Novel Aspects in the Management of Cholestatic Liver Diseases

Abstract

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.

C/EBP homologous protein–induced loss of intestinal epithelial stemness contributes to bile duct ligation–induced cholestatic liver injury in mice

“…The accumulation of hydrophobic bile acids is believed to induce chronic inflammation and hepatocyte apoptosis . Recent clinical studies indicate that disruption of intestinal barrier function and subsequent bacterial translocation also contribute to cholestatic liver disease progression, such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and noncholestatic liver diseases by inducing hepatic inflammation . It has been reported that PSC represents one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD) .…”

“…(3) It has been reported that PSC represents one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD). (3) The close association between PSC and IBD highlights the importance of the gut-liver axis. (4) Furthermore, disruption of the intestinal barrier was not only observed in obstructive jaundice patients, but also in bile duct ligation (BDL) rodent models of cholestatic liver diseases.…”

The Protective Effect of Heme Oxygenase-1 against Intestinal Barrier Dysfunction in Cholestatic Liver Injury Is Associated with NF-κB Inhibition

“…A high concentration of bile acids, especially the hydrophobic bile acids, is particularly toxic and promotes hepatocyte damage, liver fibrosis, cirrhosis and hepatocellular carcinoma under cholestatic conditions (29,30). Notably, the reduced flow of bile acids into the small intestine facilitates the movement of flora and bacterial endotoxins from the portal vein into the liver and causes disruption of the intestinal epithelial barrier (31)(32)(33). Our previous study found that chronic liver injury patients also displayed intestinal barrier dysfunction, manifesting as significantly elevated serum endotoxin, DAO and D-Lac compared with normal controls (data not shown).…”

Complications, symptoms, quality of life and pregnancy in cholestatic liver disease

“…Obeticholic acid (OCA) is a novel farnesoid X receptor agonist that has been recently FDA-approved for treatment of PBC. [89][90][91][92][93] OCA (at a dose of 10 or 5 mg titrated to 10 mg/d) induced 35% reduction in ALP from baseline, normal bilirubin level and improvements in GGT, ALT and AST after 12 months of therapy. Patients who failed to achieve these endpoints had significantly increased risk for LT and death compared to patients who achieved those endpoints (HR 2.83, P < .001).…”

“…Experts recommend starting with full dose UDCA (13‐15 mg/kg/d) in 2‐4 divided doses (with food); in patients who are intolerant of the full weight‐based dose, the dose can be lowered and/or tapered up over a period of 1‐2 weeks. Obeticholic acid (OCA) is a novel farnesoid X receptor agonist that has been recently FDA‐approved for treatment of PBC . OCA (at a dose of 10 or 5 mg titrated to 10 mg/d) induced 35% reduction in ALP from baseline, normal bilirubin level and improvements in GGT, ALT and AST after 12 months of therapy.…”