[Bile acids and their therapeutic use in children]

Abstract

Bile acids are natural detergents and the end-products of cholesterol metabolism. Their functions are mostly digestive: induction of bile flow and solubilization of biliary and alimentary lipids. They circulate along the enterohepatic cycle, and probably also along a shorter route, the cholehepatic shunt. They are relatively hydrophobic and perpetuate or worsen the hepatic lesions when their excretion is impaired in cholestasis, because of their affinity for biological membranes. Their functions depend on their relative hydrophilicity and ionization, ie on their structure and state of conjugation. They have an immunosuppressive effect in vivo and in vitro. Ursodeoxycholic acid (UDC) is a hydrophilic bile acid used in chronic cholestatic diseases. Biological improvement has been proven in autoimmune cholangiopathies in adults, and cystic fibrosis-associated liver disease in children. Clinical studies are on the way for other indications. It is still too early to evaluate the long-term clinical benefits, eg the reduction in needs for liver transplantation. UDC acid may induce a bicarbonate-rich hypercholeresis through the cholehepatic shunt, that would explain its efficacy in cystic fibrosis. In disorders of bile acid synthesis or transport, it could shunt the enzymatic block, or reestablish the bile flow through its osmotic effect. Like other bile acids it interacts with membranes, and is thought to stabilize them. In chronic cholestasis it would protect the membranes against the adverse effect of non-excreted endogenous bile acids. This interaction can also explain its immunosuppressive effect, through non-specific inhibition of transmission at the cell surface. That would explain the preferential clinical efficacy of UDC in autoimmune cholestasis, and stimulate its evaluation in "immunological" indications, such as liver transplantation and hepatic graft versus host disease.