received UDCA 600 mg orally per day for 6 months. Another 15 patients with matched sex, age and initial serum alanine aminotransferase (ALT) levels were chosen as the control group. Three parameters (i.e. serum ALT levels, serum hepatitis C virus (HCV) RNA and serum cytokines) were measured before and after UDCA treatment. After the treatment period, the mean serum ALT levels in both groups were not significantly different (153.8 ± 111.0 U/L vs 112.1 ± 53.8 U/L, P > 0.05) and mean serum ALT level in the UDCA-treated group did not decrease after the treatment (pre-treatment vs post-treatment value: 139.1 ± 73.1 U/L vs 153.8 ± 111.0 U/L, P > 0.05). In addition, all of the patients with positive HCV RNA before treatment still had active HCV viraemia after the UDCA treatment. Also, the serum levels of interleukin-6 (IL-6) and the tumour necrosis factor-α (TNF-α) were not significantly different between the two groups before and after the treatment period. In conclusion, a regimen of UDCA as prescribed in the present study did not show obvious benefits in the treatment of Chinese patients with chronic hepatitis C.     

Effect of Ursodeoxycholic Acid Treatment on Intestinal Absorption of Triglycerides in Man

The aim of the present study was to evaluate whether treatment with ursodeoxycholic acid (UDCA) may affect the absorption of dietary fat in man. Fifteen healthy subjects volunteered for the study. They were treated with UDCA in a daily dose of 15 mg/kg body weight for 4 weeks. Before and during treatment fat absorption was measured with a ¹⁴C-triolein breath test. In addition, fasting serum bile acids were measured in 11 of the subjects. The maximum specific activity of ¹⁴CO₂ was not significantly changed during the treatment period. However, the cumulative output of ¹⁴CO₂ during a 6-h period was decreased by about 25% (p < 0.03). Several subjects with decreased outputs also lost 1–2 kg of body weight during the study period. UDCA treatment raised the serum level of this bile acid from 0.18 ± 0.11 μmol/1 to 5.98 ± 1.08 μmol/l. The concentrations of the other bile acids were not significantly changed. It is suggested that UDCA treatment may in some patients be associated with an impaired fat absorption. Whether this effect is of any clinical importance remains to be elucidated.     

Management of intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease during pregnancy, characterized by otherwise unexplained pruritus in late second and third trimester of pregnancy and elevated bile acids and/or transaminases. ICP is associated with an increased risk of adverse perinatal outcomes for the fetus and the later development of hepatobiliary disease for the mother. Bile acids should be monitored throughout pregnancy since fetal risk is increased at serum bile acids >40 µmol/l. Management of ICP consists of treatment with ursodeoxycholic acid, which reduces pruritus. Early elective delivery is common practice but should be performed on an individualized basis as long as strong evidence supporting this practice is lacking. Mothers should be followed-up for normalization of liver function tests 6–12 weeks after delivery. Future research in large-scale studies is needed to address the impact of ursodeoxycholic acid and early elective delivery on fetal outcome.