Ursodeoxycholic acid protects against secondary biliary cirrhosis in rats by preventing mitochondrial oxidative stress

Ursodeoxycholic acid (UDCA) improves clinical and biochemical indices in primary biliary cirrhosis and prolongs survival free of liver transplantation. Recently, it was suggested that the cytoprotective mechanisms of UDCA may be mediated by protection against oxidative stress, which is involved in the development of cirrhosis induced by chronic cholestasis. The aims of the current study were 1) to identify the mechanisms involved in glutathione depletion, oxidative stress, and mitochondrial impairment during biliary cirrhosis induced by chronic cholestasis in rats; and 2) to determine the mechanisms associated with the protective effects of UDCA against secondary biliary cirrhosis. The findings of the current study indicate that UDCA partially prevents hepatic and mitochondrial glutathione depletion and oxidation resulting from chronic cholestasis. Impairment of biliary excretion was accompanied by decreased steady-state hepatic levels of gamma-glutamyl cysteine synthetase and gamma-cystathionase messenger RNAs. UDCA treatment led to up-regulation of gamma-glutamyl cysteine synthetase in animals with secondary biliary cirrhosis and prevented the marked increases in mitochondrial peroxide production and hydroxynonenal-protein adduct production that are observed during chronic cholestasis. A population of damaged and primarily apoptotic hepatocytes characterized by dramatic decreases in mitochondrial cardiolipin levels and membrane potential as well as phosphatidylserine exposure evolves in secondary biliary cirrhosis. UDCA treatment prevents the growth of this population along with the decreases in mitochondrial cardiolipin levels and membrane potential that are induced by chronic cholestasis. In conclusion, UDCA treatment enhances the antioxidant defense mediated by glutathione; in doing so, this treatment prevents cardiolipin depletion and cell injury in animals with secondary biliary cirrhosis.     

Treatment of cholestatic liver diseases; the role of ursodeoxycholic acid]

Ursodeoxycholic acid (UDCA) allows symptomatic treatment of cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, intrahepatic biliary atresia, and cholestasis of cystic fibrosis. Patients should be treated at an early stage of the disease in order to prevent progression to cirrhosis. Since UDCA has no toxic effects longterm treatment with this substance is possible without the risk of undesired side effects. In patients with primary biliary cirrhosis and rapid progression of the disease, UDCA may be combined with an immunosuppressive substance (i.e. cyclosporin). In primary sclerosing cholangitis, biliary atresia and cholestasis of cystic fibrosis, UDCA at present seems the only treatment of which a benefit for the patients can be expected. In endstage disease liver transplantation is indicated. The role of UDCA in chronic hepatitis and alcohol induced liver disease needs to be clarified in further studies. Whether the improvement of laboratory tests in such patients indicates amelioration of the course of disease, still is unclear.     

Use of ursodeoxycholic acid in patients with liver disease

Ursodeoxycholic acid (UDCA), the 7β-epimer of chenodeoxycholic acid, has multiple hepatoprotective activities. UDCA modifies the bile acid pool, decreasing levels of endogenous, hydrophobic bile acids while increasing the proportion of nontoxic hydrophilic bile acids. UDCA has a choleretic effect, increasing hepatocellular bile acid excretion, as well as cytoprotective, antiapoptotic, and immunomodulatory properties. UDCA has been shown to delay development of gastroesophageal varices and progression to cirrhosis as well as to improve long-term survival in patients with primary biliary cirrhosis. Significant improvement of abnormal liver tests may be achieved during UDCA therapy in patients with primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, cystic fibrosis-associated liver disease, nonalcoholic fatty liver disease, graft-versus-host disease of the liver, total parenteral nutrition-induced cholestasis, and in some pediatric cholestatic liver diseases. However, unlike the effecs of UDCA in primary biliary cirrhosis, the long-term effects of UDCA in disease progression and survival in these other conditions remain to be established.     

Latest and Emerging Therapies for Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the two most common causes of chronic cholestatic liver disease in adults. In PBC, therapy with ursodeoxycholic acid (UDCA) is safe and has been associated with tangible biochemical, histologic, and survival benefits. However, a need for different or adjuvant therapies remains for specific subsets of PBC patients, including those who do not respond to UDCA and those who have advanced histologic disease at presentation. Similarly, beneficial therapies for disease-related symptoms that do not typically respond to UDCA (eg, fatigue and pruritus) are still needed. In contrast to PBC, no medical therapy of proven benefit has been identified for patients with PSC. In PBC and PSC, adequate management of complications of chronic cholestasis is important. For both diseases, liver transplantation is the only curative option.     

Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited

Ursodeoxycholic acid (UCDA) is increasingly used for the treatment of cholestatic liver diseases. Experimental evidence suggests three major mechanisms of action: (1) protection of cholangiocytes against cytotoxicity of hydrophobic bile acids, resulting from modulation of the composition of mixed phospholipid-rich micelles, reduction of bile acid cytotoxicity of bile and, possibly, decrease of the concentration of hydrophobic bile acids in the cholangiocytes; (2) stimulation of hepatobiliary secretion, putatively via Ca(2+)- and protein kinase C-alpha-dependent mechanisms and/or activation of p38(MAPK) and extracellular signal-regulated kinases (Erk) resulting in insertion of transporter molecules (e.g., bile salt export pump, BSEP, and conjugate export pump, MRP2) into the canalicular membrane of the hepatocyte and, possibly, activation of inserted carriers; (3) protection of hepatocytes against bile acid-induced apoptosis, involving inhibition of mitochondrial membrane permeability transition (MMPT), and possibly, stimulation of a survival pathway. In primary biliary cirrhosis, UDCA (13-15 mg/kg/d) improves serum liver chemistries, may delay disease progression to severe fibrosis or cirrhosis, and may prolong transplant-free survival. In primary sclerosing cholangitis, UDCA (13-20 mg/kg/d) improves serum liver chemistries and surrogate markers of prognosis, but effects on disease progression must be further evaluated. Anticholestatic effects of UDCA have also been reported in intrahepatic cholestasis of pregnancy, liver disease of cystic fibrosis, progressive familial intrahepatic cholestasis, and chronic graft-versus-host disease. Future efforts will focus on definition of additional clinical uses of UDCA, on optimized dosage regimens, as well as on further elucidation of mechanisms of action of UDCA at the molecular level.     

The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: A prospective, multicenter study.

Aim: Treatment with ursodeoxycholic acid (UDCA) improves the survival of stage I and II primary biliary cirrhosis (PBC) patients. However, new therapeutic options are needed for patients who are refractory to UDCA and for those whose disease is at an advanced stage. Bezafibrate could be useful in PBC treatment, since it increases phospholipid output into the bile and reduces the cytotoxicity of hydrophobic bile acids, which are increased with cholestasis. Methods: We conducted two prospective, multicenter randomized open studies in non-cirrhotic patients with PBC to evaluate the efficacy of bezafibrate. One study compared UDCA and bezafibrate monotherapy (study 1: 45 patients [37 females], mean age 55.9 years), and the other evaluated the addition of bezafibrate to patients who were refractory to UDCA (study 2: 21 patients [18 females], mean age 54.1 years). Results: Study 1 demonstrated that bezafibrate monotherapy was as effective as UDCA and study 2 revealed that bezafibrate combined with UDCA was effective in improving and maintaining biliary enzymes where the ineffectiveness of long-term treatment with UDCA was confirmed. Conclusion: This multicenter, randomized, open study revealed that combination therapy of bezafibrate and UDCA improved biliary enzymes in non-cirrhotic Japanese patients with PBC refractory to UDCA. Further studies are needed to evaluate whether combination therapy improves histological staging and prognosis.     

Mechanism of hepatoprotective action of bile salts in liver disease

Ursodeoxycholic acid (UDCA) improves liver enzymes and in many instances liver histology in cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis. Besides classic cholestatic diseases, UDCA also improves liver biochemistry in alcoholic liver disease and in chronic viral hepatitis C. The main target of UDCA treatment, however, is cholestasis, and consequently the mechanisms responsible for the beneficial effects in these diseases are of interest, and are discussed in detail in this article.     

Treatment of primary sclerosing cholangitis

Opinion statement Aims of treatment for primary sclerosing cholangitis are as follows: prevention of progression of hepatobiliary disease, reduction of symptoms and consequences of cholestasis (pruritus, osteoporosis), and prevention of complications (colorectal cancer, hepatobiliary cancer). Ursodeoxycholic acid (UDCA) improves biliary secretion and laboratory parameters of cholestasis, but its effects on liver histology and survival are not clear. It reduces the incidence of dysplasias and carcinomas of the colon in patients with colitis and possibly has a beneficial effect on the incidence of bile duct carcinomas. At present, UDCA represents the most promising therapeutic option. Immunosuppressive treatment has not been proven to be effective; it appears to be indicated in the overlap syndrome with autoimmune hepatitis but may be harmful in bacterial cholangitis. Bacterial cholangitis is common in patients with dominant stenoses and requires antibiotic treatment. Endoscopic treatment of dominant stenoses improves cholestasis and prolongs survival in comparison to predicted survival. Pruritus represents a problem in some patients, and cholestyramine represents the first-line treatment. If ineffective, opioid antagonists, rifampin, or ondansetron may be tried. For treatment of osteoporosis and osteopenia, calcium and vitamin D supplementation are recommended, and in selected cases, bisphosphonates may be indicated. In patients with severe cholestasis and coagulation defects, parenteral supplementation of vitamin K may be indicated. During treatment, all patients should be regularly screened for colonic and bile duct carcinomas. Patients with cirrhosis of the liver and its complications are treated accordingly, and in end-stage disease, liver transplantation is indicated.     

Review: Treatment of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a slowly progressive chronic cholestatic disease of the liver thought to be caused by immune destruction of the interlobular bile ducts. One-third of patients are asymptomatic and one-third of these develop symptoms within 5 years. Therapeutic regimens should be directed at the control of symptoms, prevention of complications and specific therapy aimed at controlling progression of the disease. Symptoms may be secondary to cholestasis or due to other associated diseases. The cause of pruritus secondary to cholestasis remains unknown; the anion exchange resin cholestyramine generally brings relief. In patients resistant or intolerant to this therapy, rifampin may be helpful, as well as ultraviolet light without sunblock. Liver transplantation may rarely be the only option for uncontrollable pruritus. Clinical manifestations of keratoconjunctivitis sicca and xerostomia need constant attention to prevent corneal ulcers and dental caries. Preventative therapy includes regular screening for thyroid dysfunction and replacement therapy when necessary and the administration of the fat soluble vitamins A, D and K once hyperbilirubinaemia is present. Osteoporosis is a complication of all cholestatic liver disease. There is no satisfactory preventative therapy. It may be appropriate to give hormone replacement therapy to all post-menopausal women with PBC to reduce osteoporosis. Liver transplantation is the best option for those with fractures. Oesophageal varices may develop early in the course of PBC, non-selective beta-blocker therapy should be used as prophylaxis against variceal haemorrhage. The only specific therapy shown to cause both a biochemical and survival benefit in patients with PBC is ursodeoxycholic acid (UDCA). Treatment with UDCA delays progression, but does not result in a cure of this disease. Currently, liver transplantation is the only definitive treatment available for end-stage disease.     

Treatment of primary biliary cirrhosis: therapy with choleretic and immunosuppressive agents

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of presumed autoimmune etiology affecting predominantly middle-aged women; it is a slowly progressive disease causing loss of intrahepatic bile ducts, resulting in advanced fibrosis, cirrhosis, and liver failure. Many drugs have been studied for treatment, including agents with choleretic and immunosuppressive properties. Ursodeoxycholic acid (UDCA) has been evaluated most widely. After liver failure, the only effective treatment is liver transplantation. Effective therapy reduces the need for transplantation and improves life expectancy. For advanced liver disease or incomplete response to UDCA, new therapies to cure or retard the progression of disease in PBC are needed.     

Proposed therapies in primary biliary cholangitis

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a model autoimmune disease with chronic cholestasis characterized by the hallmark of anti-mitochondrial antibodies and treated with ursodeoxycholic acid (UDCA). However, approximately 20-40% of patients incompletely respond to UDCA and have an increased risk of disease progression. Although there have been significant advances in the immunobiology of PBC, these have yet to be translated into newer therapeutic modalities. Current approaches to controlling the immune response include broad immunosuppression with corticosteroids as well as targeted therapies directed against T and B cells. In contrast, ameliorating cholestasis is the focus of other therapies in development, including obeticholic acid. In this article the authors will discuss ongoing clinical trials and, in particular, the rationale for choosing agents that may effectively target the aberrant immune response.     

Treatment of primary biliary cirrhosis.

Although primary biliary cirrhosis (PBC) is generally a progressive disease, the rate of progression varies greatly from one patient to another. The terminal phase is characterized by hyperbilirubinaemia (>100 micromol/l), a major decrease in the number of intrahepatic bile ducts, and extensive fibrosis or cirrhosis. It is now well established that orthotopic liver transplantation is the treatment of choice for patients entering the terminal phase of the disease.A variety of therapeutic agents have been proposed for treatment of patients with PBC. However, most have been found ineffective or too toxic to be widely used. In contrast, there is accumulating evidence from large therapeutic trials that long-term administration of ursodeoxycholic acid (UDCA) is safe and prolongs survival free of liver transplantation. Treatment with UDCA slows the histological progression and delays the onset of cirrhosis.In patients who have a sub-optimal response to UDCA therapy alone, the combination of colchicine or methotrexate with UDCA has minimal or no additional benefit, whereas that with corticosteroids is more promising but not yet demonstrated.Among causes of non-response to UDCA therapy, the most common is the PBC-autoimmune hepatitis overlap syndrome. The benefit from the combination of corticosteroids and UDCA in this setting is obvious.Further studies are needed to define the patients who are most likely to respond to UDCA therapy and to assess the benefit of combined medical treatments.     

Chronic intrahepatic cholestasis of sarcoidosis.

The development of the syndrome of chronic intrahepatic cholestasis in five young, black men who had systemic granulomatous disease and clinical features consistent with those of sarcoidosis is described. Clinical and biochemical aspects, similar to those of primary biliary cirrhosis, included pruritus, jaundice, hepatomegaly and striking elevations of serum levels of alkaline phosphatase and cholesterol. (One patient had skin xanthomas.) Mitochondrial antibodies were not found; and survival of the patients (7 to 18 years) exceeded the usual survival of patients with primary biliary cirrhosis. The histologic abnormalities included noncaseating granulomas, chronic intrahepatic cholestasis, increased copper in hepatocytes, progressive diminution in number of interiobular bile ducts, periportal fibrosis and the eventual development of a micronodular "biliary" cirrhosis. The histologic evolution of the disease suggests a slow, progressive destruction of the bile ducts by granulomas. Although the end stage of this syndrome resembles primary biliary cirrhosis, the characteristic nonsuppurative, destructive cholangitis of primary biliary cirrhosis was not present.     

原发性胆汁性肝硬化的治疗进展

原发性胆汁性肝硬化（PBC）是一种慢性肝内胆汁淤积性疾病。熊去氧胆酸（UDCA）是惟一经随机对照临床试验证实的治疗PBC安全有效的药物。经UDCA治疗1年后有较好生化应答的患者,其长期预后较好。目前,对UDCA应答欠佳患者的治疗方法尚不确定。肝移植是治疗终末期PBC患者惟一有效的方法     

Tamoxifen: a novel treatment for primary biliary cirrhosis?

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease, which predominantly affects women. It is characterised histologically by necroinflammation of small intrahepatic bile ducts and biochemically by elevated serum alkaline phosphatase, levels of which at diagnosis predict survival. Ursodeoxycholic acid (UDCA) is the only treatment shown to improve liver biochemistry and survival. We report two patients with PBC who show a fall in serum alkaline phosphates levels whilst receiving tamoxifen therapy. Tamoxifen may exert this effect, which warrants further study, either via cholangiocyte estrogen receptors, inhibiting cholangiocyte proliferation and inducing apoptosis or by activating pregnane X receptor, analogous to the mode of action of UDCA.     

Medical treatment of primary biliary cirrhosis and primary sclerosing cholangitis.

Treatment of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) with ursodeoxycholic acid (UDCA) has been in common use since 1985. In PBC, treatment with UDCA improves laboratory data, liver histology, enables a longer transplantation-free interval and prolongs disease survival. Because UDCA is unable to cure the disease newer drugs or combination therapies are still needed. Studies with UDCA and immunosuppressants such as prednisone, budesonide and azathioprine have shown that in selected patients combination therapy may be superior to UDCA monotherapy. PSC is treated successfully with UDCA and endoscopic dilatation of the bile duct strictures. Treatment of extrahepatic manifestations of cholestatic liver disease such as pruritus, fatigue, osteoporosis and steatorrhea can be problematic and time-consuming.     

The natural history of PBC: has it changed?

The prognosis and natural history of primary biliary cirrhosis (PBC) have improved significantly during the last few decades. Patients are diagnosed at earlier stages, are more likely to be asymptomatic at diagnosis, and are more likely to receive medical treatment. The survival of asymptomatic patients is longer than the median survival of symptomatic patients. The natural history of PBC has been assessed in the presence of effective therapy, ursodeoxycholic acid (UDCA). Evidence suggests that UDCA delays histological progression in PBC and decreases the risk of development of esophageal varices. Survival of UDCA-treated patients is better than that of untreated patients and also is better than that predicted by the Mayo model. For patients in early stages of PBC, UDCA treatment may normalize survival. However, patients with stage III and IV PBC do not respond as well to UDCA. Therefore, there is a continued need for additional treatment in patients with advanced disease.     

3rd place in the competition of scientific work in hepatology in 2010. Treatment of patients with overlap of primary biliary cirrhosis and autoimmune hepatitis

This paper analyzes the results of different treatments overlap (OS) of primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH): ursodeoxycholic acid monotherapy (UDCA) monotherapy with prednisolone (PD), the combination of PD with UDCA. Results of treatment of 16 OS patients with glucocorticoid last generation--budesonide (BS) in combination with UDCA. The treatment results were estimated in reducing severity of intrahepatic cholestasis (IHC), proposed by the author, as well as the degree of reduction of the biochemical activity of enzymes. Evaluated the quality of life by SF-36 questionnaire. In addition, the efficacy of budesonide in combination with UDCA was assessed by morphological examination of liver tissue in the dynamics after 6 months of treatment. The paper convincingly demonstrate that combination therapy OS is more effective in monotherapy reducing clinical and biochemical disease activity, as well as positive effects on quality of life. The advantages of the use of budesonide in combination with UDCA prior systemic glucocorticoids: a high efficiency and low risk of side effects.     

A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cirrhosis: ten-year results

Primary biliary cirrhosis frequently progresses despite treatment with ursodeoxycholic acid (UDCA), the only approved therapy. Previous studies suggested that colchicine and methotrexate may improve biochemical tests of liver function, symptoms, and liver histology. The aim of the present study was to determine if the addition of colchicine or methotrexate to UDCA would improve survival free of liver transplantation. Eighty-five patients with histologically confirmed primary biliary cirrhosis whose serum alkaline phosphatase levels were at least twice the normal level and who were not yet candidates for liver transplantation were randomly assigned to receive colchicine or methotrexate in a double-blind study. UDCA was administered to all patients after 2 years. The primary end point was survival free of liver transplantation. Patients were followed up for a total of up to 10 years or until treatment failure. Data were analyzed on an intention-to-treat basis. Transplant-free survival was similar in both groups: 0.57 for colchicine plus UDCA and 0.44 for methotrexate plus UDCA, results that are similar to those predicted by the Mayo prognostic model. Significant improvement in liver biochemical tests and liver histology was observed in a subset of patients in both treatment groups who remained in the study for all 10 years. In conclusion, neither colchcine plus UDCA nor methotrexate plus UDCA improved survival beyond that predicted by the Mayo prognostic model. However, clinical, histologic, and biochemical improvement observed among those who remained in the study for 10 years suggests a possible benefit of these drugs in a subset of patients.     

Ileal absorption of bile acids in patients with chronic cholestasis

The effect of cholestasis on ileal bile acid absorption is controversial in animal models (up-or down-regulation) and unknown in humans. We therefore studied values of the selena homotaurocholic acid (SeHCAT) test before and after long-term administration (>3 months, 13–15 mg/kg/day) of ursodeoxycholic acid (UDCA) in 27 patients with chronic cholestatic liver diseases (24 women, 3 men; mean age, 50 years; 24 primary biliary cirrhosis, 2 secondary biliary cirrhosis, 2 others). The control group consisted of 14 healthy volunteers. Seven-day SeHCAT percentage retention was identical in the 12 untreated cholestatic patients (serum bilirubin, 75 ± 42 µmol/L, alkaline phosphatase, 4.2 ± 1.0N; mean ± SEM) and in the control group (43.6 ± 2.9 and 43.8 ± 4.2%, respectively). In the 22 patients treated by UDCA for 38 ± 8 months, SeHCAT percentage retention was 20.3 ± 3.0%. In the seven patients with the SeHCAT test done before and after UDCA treatment (16 ± 5 months), SeHCAT percentage retention decreased significantly under UDCA therapy (42.0 ± 4.4 vs 19.4 ± 4.1%; P < 0.02). We conclude that, in patients with chronic cholestasis (1) SeHCAT percentage retention is not altered—taken together with the known defect of biliary excretion, this lack of increase in SeHCAT percentage retention argues against up-regulation of bile acid ileal transport; and (2) UDCA treatment induces a decrease in the SeHCAT percentage retention—this effect may be related primarily to a decreased bile acid ileal absorption.