Beneficial Effect Of Ursodeoxycholic Acid Research Articles

Effect of Maternal Ursodeoxycholic Acid Treatment on Fetal Atrioventricular Conduction in Patients with Intrahepatic Cholestasis of Pregnancy.

The aim of this study was, first, to investigate the difference in fetal atrioventricular conduction in patients with and without intrahepatic cholestasis of pregnancy (ICP) by measuring the fetal PR interval; second, to evaluate the altering effect of ursodeoxycholic acid (UDCA) treatment on the fetal PR interval in ICP patients. The study consisted of 42 ICP patients and 48 healthy pregnant women. Fetal echocardiography was performed to measure the mechanical PR interval. The fetal PR interval and the clinical characteristics were compared between the two groups. The effect of UDCA treatment on the fetal PR interval in ICP patients was evaluated. In ICP patients, significantly longer fetal PR intervals were observed than in the control group (123.21 ± 8.54 vs. 115.13 ± 5.95 ms, p < 0.001). In the ICP group, there was a positive correlation between the fetal PR interval and maternal fasting total bile acid (TBA) levels (r = 0.514, p = 0.001). After 1 week of treatment with UDCA in patients with ICP, the PR interval was shorter than before, although the reduction was not statistically significant (120.98 ± 6.70 vs. 123.21 ± 8.54 ms, p = 0.095). In patients with severe ICP (TBA >40 mmol/L, n = 10), a significant reduction in the fetal PR interval was observed after treatment with UDCA (127.5 ms [IQR, 118.0-134.75] before vs. 122 ms [IQR, 109.5-126.5] after, p = 0.037). Fetal PR interval increased in ICP patients in correlation with maternal serum TBA concentration. Treatment with UDCA may have limited positive effects on the fetal AV conduction system. The beneficial effects of UDCA on the fetal PR interval may be more pronounced in patients with higher bile acid levels.

The therapeutic mechanisms and beneficial effects of ursodeoxycholic acid in the treatment of nonalcoholic fatty liver disease: a systematic review.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, with an increasing prevalence in all regions of the world. Its spectrum includes hepatic steatosis (HS) and non-alcoholic steatohepatitis (NASH) with progression to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NAFLD may represent the hepatic manifestation of the metabolic syndrome (MS), with a prevalence directly proportional to the prevalence of obesity and MS. The standard treatment for patients with NAFLD is lifestyle modification, which in medical practice has many limitations. To overcome them, numerous drugs with benefits in the prevention and treatment of the disease have been studied. Currently, the most used substances are vitamin E and Pioglitazone, with numerous benefits. Furthermore, new strategies and beneficial treatments are needed for the prevention of the disease, which is currently a priority in both the health and research fields. One of the most studied agents in the last decades has been ursodeoxycholic acid (UDCA), which is of great interest in the treatment of NAFLD due to its hepatoprotective effects.

Beneficial effects of UDCA and norUDCA in a rodent model of steatosis are linked to modulation of GPBAR1/FXR signaling

Non-alcoholic steatosis (NAFLD) and steatohepatitis (NASH) are two highly prevalent human disorders for which therapy remains suboptimal. Bile acids play an essential role in regulating liver metabolism, and several bile acids-based therapy are currently investigated for their potential therapeutic efficacy in NAFLD/NASH. Bile acids exert their functions, at least in part, by modulating two main receptors the Farnesoid-x-receptor (FXR) and the G protein-coupled receptor, GPBAR1. In the present study we have compared the pharmacological effects of two bile acids, the ursodeoxycholic acid (UDCA) and its derivative norUDCA, in a model of NAFLD/NASH induced by feeding mice with a Western diet for 12 weeks. The results of these studies demonstrated that both UDCA and norUDCA protected against development of steatosis and fibrosis, but did not reduce the hepatocytes ballooning nor the development of a pro-atherogenic lipid profile. Both agents reduced liver lipogenesis and ameliorated insulin sensitivity and adipocytes signaling as shown by increased expression of adiponectin. Mechanistically, UDCA acts as weak GPBAR1 agonist, while norUDCA exerted no effect on both GPBAR1 and FXR. In vivo administration of UDCA resets bile acid synthesis and promotes a shift toward bile acids species that are GPBAR1 agonists, UDCA, TUDCA and hyodeoxycholic acid, and increases GLP1 expression in the ileum. In contrast norUDCA is poorly metabolized exerting a minimal impact on GPBAR1 signaling. Together, these data, highlight the potential role of UDCA and norUDCA in treating of NAFLD, though these beneficial effects are supported by different mechanisms.

Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia.

A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly 3α,7α,12α-trihydroxy-5β-cholestanoic acid (THCA). We aimed to investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. Among 33 patients with unexplained hypertransaminasemia from 11 hospitals and 13 of their relatives, seven individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by high-performance liquid chromatography-mass spectrometry. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in two patients and three family members. Two additional nonrelated patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In patients with ADAH, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized aminotransferase levels. Incubation of HuH-7 hepatoma cells with THCA, which was efficiently taken up, but not through BA transporters, increased reactive oxygen species production (flow cytometry), endoplasmic reticulum stress biomarkers (GRP78, CHOP, and XBP1-S/XBP1-U ratio), and BAXα expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was decreased (tetrazolium salt-based cell viability test). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a noninvasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.

Factors associated with adherence to ursodeoxycholic acid or placebo in patients after bariatric surgery.

Ursodeoxycholic acid (UDCA) reduces symptomatic gallstone disease after Roux-en-Y gastric bypass (RYGB). The beneficial effect of UDCA is reduced by poor adherence. We aimed to identify factors associated with poor adherence to UDCA or placebo after bariatric surgery. Outpatient clinic and department for bariatric surgery in three hospitals in the Netherlands. Patients in the multicenter, double-blind, randomized, placebo-controlled UPGRADE trial were assessed for adherence to 900 mg UDCA or placebo for 6 months through a pill count, inquiries during follow-up, and a questionnaire. Poor adherence was defined as the usage of <300 of 364 pills within a maximum of 8 months postoperatively. Multivariable logistic regression analysis was used to identify factors contributing to poor adherence. In total, 967 patients were included (mean age [standard deviation (SD)]: 45.1 [11.1] years; female: 772 [80%]; RYGB: 889 [92%]; sleeve gastrectomy: 78 [8%]), of whom 357 (37%) were poor adherers. Factors associated with poor adherence were age (OR .97; 95% confidence interval [CI] .96-.98, a decrease in age increases the odds for poor adherence), foreign origin (odds ratio [OR] 2.07; 95%CI 1.50-2.84), unemployment (OR 1.73; 95%CI 1.28-2.34), and sleeve gastrectomy (OR 1.79; 95%CI 1.06-3.01). Furthermore, a difference in adherence status was also noted for the centers of surgery. The adherence rate to UDCA and placebo in the UPGRADE trial was suboptimal. Several factors were independently associated with poor adherence. Our findings can help to identify patients who may benefit from extra guidance to improve adherence.

Ursodeoxycholic Acid: Efficacy and Safety in the Treatment of Nonalcoholic Fatty Liver Disease (Meta-Analysis)

Вackground: Non-alcoholic liver disease (NAFLD) is a widely spread disease that needs an effective and safe treatment strategy. One of pharmacological treatments for people with NAFLD is ursodeoxycholic acid (UDCA). The use of UDCA is pathogenetically justified because of its cytoprotective, antiapoptotic, antioxidant, and hypoglycemic properties. Aim: Our meta-analysis (M-A) aimed to assess the benefits and harms of UDCA in people with NAFLD. Material and methods: We identified trials through electronic searches in the Cochrane Hepato-Biliary (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, SCI, LILACS, eLibrary (May 2018). We considered for inclusion randomised clinical trials (RCTs) assessing URSO versus placebo/no intervention in adult participants with NAFLD. We allowed co-interventions in the trial groups if they were similar. We followed Cochrane methodology, CHB Group methodology using Review Manager 5 and Trial Sequential Analysis to perform meta-analysis (M-A), assessed bias risk of the trials, quality of evidence using GRADE. Results: Four RCT, at high bias risk, low quality of evidence, provided data for analysis: 254 participants at different stages of NAFLD received oral UDCA (median of 18 months), 256 ― placebo/no intervention; age 18 to 75 years. We found no evidence of effect on mortality (there were no deaths) and on histological parameters such as steatosis (MD -0.13; CI -0.40−0.13; participants 323; trials 3; I2=43%), fibrosis (MD 0.00; CI -0.00−0.22; participants 323; trials 3; I2=0%), and inflammation (MD -0.05; CI -0.20−0.10; participants 325; trials 3; I2=0%). Also we found no evidence for significant influence of UDCA on occurrence of serious adverse events (RR 1.45, 95% CI 0.65−3.21; participants 292; trials 2; I2=0%), adverse events (RR 1.52, 95% CI 0.73−3.16; participants 510; trials 4; I2=36%) neither with traditional M-A (random-effects), nor with TSA SAE (CI 0.56−2.91; participants 292; trials 2; I2=0%, D2=0%), AE (CI 0.77–2.21; participants 510; trials 4; I2=0%, D2=0%). There was no evidence of effect on cytolysis, but beneficial effect of UDCA on cholestasis (GGTP) (data from two trials only) (р0.0001). We found no data on quality of life. All the trials were funded by the industry. Conclusion: Based on the small number of trials at high risk of bias, low quality, despite the safety profile observed with our M-A, we can neither recommend nor reject the use of UDCA for people with NAFLD. Further trials with low risk of bias and high quality are required to assess the benefits and harms of UDCA.

Effect of Ursodeoxycholic Acid on Pentylenetetrazole Kindling and Kindling Induced Memory Impairment in Rat

BACKGROUND AND OBJECTIVE: Epilepsy is one of the common diseases of the brain that about 30-40 of patients with epilepsy experience recurent attacks due to drug resistance. Recently, the beneficial effects of Ursodeoxycholic acid on brain disorders have been considered. The aim of this study was to evaluate the effect of Ursodeoxycholic acid(UDCA)on the Pentylenetetrazole (PTZ) induced kindling, and related learning and memory impairments on Morris water maze. METHODS: This experimental study was done on 32 male Winstar rats divided into 4 groups. The first(n=7)and the second (n=9) groups have received three injections of 0.5 ml NaCl or 50 mg/kg of UDCA respectively and third(n=7) and fourth(n=9) groups have received fifteen injections of 0.5 ml NaCl or 50 mg/kg of UDCA respectively. All injections were given intraperitoneally(ip)(every 48 hours). In all groups, chemical kindling were started after third injections. Twenty-four hour after the last injection, spatial memory was investigated in the Morris water maze. FINDING: Fifteen injections of UDCA significantly reduced the seizure stage from 3.5±0.17 to 3.08±0.11 and duration of stages five from 12.38±1.2 to 8.61±0.58 and increased time to reach the stage five seizures from 1021.65±72.07 to 1252.41±49.63 as compared to control group. However, three injections of UDCA have no effect on the kindling process. However, three time administration of UDCA significantly increased reference memory from 18.72±1.2 s to 26.11±1.8 s. CONCLUSION: Ursodeoxycholic acid inhibits chemical kindling and improves kindling induced memory impairment. © 2018, Babol University of Medical Sciences. All rights reserved.

Evidence for the association between IgG-antimitochondrial antibody and biochemical response to ursodeoxycholic acid treatment in primary biliary cholangitis.

Antimitochondrial antibody (AMA) is considered the serological hallmark of primary biliary cholangitis (PBC), while data regarding the profile of AMA during ursodeoxycholic acid (UDCA) treatment are scarce. Here, we assessed the influence of UDCA treatment on titers of AMA and factors relevant to its production. Serum IgA-AMA, IgM-AMA, IgG-AMA, B cell-activating factor of the tumor necrosis factor family (BAFF), and the frequency of circulating plasmablasts were detected in PBC patients, including those who received UDCA therapy for 24 weeks, healthy controls, chronic hepatitis B patients, and autoimmune hepatitis patients. Consecutive liver sections from controls and PBC patients were stained by immunohistochemistry for detection of intrahepatic CD38+ , IgA+ , IgM+ , and IgG+ cells. Significant decrease in titers of IgG-AMA was found only confined to PBC patients with biochemical response to UDCA treatment (P = 0.005), and similar pattern was also observed at week 24 in quantifying circulating plasmablasts (P = 0.025) and serum BAFF (P = 0.013). Notably, positive correlation between serum BAFF levels and titers of IgG-AMA, and the frequency of circulating plasmablasts were observed in PBC patients (r = 0.464, P = 0.034 and r = 0.700, P < 0.001, respectively). Additionally, in situ staining revealed significant accumulation of CD38+ and IgG+ cells within the portal tracts of PBC liver. Decreased titers of serum IgG-AMA are associated with biochemical response to UDCA treatment, implicating the potentiality of this hallmark in therapeutic response evaluation and the beneficial effect of UDCA on humoral immunity in PBC patients.

Beneficial effects of ursodeoxycholic acid via inhibition of airway remodelling, apoptosis of airway epithelial cells, and Th2 immune response in murine model of chronic asthma

Background and aimsIn previous studies, anti-inflammatory, anti-apoptotic and immunomodulatory effects of ursodeoxycholic acid (UDCA) on liver diseases have been shown. In this study, we aimed to investigate the effects of UDCA on airway remodelling, epithelial apoptosis, and T Helper (Th)-2 derived cytokine levels in a murine model of chronic asthma. MethodsTwenty-seven BALB/c mice were divided into five groups; PBS-Control, OVA-Placebo, OVA-50mg/kg UDCA, OVA-150mg/kg UDCA, OVA-Dexamethasone. Mice in groups OVA-50mg/kg UDCA, OVA-150mg/kg UDCA, OVA-Dexamethasone received the UDCA (50mg/kg), UDCA (150mg/kg), and dexamethasone, respectively. Epithelium thickness, sub-epithelial smooth muscle thickness, number of mast and goblet cells of samples isolated from the lung were measured. Immunohistochemical scorings of the lung tissue for matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEG-F), transforming growth factor-beta (TGF-β), terminal deoxynucleotidyl transferase-mediated dUTP nick endlabeling (TUNEL) and cysteine-dependent aspartate-specific proteases (caspase)-3 were determined. IL-4, IL-5, IL-13, Nitric oxide, ovalbumin-specific immunoglobulin (Ig) E levels were quantified. ResultsThe dose of 150mg/kg UDCA treatment led to lower epithelial thickness, sub-epithelial smooth muscle thickness, goblet and mast cell numbers compared to placebo. Except for MMP-9 and TUNEL all immunohistochemical scores were similar in both UDCA treated groups and the placebo. All cytokine levels were significantly lower in group IV compared to the placebo. ConclusionsThese findings suggested that the dose of 150mg/kg UDCA improved all histopathological changes of airway remodelling and its beneficial effects might be related to modulating Th-2 derived cytokines and the inhibition of apoptosis of airway epithelial cells.

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

Endoplasmic reticulum (ER) stress, resulting from the accumulation of misfolded and/or unfolded proteins in ER membranes, is involved in the pathogenesis of diabetic nephropathy (DN). The aim of this study was to investigate the role of ER stress inhibitors ursodeoxycholic acid (UDCA) and 4-phenylbutyrate (4-PBA) in the treatment of DN in db/db mice. Findings have revealed that diabetic db/db mice were more hyperglycemic than their non-diabetic controls, and exhibited a marked increase in body weight, water intake, urine volume, fasting plasma glucose, systolic blood pressure, glucose and insulin tolerance. UDCA (40 mg/kg/day) or 4-PBA (100 mg/kg/day) treatment for 12 weeks resulted in an improvement in these biochemical and physical parameters. Moreover, UDCA or 4-PBA intervention markedly decreased urinary albuminuria and attenuated mesangial expansion in diabetic db/db mice, compared with db/db mice treated with vehicle. These beneficial effects of UDCA or 4-PBA on DN were associated with the inhibition of ER stress, as evidenced by the decreased expression of BiP, phospho-IRE1α, phospho-eIF2α, CHOP, ATF-6 and spliced X-box binding protein-1 in vitro and in vivo. UDCA or 4-PBA prevented hyperglycemia-induced or high glucose (HG)-induced apoptosis in podocytes in vivo and in vitro via the inhibition of caspase-3 and caspase-12 activation. Autophagy deficiency was also seen in glomeruli in diabetic mice and HG-incubated podocytes, exhibiting decreased expression of LC3B and Beclin-1, which could be restored by UDCA or 4-PBA treatment. Taken together, our results have revealed an important role of ER stress in the development of DN, and UDCA or 4-PBA treatment may be a potential novel therapeutic approach for the treatment of DN.

Beneficial Effect of Ursodeoxycholic Acid on High GlucoseInduced Long QT Interval Arrhythmia in Isolated Rat Heart

Beneficial Effect of Ursodeoxycholic Acid on High GlucoseInduced Long QT Interval Arrhythmia in Isolated Rat Heart

Spotlight on the September 8 Issue

#### Notable in Neurology This issue features an article assessing the beneficial effect of ursodeoxycholic acid on mitochondrial dysfunction in LRRK2 G2019S carriers and in vivo models and another identifying the natural history of succinic semialdehyde dehydrogenase deficiency through adulthood. Another article focuses on the pathogenic effects of antibodies on gut and brain neurons in anti-DPPX encephalitis. ### Putaminal serotonergic innervation: Monitoring dyskinesia risk in Parkinson disease The authors acquired 2 PET scans and 3T MRI from 30 patients with Parkinson disease without dementia or depression divided into 3 matched groups. Relative serotonergic innervation of the putamen and …

UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2(G2019S) carriers and in vivo.

To further characterize mitochondrial dysfunction in LRRK2(G2019S) mutant Parkinson disease (PD) patient tissue (M-LRRK2(G2019S)), determine whether ursodeoxycholic acid (UDCA) also exerts a beneficial effect on mitochondrial dysfunction in nonmanifesting LRRK2(G2019S) mutation carriers (NM-LRRK2(G2019S)), and assess UDCA for its beneficial effect on neuronal dysfunction in vivo. Intracellular adenosine 5'-triphosphate (ATP) levels, oxygen consumption, and activity of the individual complexes of the mitochondrial respiratory chain as well as mitochondrial morphology were measured in M-LRRK2(G2019S), NM-LRRK2(G2019S), and controls. UDCA was assessed for its rescue effect on intracellular ATP levels in NM-LRRK2(G2019S) and in a LRRK2 transgenic fly model with dopaminergic expression of LRRK2(G2019S). Crucial parameters of mitochondrial function were similarly reduced in both M-LRRK2(G2019S) and NM-LRRK2(G2019S) with a specific decrease in respiratory chain complex IV activity. Mitochondrial dysfunction precedes changes in mitochondrial morphology but is normalized after siRNA-mediated knockdown of LRRK2. UDCA improved mitochondrial function in NM-LRRK2(G2019) and rescued the loss of visual function in LRRK2(G2019S) flies. There is clear preclinical impairment of mitochondrial function in NM-LRRK2(G2019S) that is distinct from the mitochondrial impairment observed in parkin-related PD. The beneficial effect of UDCA on mitochondrial function in both NM-LRRK2(G2019S) and M-LRRK2(G2019S) as well as on the function of dopaminergic neurons expressing LRRK2(G2019S) suggests that UDCA is a promising drug for future neuroprotective trials.

Impact of ursodeoxycholic acid on a CCK1R cholesterol-binding site may contribute to its positive effects in digestive function.

Dysfunction of the type 1 cholecystokinin (CCK) receptor (CCK1R) as a result of increased gallbladder muscularis membrane cholesterol has been implicated in the pathogenesis of cholesterol gallstones. Administration of ursodeoxycholic acid, which is structurally related to cholesterol, has been shown to have beneficial effects on gallstone formation. Our aims were to explore the possible direct effects and mechanism of action of bile acids on CCK receptor function. We studied the effects of structurally related hydrophobic chenodeoxycholic acid and hydrophilic ursodeoxycholic acid in vitro on CCK receptor function in the setting of normal and elevated membrane cholesterol. We also examined their effects on a cholesterol-insensitive CCK1R mutant (Y140A) disrupting a key site of cholesterol action. The results show that, similar to the impact of cholesterol on CCK receptors, bile acid effects were limited to CCK1R, with no effects on CCK2R. Chenodeoxycholic acid had a negative impact on CCK1R function, while ursodeoxycholic acid had no effect on CCK1R function in normal membranes but was protective against the negative impact of elevated cholesterol on this receptor. The cholesterol-insensitive CCK1R mutant Y140A was resistant to effects of both bile acids. These data suggest that bile acids compete with the action of cholesterol on CCK1R, probably by interacting at the same site, although the conformational impact of each bile acid appears to be different, with ursodeoxycholic acid capable of correcting the abnormal conformation of CCK1R in a high-cholesterol environment. This mechanism may contribute to the beneficial effect of ursodeoxycholic acid in reducing cholesterol gallstone formation.

Mo1930 Beneficial Effect of Ursodeoxycholic Acid (UDCA) and Its Derivative UDCA-Cpa in Attenuation of Functional Impairment of Esophageal Mucosa in Rat Model of Barrett's Esophagus

Mo1930 Beneficial Effect of Ursodeoxycholic Acid (UDCA) and Its Derivative UDCA-Cpa in Attenuation of Functional Impairment of Esophageal Mucosa in Rat Model of Barrett's Esophagus

Ursodeoxycholic acid dose‐dependently improves liver injury in rats fed a methionine‐ and choline‐deficient diet

The data on the beneficial effect of ursodeoxycholic acid (UDCA) in non-alcoholic steatohepatitis (NASH) are controversial. The difference of opinion is connected with UDCA dosage to be used. Therefore, we evaluated the dose-dependent efficacy of UDCA in experimental NASH. Male Wistar rats were fed the methionine- and choline-deficient (MCD) diet for 10 weeks. Rats were administrated UDCA (10, 20, 40 and 80 mg/kg bodyweight intragastrically) after 6 weeks of the MCD diet. Animals fed the MCD diet developed severe steatohepatitis. Treatment with UDCA dose-dependently decreased liver damage, but only high-dose UDCA (80 mg/kg) significantly diminished ultrastructural changes in addition to preventing steatosis, ballooning and inflammatory changes in the liver. The activities of serum marker enzymes and the content of liver triglyceride and blood glucose were increased in MCD diet-fed rats, but decreased in all the UDCA-treated groups. Serum insulin concentration was decreased whereas the quantitative insulin sensitivity check index did not changed in MCD diet-fed groups. Serum tumor necrosis factor-α content was strongly increased after MCD diet and normalized in the UDCA-treated rats, with the most pronounced effect in the highest dose groups, 40 and 80 mg/kg. The contents of endogenous ethanol in blood and intestinal mucus were increased in MCD diet-fed rats which were significantly lowered by UDCA (40 and 80 mg/kg per day). The present data demonstrate a beneficial effect of UDCA that manifested by the decrease of liver steatosis, inflammatory signs and serum tumor necrosis factor-α content especially of the highest 40 and 80 mg/kg day doses.

Effect of Ursodeoxycholic Acid on Liver Function in Children After Successful Surgery for Biliary Atresia

Although ursodeoxycholic acid has been used to treat various cholestatic liver diseases in children, few data are available about its efficacy in biliary atresia. The aim of this study was to assess the effect of ursodeoxycholic acid treatment on liver function in children who underwent successful surgery for biliary atresia. We prospectively studied 16 children with biliary atresia who underwent successful portoenterostomies (postoperative conjugated bilirubin concentration: <34 micromol/L) and were treated with ursodeoxycholic acid for at least 18 months after surgery. Ursodeoxycholic acid treatment was then discontinued. Clinical and biological assessment was performed at the time of discontinuation of ursodeoxycholic acid treatment (T0), at follow-up (T1) and, if the clinical or biological status worsened, after resumption of ursodeoxycholic acid treatment (T2). Ursodeoxycholic acid treatment was resumed in 13 cases. In 1 patient, jaundice recurred after ursodeoxycholic acid therapy was discontinued but abated after resumption of treatment. In 13 children, liver function worsened significantly when ursodeoxycholic acid was discontinued. T1 versus T0 concentrations expressed as multiples of the upper limit of the normal range (in parentheses) were as follows: alanine aminotransferase, 3.0 xN (0.8-7.0) vs 1.5 xN (0.5-5.4); gamma glutamyl transpeptidase, 8.0 xN (1.8-30.2) vs 4.2 xN (0.5-27.4); and aspartate aminotransferase, 1.7 xN (0.7-6.0) vs 1.3 xN (0.6-3.4). When ursodeoxycholic acid treatment was resumed, liver function had improved in all patients by T2. Concentrations of endogenous bile acids tended to be elevated at T1 (not significant) and were significantly decreased at T2. Our study demonstrates the beneficial effect of ursodeoxycholic acid on liver function in children after successful surgery for biliary atresia.

Liver Disease Associated with ZZ α1‐Antitrypsin Deficiency and Ursodeoxycholic Acid Therapy in Children

To investigate the effect of ursodeoxycholic acid (UDCA) in children with liver disease associated with ZZ alpha1-antitrypsin (AAT) deficiency. A total of 42 affected children received UDCA (30 mg x kg x day(-1)) and underwent clinical and biochemical follow-up at least yearly. In group 1, 22 children whose mean initial gamma-glutamyl-transpeptidase (GGT) was 7.4 x N normalized serum liver test results after a mean treatment of 2.6 years. In 16 of these children, UDCA was discontinued. Relapse was observed in 11 children, and liver test results returned to normal after UDCA resumption. In the other 5 children, liver test results remained normal during a mean period of 2.5 years. In group 2, 11 children (mean initial GGT 12.8 x N) had improved liver test results after a mean treatment of 2.3 years. In group 3, 9 children (mean initial GGT 33.8 x N) had no liver test result improvement and evolution toward cirrhosis, requiring liver transplantation in 7. Most of the children in group 1 had normal results of clinical examination after UDCA treatment, versus none in group 3 (P < or = 0.00001). Initial GGT (P < or = 0.002) and total bilirubin (P < or = 0.05) levels were significantly lower in group 1 than in group 3. Combined initial values of GGT < or =5.5 x N and total bilirubin < or =66 micromol/L were associated with normalization of liver test results in 90% of children. UDCA may significantly improve clinical status and liver test results in some children with liver disease associated with ZZ AAT deficiency. No beneficial effect of UDCA was shown in children with the most severe liver involvement. Initial levels of GGT and total bilirubin may be of prognostic value for therapy effectiveness.

The Long-term Beneficial Effects of Ursodeoxycholic Acid in Primary Biliary Cirrhosis are Highly Questionable

1Copenhagen Trial UnitCopenhagen University Hospital, H.S Rigs hospitalet2100 Copenhagen, Denmark; [email protected] 2Clinic of International Medicine IBispebjerg University Hospital2400 Copenhagen; Denmark

668 Beneficial effect of ursodeoxycholic acid (UDCA) on endogenous ethanol and intestinal bacterial flora in rats fed methionine-choline deficient diet (MCDD)

668 Beneficial effect of ursodeoxycholic acid (UDCA) on endogenous ethanol and intestinal bacterial flora in rats fed methionine-choline deficient diet (MCDD)