Disorder Of Bile Acid Synthesis Research Articles

Les acides biliaires et leur utilisation thérapeutique chez l'enfant

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 hypercholerecis 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 the 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.

Hereditary metabolic disease in infancy

This review draws the attention of neonatologists and pediatricians to recently described, important hereditary metabolic disorders that may present in early infancy. It also reports new information on more familiar conditions. The discussion is divided into four areas: 1) defects of the electron transport chain; 2) the peroxisomal disorders; 3) inborn errors of small molecules that cause congenital malformations; and 4) several other recently identified metabolic diseases, namely the blood-brain barrier glucose transport defect, disorders of bile acid synthesis, and the carbohydrate-deficient glycoprotein syndrome. Several of these inborn errors illustrate new pathophysiologic principles. Clinical recognition of these conditions is critical to proper management of both the infant, for whom effective specific treatment may be available, and the family, who must be made aware of the genetic implications of the disease.

Effects of cholestenone feeding in rats

In several conditions (e.g. congenital lipoid adrenal hyperplasia; disorders of bile acid synthesis), sterol metabolism is disturbed and formation of abnormal sterols can be expected. In a pilot study we investigated the effects of cholestenone, a cholesterol metabolite which occurs normally in low concentrations only. Cholestenone, fed for 3½ months, (1% w/w in the standard laboratory chow) was found to cause significant growth retardation in male Wistar rats (mean weight 270 g (n=3) vs. 380 g (n=3) of controls). The adrenals were grossly enlarged (mean weight 44.4 mg vs. 19.1 mg in controls). Growth retardation also occurred in female rats fed cholestenone. Their ovaria as well as adrenals were hyperplastic and pale yellow. Isolated adrenal cells of test animals showed complete loss of sensivity for ACTH at a concentration of 100μU/ml.They were unable to synthesize corticosterone from exogenous 25-OH-cholesterol. Corticosterone production from exogenous pregnenolone dropped to 20% of control values. In the blood and other tissues cholesterol, both free and esterified, was partly replaced by cholestanol and its esters. Resistance of the erythrocytes to osmotic shock was significantly decreased.