Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

Stojaković, Tatjana; Putz-Bankuti, Csilla; Fauler, Günter; Scharnagl, Hubert; Wagner, Martin; Stadlbauer, Vanessa; Gurakuqi, Gerald; Stauber, Rudolf; März, Winfried; Trauner, Michael

doi:10.1002/hep.21741

Cited by 79 publications

(49 citation statements)

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“…In addition, statins activate pregnane X receptor (PXR), which induces bile detoxification and alternative export [53]. Unfortunately, atorvatstatin did not improve cholestasis in patients with PBC who had an incomplete biochemical response to UDCA [54]. Ligands for the nuclear bile acid/farnesoid X receptor (FXR) target multiple genes involved in bile formation, inflammation and fibrosis and have already entered phase II clinical trials in North America and Europe [51,52].…”

Section: Potential Therapeutic Implicationsmentioning

confidence: 98%

Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases

Trauner

Fickert

Halilbasic

et al. 2008

Wien Med Wochenschr

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101

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Alterations in bile secretion at the hepatocellular and cholangiocellular levels may cause cholestasis. Formation of 'toxic bile' may be the consequence of abnormal bile composition and can result in hepatocellular and/or bile duct injury. The canalicular phospholipid flippase (Mdr2/MDR3) normally mediates biliary excretion of phospholipids, which normally form mixed micelles with bile acids and cholesterol to protect the bile duct epithelium from the detergent properties of bile acids. Mdr2 knockout mice are not capable of excreting phospholipids into bile and spontaneously develop bile duct injury with macroscopic and microscopic features closely resembling human sclerosing cholangitis. MDR3 mutations have been linked to a broad spectrum of hepatobiliary disorders in humans ranging from progressive familial intrahepatic cholestasis in neonates to intrahepatic cholestasis of pregnancy, drug-induced cholestasis, intrahepatic cholelithiasis, sclerosing cholangitis and biliary cirrhosis in adults. Other examples for bile injury due to the formation of toxic bile include the cholangiopathy seen in cystic fibrosis, after lithocholate feeding (in mice) and vanishing bile duct syndromes induced by drugs and xenobiotics. Therapeutic strategies for cholangiopathies may target bile composition/toxicity and the affected bile duct epithelium itself, and ideally should also have anti-cholestatic, anti-fibrotic and anti-neoplastic properties. Ursodeoxycholic acid (UDCA) shows some of these properties, but is of limited efficacy in the treatment of human cholangiopathies. By contrast to UDCA, its side chain-shortened homologue norUDCA undergoes cholehepatic shunting leading to a bicarbonate-rich hypercholeresis. Moreover, norUDCA has anti-inflammatory, anti-fibrotic and anti-proliferative effects, and stimulates bile acid detoxification. Upcoming clinical trials will have to demonstrate whether norUDCA or other side chain-modified bile acids are also clinically effective in humans. Finally, drugs for the treatment of cholangiopathies may target bile toxicity via nuclear receptors (FXR, PPARalpha) regulating biliary phospholipid and bile acid excretion.

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Section: Potential Therapeutic Implicationsmentioning

confidence: 98%

Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases

Trauner

Fickert

Halilbasic

et al. 2008

Wien Med Wochenschr

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101

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“…Many of these findings, however, are from experimental animal models that not fully recreate human diseases, thus expectations are yet to be verified [98]. Activation of PXR (that shares similar functions with FXR) resulted not effective in ameliorating cholestatic injury in patients with primary biliary cirrhosis [109]. Activation of FXR by the synthetic agonist GW4064 reduced neutral lipid accumulation in the livers of db/db mice [106].…”

Section: Farnesoid X Receptor (Fxr) Lipid Metabolism and Chronic Livmentioning

confidence: 99%

From the metabolic syndrome to NAFLD or vice versa?

Vanni

Bugianesi

Kotronen

et al. 2010

Digestive and Liver Disease

437

351

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The metabolic syndrome encompasses metabolic and cardiovascular risk factors which predict diabetes and cardiovascular disease (CVD) better than any of its individual components. Nonalcoholic fatty liver disease (NAFLD) comprises a disease spectrum which includes variable degrees of simple steatosis (nonalcoholic fatty liver, NAFL), nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is the hepatic manifestation of the metabolic syndrome, with insulin resistance as the main pathogenetic mechanism. Recent data indicate that hyperinsulinemia is probably the consequence rather than cause of NAFLD and NAFLD can be considered an independent predictor of cardiovascular disease. Serum free fatty acids derived from lipolysis of visceral adipose tissue are the main source of hepatic triglycerides in NAFLD, although hepatic de novo lipogenesis and dietary fat supply contribute to the pathogenesis of NAFLD. Approximately 10-25% NAFLD patients develop NASH, the evolutive form of hepatic steatosis. Presumably in a genetically predisposed environment, this increased lipid overload overwhelms the oxidative capacity and reactive oxygen species are generated, leading to lipid peroxidation, cytokine induction, chemoattraction of inflammatory cells, hepatic stellate cell activation and finally fibrogenesis with extracellular matrix deposition. No currently available therapies for NAFLD and NASH exist. Recently nuclear receptors have emerged as key regulators of lipid and carbohydrate metabolism for which specific pharmacological ligands are available, making them attractive therapeutic targets for NAFLD and NASH.Abbreviations ALT, alanine aminotransferase; BMI, body mass index; CVD, cardiovascular disease; FFA, free fatty acids; HDL, high density lipoprotein; 1H-MRS, proton magnetic resonance spectroscopy; IDF, International Diabetes Federation; LDL, low density lipoprotein; NAFLD, nonalcoholic fatty liver disease; SNP, single nucleotide polymorphism; VLDL, very low density lipoprotein IntroductionThe metabolic syndrome is a cluster of metabolic and cardiovascular risk factors which predicts diabetes and cardiovascular disease (CVD) better than any of its individual components [1]. The latest definition of the metabolic syndrome by International Diabetes Federation (IDF) includes abdominal obesity defined by increased waist circumference (≥94 cm in men and ≥80 cm in women) and two or more of the following features: elevated blood pressure, fasting glucose or triglyceride concentrations, or low HDL cholesterol [1]. The term nonalcoholic fatty liver disease (NAFLD) comprises a disease spectrum which includes variable degrees of simple steatosis (nonalcoholic fatty liver, NAFL), nonalcoholic steatohepatitis (NASH) and cirrhosis [2] and [3]. NAFLD can be considered the hepatic manifestation of the metabolic syndrome. Simple steatosis is benign, whereas NASH is defined by the presence of hepatocyte injury, inflammation and/or fibrosis which can lead to cirrhosis, liver failure and hepatocellular carcinoma. In contrast to t...

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“…Plasma total cholesterol and triglycerides were determined enzymatically (26). Cholestanol, campesterol, sitosterol, and lathosterol were quantified in plasma using a recently published gas chromatography and mass spectrometry (GCMS)-based method (29).…”

Section: Laboratory Proceduresmentioning

confidence: 99%

The relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease

Silbernagel

Fauler

Renner

et al. 2009

Journal of Lipid Research

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Changes in the balance of cholesterol absorption and synthesis and moderately elevated plasma plant sterols have been suggested to be atherogenic. Measuring cholestanol, lathosterol, campesterol, and sitosterol, we investigated the relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease (CAD) in 2,440 participants of the Ludwigshafen Risk and Cardiovascular health (LURIC) study. The coronary status was determined by angiography, and the severity of CAD was assessed by the Friesinger Score (FS). An increase in the ratio of cholestanol to cholesterol was associated with high FS (P 5 0.006). In contrast, a high ratio of lathosterol to cholesterol went in parallel with low FS (P , 0.001). Whereas the campesterol to cholesterol ratio significantly correlated with the FS (P 5 0.026), the relationship of the sitosterol to cholesterol ratio with the FS did not reach statistical significance in the whole group. Increased campesterol, sitosterol, and cholestanol to lathosterol ratios were associated high FS (P , 0.001). To conclude, there is a modest association of high cholesterol absorption and low cholesterol synthesis with an increased severity of CAD. An atherogenic role of plasma plant sterols themselves, however, seems unlikely in subjects without sitosterolaemia.-Silbernagel, G., G.

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Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

Cited by 79 publications

References 50 publications

Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases

Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases

From the metabolic syndrome to NAFLD or vice versa?

The relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease

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