Ursodeoxycholic acid alleviates cholestasis-induced histophysiological alterations in the male reproductive system of bile duct-ligated rats

Ursodeoxycholic acid is the most widely used drug for treating cholestatic liver diseases. However, its effect on the male reproductive system alterations associated with cholestasis has never been studied. Thus, this study aimed to investigate the effect of ursodeoxycholic acid on cholestasis-induced alterations in the male reproductive system. Cholestasis was induced by bile duct ligation. Bile duct-ligated rats had higher cholestasis biomarkers and lower levels of testosterone, LH and FSH than did the Sham rats. They also had lower reproductive organs weights, and lower sperm motility, density and normal morphology than those of Sham rats. Histologically, these animals suffered from testicular tubular atrophy, interstitial edema, thickening of basement membranes, vacuolation, and depletion of germ cells. After ursodeoxycholic acid administration, cholestasis-induced structural and functional alterations were significantly ameliorated. In conclusion, ursodeoxycholic acid can ameliorate the reproductive complications of chronic cholestasis in male patients, which represents an additional benefit to this drug.     

熊去氧胆酸与羟甲烟胺治疗慢性乙型肝炎肝内胆汁淤积的疗效比较

目的:比较熊去氧胆酸与羟甲烟胺治疗慢性乙型肝炎肝内胆汁淤积的疗效。方法:将96例慢性乙型肝炎肝内胆汁淤积患者随机分为熊去氧胆酸组(56例)和羟甲烟胺组(40例),2组在抗病毒和护肝治疗的基础上分别加用熊去氧胆酸与羟甲烟胺治疗,疗程均为4周。分别比较2组治疗2、4周后的临床疗效。结果:治疗2周时,2组患者肝功能观察指标均有明显改善,但熊去氧胆酸组降低总胆红素、直接胆红素、碱性磷酸脂酶的幅度与羟甲烟胺组比较无显著性差异(P>0.05);治疗4周时,熊去氧胆酸组血清总胆红素、直接胆红素、碱性磷酸脂酶降幅较羟甲烟胺组高,差异有统计学意义(P<0.05)。熊去氧胆酸组总有效率优于羟甲烟胺组(75%vs.70%,P=0.02)。结论:熊去氧胆酸治疗慢性乙型肝炎肝内胆汁淤积的疗效优于羟甲烟胺。     

The therapeutic effects of ursodeoxycholic acid as an anti-apoptotic agent

The dihydroxy bile acid, ursodeoxycholic acid (UDCA), has been in widespread clinical use in the Western world since the mid 1980s, when it was initially used for gallstone dissolution [1,2] and subsequently for the treatment of chronic cholestatic liver diseases [3,4]. Many clinical trials of UDCA in a variety of cholestatic disorders established biochemical and clinical improvements, and most importantly showed a significant prolongation of transplant-free survival after four years of treatment with UDCA in patients with primary biliary cirrhosis [5]. Despite its clinical efficacy, the precise mechanism(s) by which UDCA improves liver function during cholestasis is still a matter of debate [6]. It was initially considered that the choleretic effect of UDCA, coupled with its ability to cause a marked shift in the composition of the bile acid pool towards hydrophilicity, accounted for its mechanism of action. In recent years, however, it has become evident that UDCA and its conjugated derivatives are capable of exerting direct effects at the cellular, subcellular, and molecular levels by stabilising cell membranes, affecting signal transduction pathways, and regulating immune responses. In addition, we have shown that UDCA plays a unique role in modulating the apoptotic threshold in both hepatic and non-hepatic cells [7-10]. The purpose of this article is to examine the mechanism(s) by which UDCA prevents apoptotic cell death associated with cholestasis. In addition, we will also review a potentially novel and, heretofore, unrecognised role of UDCA as a therapeutic agent in the treatment of non-liver diseases associated with increased levels of apoptosis as a pathogenesis of the disorder.     

Ursodeoxycholic and tauro-ursodeoxycholic acids for the treatment of primary biliary cirrhosis: a pilot crossover study

Background: Results from animal studies and preliminary data from pilot studies in patients with primary biliary cirrhosis suggest that tauro-ursodeoxycholic acid has metabolic properties that may favour its long-term use as an alternative to ursodeoxycholic acid for patients with chronic cholestatic liver diseases. No direct comparison of tauro-ursodeoxycholic and ursodeoxycholic acids have yet been carried out in primary biliary cirrhosis.
Methods: The effects of ursodeoxycholic and tauro-ursodeoxycholic acids were compared in 23 patients with primary biliary cirrhosis according to a crossover design. Both drugs were administered at the daily dose of 500 mg, in a randomly assigned sequence for two 6-month periods separated by a 3-month wash-out period.
Results: Serum liver enzymes related to cholestasis and cytolysis consistently improved, as compared to baseline values, during the administration of both ursodeoxycholic and tauro-ursodeoxycholic acids, but no significant difference between these two bile acids was found. Both treatments were well tolerated and no patient complained of side effects.
Conclusion: In the short-term, tauro-ursodeoxycholic acid appears to be safe and at least as effective as ursodeoxycholic acid for the treatment of primary biliary cirrhosis.     

熊去氧胆酸的研究概况

熊去氧胆酸作为胆结石和胆汁淤积性肝硬化等疾病的常用药,具有利胆、保肝、降糖、降脂和免疫调节等重要特性.本文主要对熊去氧胆酸的药理作用、作用机制、临床应用、不良反应等进行了综述,为进一步的药物基础和临床研究提供新思路.     

Current pharmacotherapy for cholestatic liver disease

Importance of the field: The cholestatic liver diseases comprise a heterogeneous group of disorders which, left untreated, usually progresses to cirrhosis and liver failure. Most are recognized before the onset of advanced fibrosis, thereby affording an opportunity for disease modifying therapy.

Areas covered: This review will cover the current pharmacologic management of the most common causes of cholestatic liver disease in adults, including primary biliary cirrhosis, primary biliary cirrhosis-autoimmune hepatitis overlap syndrome, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, intestinal failure-associated liver disease, and immunoglobulin G4-associated cholangitis. Pharmacologic management of complications of cholestasis will also be reviewed.

Expert opinion: Effective therapy for most cholestatic liver disease is lacking. Ursodeoxycholic acid (UDCA) slows the progression of primary biliary cirrhosis but the majority of patients do not have a full response. Even in those with a complete response, UDCA does not cure the disease. There is currently no effective medical therapy for primary sclerosing cholangitis. Symptoms and serum liver biochemistry values in intrahepatic cholestasis of pregnancy are improved with UDCA, but it is not certain if this alters the course of disease. Immunoglobulin G4-associated cholangitis is responsive to steroids but may relapse. The farnesoid X receptor agonists are a promising new class of drugs currently being tested in cholestatic liver disease.     

Methotrexate therapy for the symptomatic treatment of primary biliary cirrhosis patients, who are biochemical incomplete responders to ursodeoxycholic acid therapy

BACKGROUND: Ursodeoxycholic acid is widely used as the standard therapy for the treatment of primary biliary cirrhosis and other cholestatic liver diseases. Although it has been shown to improve biochemical markers and delay disease progression, its effect upon fatigue and pruritus, is at best uncertain. AIM: To assess the safety and efficacy of methotrexate for treating symptomatic primary biliary cirrhosis patients who were biochemical partial responders or non-responders to ursodeoxycholic acid therapy. METHODS: We treated eight consecutive primary biliary cirrhosis patients with methotrexate who were followed in a single hepatology clinical practice, who were symptomatic, and who had had an incomplete biochemical response to ursodeoxycholic acid therapy. Pruritus and fatigue were assessed at each clinic visit and graded from 0 (asymptomatic) to 4 (incapacitating). RESULTS: The median dose of methotrexate was 13.75 mg/week (range 7.5-15) and the mean duration of methotrexate therapy was 49 months (range 11-126). At the end of follow-up pruritus in six of seven patients had improved, and fatigue in all patients had improved with the addition of methotrexate therapy (pruritus: baseline 2.9 +/- 1.1 vs. end of treatment 0.6 +/- 1.5, P < or = 0.0175, and fatigue: baseline 3.0 +/- 0.8, vs. end of treatment 1.0 +/- 0.8, P < or = 0.0023). Improvement in symptoms was associated with a significant improvement in biochemical markers of cholestasis. No significant adverse effects of methotrexate were documented. CONCLUSIONS: Methotrexate should be considered as a potential additive treatment for symptomatic primary biliary cirrhosis patients who are incomplete biochemical responders to ursodeoxycholic acid therapy.     

Pharmacological treatment of biliary cirrhosis with ursodeoxycholic acid

Importance of the field: Primary biliary cirrhosis is a cholestatic liver disease that at one time was the leading indication for liver transplantation. Treatment with ursodeoxycholic acid has clearly improved the natural history of primary biliary cirrhosis.

Areas covered in this review: The treatment of primary biliary cirrhosis with a focus on ursodeoxycholic acid is covered. Papers related to treatment of primary biliary cirrhosis and associated conditions, using a variety of drugs but with a focus on ursodeoxycholic acid, are included. The papers reviewed date from 1984 – 2009.

What will the reader gain: The reader will gain an up-to-date understanding of current treatment strategies for primary biliary cirrhosis using ursodeoxycholic acid and an appreciation of what conditions are improved with this therapy and what associated conditions are not.

Take-home message: Ursodeoxycholic acid in a dose of 13 – 15 mg/kg/day should be considered in all patients with primary biliary cirrhosis who have abnormal liver enzymes.     

Clinical efficacy and effectiveness of ursodeoxycholic acid in cholestatic liver diseases

Ursodeoxycholic acid (UDCA), previously used for cholesterol gallstone dissolution, is currently considered the first choice therapy for many forms of cholestatic syndromes. Many mechanisms and sites of action have been proposed for UDCA, but definitive data are still missing regarding the key points of its efficacy and optimal dosage in order to achieve a sustained clinical effect. Among the suggested mechanisms of action of UDCA, changes in bile acid pool composition, hepatocyte membrane protection, immunomodulatory effects and bicarbonate-rich hypercholeresis have been extensively studied. However, recent evidence indicate that UDCA is a potent intracellular signalling agent that counterbalances impaired biliary secretion, inhibits hepatocyte apoptosis and protects injured cholangiocytes against toxic effects of bile acids. It is clear that the relative contribution of these mechanisms to the anticholestatic action of UDCA depends on the type and stage of the liver injury. Available clinical evidence suggest that UDCA treatment has to be initiated as early as possible and that higher doses could be more efficacious in inducing and maintaining clinical remission of cholestatic diseases. The future availability of UDCA derivatives will possibly enhance the chances to effectively treat chronic cholestatic diseases.     

Effect of ursodeoxycholic acid administration in patients with acute viral hepatitis: a pilot study

BACKGROUND: Ursodeoxycholic acid (UDCA) is able to improve biochemical markers of cholestasis, with a parallel decrease in transaminases, in various cholestatic liver diseases. AIM: To evaluate the effects of UDCA administration on acute viral hepatitis-related cholestasis and the course of acute viral hepatitis. METHODS: Seventy-nine consecutive patients with acute viral hepatitis (HBV: 43, HCV: 11, HAV: 15, HEV: 3, Non A-E: 7) were randomized to receive either UDCA for 3 weeks or no treatment. Liver biochemistry and serum bile acid determinations were run at weekly intervals. RESULTS: No significant differences were observed in mean percentage decreases in transaminases between treated and untreated patients. By contrast, cholestatic indexes decreased significantly more quickly in patients treated with UDCA than in controls, and this effect was more evident in patients with increasing alanine transaminase levels at admission. After a peak at the end of the first week of therapy, serum levels of conjugated ursodeoxycholic acid (CUDCA) showed a gradual decrease. Conjugated cholic acid (CCA) and chenodeoxycholic acid (CCDCA) showed a progressive decrease with the resolution of viral hepatitis, but no influence of UDCA administration was observed. CONCLUSIONS: Our study demonstrates that UDCA significantly improves cholestatic indices in patients with acute viral hepatitis, but this effect does not seem to affect the course of the illness.     

Digestive disease week 2000. American Association for the Study of Liver Diseases

The latest advances in hepatology were presented in oral and poster presentations. In order to cover the varying subspecialties, the sessions were divided into various sections including 'Acute Liver Failure and Artificial Liver Support', 'Biliary Tract and Immunologic Liver Diseases', 'Cellular and Molecular Biology', 'Clinical and Experimental Hepatobiliary Surgery', 'Hepatotoxicity and Cell Death', 'Transport and Biliary Physiology', 'Viral Hepatitis', 'Evaluation and Treatment of Biliary Disease', 'Necrosis/Apoptosis', 'Portal Hypertension', 'Blood Flow and Vascular Disorders of Cirrhosis', 'Liver Transplantation', 'Fibrogenesis', 'Hepatocellular Carcinoma', 'Metabolism and Genetic Disease', and 'Public Policy, Epidemiology and Decision Analysis'. Drug therapy focused on treatments for viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis, and recurrent viral disease following liver transplant. High dose interferon therapy or various combinations of interferon/ribavirin (ICN Pharmaceuticals Inc) therapy seem to offer the best current therapy for chronic HCV. PEGylated interferon (F Hoffmann-La Roche Ltd) offers hope for treatment and histologic improvement in patients with chronic HCV. Following liver transplantation, combination interferon/ribavirin therapy may also find success, but caution with new potent immunosuppressant monoclonal antibodies is advised. For HBV, intramuscular H-BIG (NABI) appears to be effective and less costly than iv H-BIG administration following liver transplantation. Percutaneous radiofrequency ablation may hold promise over conventional ethanol injection therapy for small hepatocellular carcinoma. Autoimmune hepatitis may respond to tacrolimus therapy whereas budesonide therapy did not provide any advantage to prednisone therapy. For primary biliary cirrhosis, eicosapentate and ursodeoxycholic acid may provide benefit to some patients while silymarin from milk thistle did not provide any additional benefit. In primary sclerosing cholangitis, high dose ursodeoxycholic acid may provide benefit. Ursodeoxycholic acid may also provide benefit for mothers with intrahepatic cholestasis of pregnancy by decreasing pruritus, lowering laboratory values and allowing deliveries to occur closer to term.     

Ursodeoxycholic acid induced generalized fixed drug eruption

Fixed drug eruption (FDE) is a rare form of drug allergies that recur at the same cutaneous or mucosal site in every usage of drug. Single or multiple round, sharply demarcated and dusky red plaques appear soon after drug exposure. Ursodeoxycholic acid (UDCA: 3α,7β-dihydroxy-5β-cholanic acid) is used for the treatment of cholestatic liver diseases. Some side effects may be observed, such as diarrhea, dyspepsia, pruritus and headaches. We encountered only three cases of lichenoid reaction regarding the use of UDCA among previous studies. In this article, we reported a generalized FDE case related to UDCA intake in a 59-year-old male patient with cholestasis for the first time in the literature.     

熊去氧胆酸联用思美泰对妊娠期肝内胆汁淤积症患者生化指标及瘙痒程度的影响

目的 分析熊去氧胆酸联用思美泰对妊娠期肝内胆汁淤积症（ICP）患者生化指标及瘙痒程度的影响.方法 选择医院ICP患者129例,随机均分为3组,分别给予熊去氧胆酸、思美泰单用及联合使用,比较其肝脏相关生化指标、瘙痒评分及缓解时间、妊娠结局等情况.结果 联合用药组患者治疗后丙氨酸氨基转移酶（46.12±14.25）U/L,天门冬酸氨基转移酶（43.18±11.25）U/L,总胆汁酸（12.04±4.92）μmol/L,总胆红素（13.29±3.84）μmol/L,平均瘙痒评分（2.01±0.54）分,平均瘙痒缓解时间（3.13±0.74）d,妊娠不良结局发生率2.33％,均明显低于对照组;联合用药组的平均结束妊娠孕周（37.04±1.23）周,明显长于单独用药组（P＜0.05）.结论 熊去氧胆酸联用思美泰可有效改善ICP患者的肝功能指标,缓解瘙痒程度,改善妊娠结局,具有积极的临床意义.     

熊去氧胆酸治疗早产儿胃肠外营养相关性胆汁淤积症的疗效及对患儿血清内毒素水平的影响

目的： 探讨熊去氧胆酸治疗早产儿胃肠外营养相关性胆汁淤积症的疗效及对患儿血清内毒素水平的影响。方法： 选自2013年1月—2015年12月期间我院收治的胃肠外营养相关性胆汁淤积症早产儿64例,依据随机数字表法随机分为观察组32例与对照组32例。对照组采取常规对症治疗,观察组在对照组基础上结合熊去氧胆酸胶囊。两组疗程均为2周。比较两组患儿肝功能指标水平变化,以及不良反应发生情况。结果： 两组血清TB、ALT、AST水平治疗前比较无统计学差异（P>0.05）;两组血清TB、ALT、AST水平治疗后明显降低（P<0.05）;观察组血清TB、ALT、AST水平治疗后低于对照组（P<0.05）;两组血清内毒素水平治疗前比较无统计学差异（P>0.05）;两组血清内毒素水平治疗后明显降低（P<0.05）;观察组血清内毒素水平治疗后低于对照组（P<0.05）;两组不良反应发生率比较无统计学差异（P>0.05）。结论： 熊去氧胆酸治疗早产儿胃肠外营养相关性胆汁淤积症的效果明显,可明显改善患儿肝功能,降低血清内毒素水平,具有重要临床研究价值。     

Modulation of hepatocyte apoptosis: cross-talk between bile acids and nuclear steroid receptors

The efficient removal of unwanted cells, such as senescent, damaged, mutated or infected cells is crucial for the maintenance of normal liver function. In fact, apoptosis has emerged as a potential contributor to the pathogenesis of a number of hepatic disorders, such as viral hepatitis, autoimmune diseases, ethanol-induced injury, cholestasis, and hepatocellular carcinoma. In contrast to the effect of cytotoxic bile acids in the liver, ursodeoxycholic acid (UDCA) has increasingly been used for the treatment of various liver disorders. The clinical efficacy of this hydrophilic bile acid was first recognized by its use in traditional Asian medicine. However, many studies have subsequently confirmed that UDCA improves liver function by three major mechanisms of action, including protection of cholangiocytes against the cytotoxicity of hydrophobic bile acids, stimulation of hepatobiliary secretion, and inhibition of liver cell apoptosis. UDCA acts as a potent inhibitor of the classical mitochondrial pathway of apoptosis, but also interferes with alternate and upstream molecular targets such as the E2F-1/p53 pathway. Together, there is growing evidence that this hydrophilic bile acid may modulate gene expression to prevent cell death. Curiously, as a cholesterol-derived molecule, UDCA interacts with nuclear steroid receptors, such as the glucocorticoid receptor. Nuclear steroid receptors play crucial roles in mediating steroid hormone signaling involved in many biological processes, including apoptosis. Here, we review the anti-apoptotic mechanisms of UDCA in hepatic cells, and discuss a potential involvement of nuclear steroid receptors in mediating the survival effects of UDCA.     

Farnesoid X receptor modulators (2011 – 2014): a patent review

Introduction: Farnesoid-X-receptor (FXR) is the receptor for primary bile acids expressed in enterohepatic tissues where it regulates bile acid uptake, metabolism and disposal. For its role as a bile acid sensor, FXR has been thought to be an important target in the treatment of cholestatic disorders, a family of diseases in which endogenous bile acids accumulate in the body. Cholestasis might occur as a consequence of inborn metabolic errors and three major disorders, intra-hepatic cholestasis in pregnancy, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis account for the vast majority of clinical cholestasis occurring in adulthood. In addition, FXR agonists are gaining attention as potential regulators of lipid and glucose metabolism and therefore as new therapeutical approaches to the treatment of fatty liver disease, type 2 diabetes and obesity.

Areas covered: New chemical entities as FXR modulators and their in vitro and in vivo efficacy are reviewed with particular focus on patents and peer-reviewed publications in the period 2011 – 2014.

Expert opinion: FXR agonists have shown robust therapeutic potential and results from clinical trials have supported their use in the treatment of liver disorders including PBC and fatty liver disease despite side effects.     

Clinical trial: modulation of human placental multidrug resistance proteins in cholestasis of pregnancy by ursodeoxycholic acid

BACKGROUND: The effects of ursodeoxycholic acid on human placental bile acids and bilirubin transporters in intrahepatic cholestasis of pregnancy are still undefined. AIM: To evaluate whether ursodeoxycholic acid affects MRP2, MRP3 and MRP4 expression in the placenta. MATERIALS AND METHODS: Forty-three pregnant women were enrolled; fourteen subjects had physiological pregnancies. Intrahepatic cholestasis of pregnancy patients were divided into two groups: (i) 13 received ursodeoxycholic acid (20 mg/kg/day) and (ii) 16 untreated. Total bile acid and bilirubin in serum and cord blood were determined in each subject. Multidrug resistance proteins expression (immunoblot, quantitative real-time PCR) was evaluated in placentas collected at delivery. anova test was used for statistical analysis of data. RESULTS: Ursodeoxycholic acid administration significantly improved maternal serum bile acid and cord blood bilirubin and bile acid levels. MRP2 protein and RNA expression was significantly increased in placentas from treated patients compared to controls (P < 0.001 and P < 0.01, respectively). MRP3 protein expression was not significantly different between the groups while RNA expression was significantly decreased in treated patients (P < 0.01). MRP4 did not show significant differences between the groups. CONCLUSIONS: Ursodeoxycholic acid administration induces placental MRP2 expression, and reduces bilirubin and bile acid levels in cord blood.