Volume 75 - 2012 - Fasc.4 - Case series
Pleiotropic functions of bile acids mediated by the farnesoid X receptor
In addition to their well-established role in the digestion and absorption of dietary lipids, bile acids (BAs) are recognized as sig- nalling molecules in a wide range of metabolic processes. Bile acids regulate their own metabolism and enterohepatic circulation by activating the farnesoid X receptor (FXR). BAs have been shown to affect lipid metabolism, to decrease levels of circulating triglyc- erides, improve hyperglycemia and insulin signalling, directly act on the arterial wall and protect hepatocytes against cholestatic liver injury. Given that BAs are an integrated part of the complex metabolic network regulated by FXR, acting as a major underly- ing pathway, specific therapeutic targeting of this nuclear receptor represents an attractive therapeutic approach for a wide range of disorders. During a phase II clinical trial, the administration of a semisynthetic BA derivative 6-ethyl-chenodeoxycholic acid (6- ECDCA) to patients with diabetes, non-alcoholic fatty liver disease (NAFLD) and primary biliary cirrhosis (PBC), led to encouraging results, despite side effects being observed in pre-clinical studies. Chemical manipulations of the side chain and the steroid nucleus of BAs could lead to the discovery of novel semisynthetic BA deriv- atives that are more specific and selective FXR activators. (Acta gastroenterol. belg., 2012, 75, 389-398).
The challenge of cholestatic pruritus
Pruritus can be the dominant symptom of cholestatic liver disease but is difficult to treat since unraveling its pathophysiology is a great challenge. Serum autotaxin activity correlates with pruritus intensity, but its causal relationship, expression pattern and exact mode of action during cholestasis remain to be estab- lished. The anion exchange resin cholestyramine, the PXR agonist rifampicin, the opioid antagonist naltrexone and the serotonine reuptake inhibitor sertraline are recommended by evidence-based guidelines as stepwise therapeutic approaches to treat itch in cholestasis. Rifampicin, the most effective antipruritic agent in cholestatic itch, has been shown to reduce autotaxin transcription in vitro. Experimental approaches include UVB phototherapy, extracorporeal albumin dialysis, nasobiliary drainage and in desperate cases even liver transplantation. Relevant clinical obser- vations along with the different metabolic, neurologic and endocrine targets of available therapies in cholestatic pruritus are reviewed here. (Acta gastroenterol. belg., 2012, 75, 399-404).
Progressive familial intrahepatic cholestasis and benign recurrent intrahepatic cholestasis : a review
Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are two rare autosomal recessive disorders, characterized by cholestasis. They are related to mutations in hepatocellular transport system genes involved in bile formation. The differentiation between PFIC and BRIC is based on phenotypic presentation : PFIC is a progressive disease, with evolution to end-stage liver disease. BRIC is characterized by intermittent recurrent cholestatic episodes, with irresistible pruri- tus, mostly without evident liver damage. Between symptomatic periods, patients are completely asymptomatic.
In this article, a short overview of the aetiology, the clinical and diagnostic characteristics and the therapy of both PFIC and BRIC are given. (Acta gastroenterol. belg., 2012, 75, 405-410).