scholarly journals Novel Aspects in the Management of Cholestatic Liver Diseases

2016 ◽  
Vol 34 (4) ◽  
pp. 340-346 ◽  
Author(s):  
Olivier Chazouillères
Keyword(s):  
Clinical Evaluation ◽  
Liver Diseases ◽  
Transient Elastography ◽  
Liver Stiffness ◽  
Pregnane X Receptor ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Biliary Cirrhosis ◽  
Bile Formation ◽  
Personalized Care

Background: There is a great need for risk stratification in patients with chronic cholestatic diseases in order to allow for more personalized care and adapted management as well as for well-designed therapeutic trials. Novel tools for monitoring primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) patients have been recently proposed. In addition, major insight has been gained into bile acid (BA) physiology during the last decade including the role of BAs as metabolic modulators and the gut-liver axis. As a consequence, alongside drugs targeting immune response or fibrotic processes, a number of novel anti-cholestatic agents have undergone pre-clinical and clinical evaluation and have shown promising results although none has been approved yet. Key Messages: Biochemical non-response to ursodeoxycholic acid (UDCA) (mainly defined by bilirubin and alkaline phosphatase levels at 1 year) is a strong prognostic factor in PBC whereas present biochemical surrogates are far from robust in PSC. By contrast, liver stiffness measurement by vibration-controlled transient elastography (VCTE) is a very promising tool in both PBC and PSC. Novel therapeutic approaches include (i) agonists of nuclear receptors, especially farnesoid X receptor (FXR), pregnane X receptor (PXR), glucocorticoid receptor (GR) and peroxisome proliferator-activated receptor α (PPARα) that are transcriptional modifiers of bile formation; (ii) agonists of TGR5, a BA membrane receptor expressed in various tissues; (iii) inhibitors of the ileal apical sodium BA transporter; (iv) derivatives of the FXR-induced fibroblast growth factor 19 from the ileum that suppresses hepatic BA synthesis and (v) norUDCA, a side chain shortened UDCA derivative with specific physicochemical and therapeutic properties. The most advanced clinical evaluation (PBC patients) relates to agonists for PPARα, FXR and GR/PXR most often in combination with UDCA, namely fibrates, obeticholic acid (OCA) and budesonide, respectively. Existing results look promising even though some side effects are worrisome such as pruritus in OCA-treated patients. Results of large well-designed studies are eagerly awaited. Conclusions: Major advances in the management of cholestatic liver diseases are in progress and promising times for these patients seem likely in the near future.

scholarly journals The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities

2021 ◽  
Vol 10 (8) ◽  
pp. 1763
Author(s):  
Marta Mazzetti ◽  
Giulia Marconi ◽  
Martina Mancinelli ◽  
Antonio Benedetti ◽  
Marco Marzioni ◽  
...  
Keyword(s):  
Liver Diseases ◽  
Immunosuppressive Drugs ◽  
Farnesoid X Receptor ◽  
New Drugs ◽  
Primary Biliary Cholangitis ◽  
Peroxisome Proliferator ◽  
Biliary Cirrhosis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Multiple Drugs ◽  
New Treatments

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are two chronic cholestatic liver diseases affecting bile ducts that may progress to biliary cirrhosis. In the past few years, the increasing knowledge in the pathogenesis of both diseases led to a growing number of clinical trials and possible new targets for therapy. In this review, we provide an update on the treatments in clinical use and summarize the new drugs in trials for PBC and PSC patients. Farnesoid X Receptor (FXR) agonists and Pan-Peroxisome Proliferator-Activated Receptor (PPAR) agonists are the most promising agents and have shown promising results in both PBC and PSC. Fibroblast Growth Factor 19 (FGF19) analogues also showed good results, especially in PBC, while, although PBC and PSC are autoimmune diseases, immunosuppressive drugs had disappointing effects. Since the gut microbiome could have a potential role in the pathogenesis of PSC, recent research focused on molecules that could change the microbiome, with good results. The near future of the medical management of these diseases may include new treatments or a combination of multiple drugs targeting different signaling pathways at different stages of the diseases.

Potential impact of screening for fatty liver disease by transient elastography with liver stiffness and controlled attenuation parameter measurements: a pilot study

2017 ◽  
Vol 55 (08) ◽  
pp. 754-760
Author(s):  
Moritz Peiseler ◽  
Anna Creutzfeldt ◽  
Insa Cassens ◽  
Claudia Glaubke ◽  
Claudia Kroll ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Pilot Study ◽  
Liver Diseases ◽  
Transient Elastography ◽  
Liver Stiffness ◽  
Chronic Liver ◽  
Chronic Liver Diseases ◽  
Normal Range ◽  
Controlled Attenuation Parameter ◽  
Attenuation Parameter

Abstract Background The prevalence of chronic liver diseases is high in developed countries, and the leading causes are amenable to prevention. The German Lebertag is to increase awareness of the burden of chronic liver diseases in the general public. We performed a pilot study using transient elastography with liver stiffness measurement (LSM) and the controlled attenuation parameter (CAP) as a screening tool for previously unrecognized liver diseases. Patients and methods LSM and CAP was performed in 60 individuals, and participants filled in a questionnaire reporting basic characteristics and past medical history. Results Median LSM and CAP values were within the normal range. Participants with self-reported diabetes mellitus had significantly elevated LSM (p = 0.02) and CAP values (p = 0.002). Participants with a BMI > 30 kg/m2 or dyslipidemia had significantly elevated CAP values (p = 0.007 and p = 0.01, respectively) with normal LSM values. Overall, 35 % of participants had elevated CAP values, indicating a high prevalence of hepatic steatosis. Discussion In a German pilot study, diabetes mellitus was a key risk factor for increased LSM and CAP values. Prevalence of steatosis was high and comparable to other Western countries. Transient elastography is a valuable tool to identify patients with increased risk for metabolic liver diseases. In people without risk factors, LSM and CAP values were within the normal range, indicating that screening for chronic liver injury was not warranted.

scholarly journals Zuotai (β-HgS)-containing 70 Wei Zhen-Zhu-Wan differs from mercury chloride and methylmercury on hepatic cytochrome P450 in mice

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 203
Author(s):  
Yu Nie ◽  
Shang-Fu Xu ◽  
Yan-Liu Lu ◽  
Xiu-Rong Zhao ◽  
Cen Li ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Western Blot ◽  
Mrna Expression ◽  
Nuclear Receptors ◽  
Pregnane X Receptor ◽  
Gastrointestinal Diseases ◽  
Farnesoid X Receptor ◽  
Tibetan Medicine ◽  
Mercury Chloride ◽  
Peroxisome Proliferator

Background: Zuotai (mainly β-HgS)-containing 70 Wei-Zhen-Zhu-Wan (70W, Rannasangpei) is a famous Tibetan medicine for treating cardiovascular and gastrointestinal diseases.  We have shown that 70W protected against CCl4 hepatotoxicity.  CCl4 is metabolized via cytochrome P450 (CYP) to produce reactive metabolites. Whether 70W has any effect on CYPs is unknown and such effects should be compared with mercury compounds for safety evaluation.   Methods: Mice were given clinical doses of 70W (0.15-1.5 g/kg, po), Zuotai (30 mg/kg, po), and compared to HgCl2 (33.6 mg/kg, po) and MeHg (3.1 mg/kg, po) for seven days. Liver RNA and protein were isolated for qPCR and Western-blot analysis. Results: 70W and Zuotai had no effects on hepatic mRNA expression of Cyp1a2, Cyp2b10, Cyp3a11, Cyp4a10 and Cyp7a1, and corresponding nuclear receptors [aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor-α (PPARα); farnesoid X receptor (FXR)]. In comparison, HgCl2 and MeHg increased mRNA expression of Cyp1a2, Cyp2b10, Cyp4a10 and Cyp7a1 except for Cyp3a11, and corresponding nuclear receptors except for PXR. Western-blot confirmed mRNA results, showing increases in CYP1A2, CYP2B1, CYP2E1, CYP4A and CYP7A1 by HgCl2 and MeHg only, and all treatments had no effects on CYP3A. Conclusions: Zuotai and Zuotai-containing 70W at clinical doses had minimal influence on hepatic CYPs and corresponding nuclear receptors, while HgCl2 and MeHg produced significant effects.  Thus, the use of total Hg content to evaluate the safety of HgS-containing 70W is inappropriate.

New non-invasive tool for assessment of liver fibrosis: transient elastography

2011 ◽  
Vol 152 (22) ◽  
pp. 860-865 ◽  
Author(s):  
Gábor Horváth
Keyword(s):  
Liver Fibrosis ◽  
Liver Biopsy ◽  
Disease Progression ◽  
Liver Diseases ◽  
Transient Elastography ◽  
Liver Stiffness ◽  
Chronic Viral Hepatitis ◽  
Non Invasive ◽  
Life Threatening ◽  
Invasive Method

Formation of connective tissue causing liver fibrosis is the common trait of chronic liver diseases. The „gold-standard” of the evaluation of liver fibrosis is liver biopsy, but it is an invasive, painful procedure, and carries a significant, although small risk of life-threatening complications. It may have contraindications, and it is certainly not the ideal procedure for serially repeated assessment of disease progression. A new, non-invasive method for the assessment of liver fibrosis by measuring liver stiffness is the transient elastography. The velocity of the propagation of a shear wave is measured by ultrasound. The procedure is painless, rapid, and no needs any preparation. So far, transient elastography has been mostly validated in chronic hepatitis C, but it is applicable in liver diseases with other etiologies. The diagnostic accuracy of transient elastography increases with stage of fibrosis, and is more accurate in advanced fibrosis (F≥2, Metavir score) and in cirrhosis. Indication of antiviral therapy for chronic viral hepatitis B and C are the main field of the application of the transient elastography, and it is also a useful tool for follow-up the disease progression. It is applicable for early, non-invasive detection of graft damage after liver transplantation. Evaluation of liver damage, the stage of liver fibrosis by transient elastography may have an important role in the decision before surgery, or application of potentially hepatotoxic drugs. Histological examination of the liver tissue is not substituted in every case by transient elastography, but liver biopsy is supplanted by measuring liver stiffness for evaluation of liver fibrosis in many cases. Orv. Hetil., 2011, 152, 860–865.

scholarly journals High-throughput toxicogenomic screening of chemicals in the environment using metabolically competent hepatic cell cultures

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jill A. Franzosa ◽  
Jessica A. Bonzo ◽  
John Jack ◽  
Nancy C. Baker ◽  
Parth Kothiya ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Screening Program ◽  
Cell Model ◽  
Quantitative Polymerase Chain Reaction ◽  
Pregnane X Receptor ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Molecular Signaling ◽  
Peroxisome Proliferator Activated Receptor

AbstractThe ToxCast in vitro screening program has provided concentration-response bioactivity data across more than a thousand assay endpoints for thousands of chemicals found in our environment and commerce. However, most ToxCast screening assays have evaluated individual biological targets in cancer cell lines lacking integrated physiological functionality (such as receptor signaling, metabolism). We evaluated differentiated HepaRGTM cells, a human liver-derived cell model understood to effectively model physiologically relevant hepatic signaling. Expression of 93 gene transcripts was measured by quantitative polymerase chain reaction using Fluidigm 96.96 dynamic arrays in response to 1060 chemicals tested in eight-point concentration-response. A Bayesian framework quantitatively modeled chemical-induced changes in gene expression via six transcription factors including: aryl hydrocarbon receptor, constitutive androstane receptor, pregnane X receptor, farnesoid X receptor, androgen receptor, and peroxisome proliferator-activated receptor alpha. For these chemicals the network model translates transcriptomic data into Bayesian inferences about molecular targets known to activate toxicological adverse outcome pathways. These data also provide new insights into the molecular signaling network of HepaRGTM cell cultures.

Multiple mechanisms of ontogenic regulation of nuclear receptors during rat liver development

2005 ◽  
Vol 288 (2) ◽  
pp. G251-G260 ◽  
Author(s):  
N. Balasubramaniyan ◽  
Mohammad Shahid ◽  
Frederick J. Suchy ◽  
M. Ananthanarayanan
Keyword(s):  
Bile Acid ◽  
Nuclear Receptors ◽  
Rat Liver ◽  
Functional Activity ◽  
Pregnane X Receptor ◽  
Farnesoid X Receptor ◽  
Liver Development ◽  
Mrna Levels ◽  
Bile Formation ◽  
Protein Levels

Nuclear receptors (NRs) play pivotal roles in the regulation of genes contributing to hepatobiliary cholesterol and bile acid homeostasis. We have previously shown that transporters involved in bile formation are developmentally regulated and are poorly developed during the fetal stage, but their expression reached gradual maturity during the postnatal period. To define the molecular mechanisms underlying this regulation and the role that class II NRs and associated members [liver receptor homolog-1 (LRH-1) and short heterodimer partner (SHP)] play, we have analyzed the ontogeny of NR expression during liver development. Real-time PCR analysis of hepatic NR expression from fetal day 17 through adult revealed that steady-state mRNA levels for all NRs were very low during the embryonic period. However, mRNA levels peaked close to that of adult rats (>6 wk-old rats) by 4 wk of age for farnesoid X receptor (FXR), pregnane X receptor (PXR), liver X receptor-α (LXRα), peroxisome proliferator-activated receptor-α (PPARα), retinoid acid receptor-α (RARα), LRH-1, and SHP, whereas RXRα mRNA lagged behind. FXR, PXR, LXRα, RARα, and PPARα functional activity in liver nuclear extracts assayed by gel EMSA demonstrated that the activity attained adult levels by 4 wk of age, exhibiting a strict correlation with mRNA levels. Surprisingly, PPARα activity was delayed as seen by EMSA assay. Protein levels for NRs also corresponded to the mRNA and functional activity except for RXRα. RXRα protein levels were higher than message levels, suggesting increased protein stability. We conclude that expression of NRs during rat liver development is primarily regulated by transcriptional mechanisms, which in turn, control the regulation of bile acid and cholesterol metabolic pathways.

Nuclear Receptors in Acute and Chronic Cholestasis

2015 ◽  
Vol 33 (3) ◽  
pp. 357-366 ◽  
Author(s):  
Ester Gonzalez-Sanchez ◽  
Delphine Firrincieli ◽  
Chantal Housset ◽  
Nicolas Chignard
Keyword(s):  
Lipid Metabolism ◽  
Nuclear Receptors ◽  
Energy Homeostasis ◽  
Therapeutic Targets ◽  
Pregnane X Receptor ◽  
Estrogen Receptor Α ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Hepatic Expression ◽  
The Impact

Background: Nuclear receptors (NRs) form a family of 48 members. NRs control hepatic processes such as bile acid homeostasis, lipid metabolism and mechanisms involved in fibrosis and inflammation. Due to their central role in the regulation of hepatoprotective mechanisms, NRs are promising therapeutic targets in cholestatic disorders. Key Messages: NRs can be classified into five different physiological clusters. NRs from the ‘bile acids and xenobiotic metabolism' and from the ‘lipid metabolism and energy homeostasis' clusters are strongly expressed in the liver. Furthermore, NRs from these clusters, such as farnesoid X receptor α (FXRα), pregnane X receptor (PXR) and peroxisome proliferator-activated receptors (PPARs), have been associated with the pathogenesis and the progression of cholestasis. The latter observation is also true for vitamin D receptor (VDR), which is barely detectable in the whole liver, but has been linked to cholestatic diseases. Involvement of VDR in cholestasis is ascribed to a strong expression in nonparenchymal liver cells, such as biliary epithelial cells, Kupffer cells and hepatic stellate cells. Likewise, NRs from other physiological clusters with low hepatic expression, such as estrogen receptor α (ERα) or reverse-Erb α/β (REV-ERB α/β), may also control pathophysiological processes in cholestasis. Conclusions: In this review, we will describe the impact of individual NRs on cholestasis. We will then discuss the potential role of these transcription factors as therapeutic targets.

scholarly journals Zuotai (β-HgS)-containing 70 Wei Zhen-Zhu-Wan (Rannasangpei) differs from mercury chloride and methylmercury on hepatic cytochrome P450

2020 ◽  
Author(s):  
Yu Nie ◽  
Shang-Fu Xu ◽  
Yan-Liu Lu ◽  
Xiu-Rong Zhao ◽  
Cen Li ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Pregnane X Receptor ◽  
Gastrointestinal Diseases ◽  
Farnesoid X Receptor ◽  
Tibetan Medicine ◽  
Mercury Chloride ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mercury Compounds ◽  
Protein Expressions

Abstract Background: Zuotai (mainly β-HgS)-containing 70 Wei-Zhen-Zhu-Wan (70W, Rannasangpei ) is a famous Tibetan medicine for cardiovascular and gastrointestinal diseases. We have shown that 70W protected against CCl 4 hepatotoxicity. CCl 4 is metabolized via cytochrome P450 (CYP450) to produce reactive metabolites. Whether 70W has any effect on CYP450 is unknown and such effects should be compared with mercury compounds for safety evaluation. Methods: Mice were given 70W (0.15-1.5 g/kg, po), Zuotai (30 mg/kg, po), HgCl 2 (33.6 mg/kg, po) and MeHg (3.1 mg/kg, po) for 7 days. Liver RNA and protein were isolated for qPCR and Western-blot analysis. Results: 70W and Zuotai had no effects on hepatic Aryl hydrocarbon receptor (AhR) and CYP1A2, but HgCl 2 and MeHg increased Cyp1a2 mRNA and CYP1A2 protein levels;70W and Zuotai had no effects on constitutive androstane receptor (CAR) ,CYP2B andCYP2E1 expressions, but HgCl 2 increased CAR and Cyp2b10 mRNA, HgCl 2 and MeHg increased CYP2B and CYP2E1 protein expressions; 70W and mercury compounds had no apparent effects on the expression of pregnane X receptor (PXR) and Cyp3a11 mRNA, as well as CYP3A proteins. 70W and mercury compounds had no apparent effects on the expression of peroxisome proliferator-activated receptor alpha (PPARα) and CYP4A; but HgCl 2 tended to increase Cyp4a10 mRNA and CYP4A protein expressions. 70W and Zuotai had no apparent effects on the expression of farnesoid X receptor (FXR) and Cyp7a1 , while HgCl 2 and MeHg increased CYP7A1 expression. Conclusions: Zuotai and Zuotai-containing 70W at clinical doses had minimal influence on hepatic CYPs, and the effects of 70W and Zuotai on CYP and corresponding nuclear receptors are different from HgCl 2 and MeHg.

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