Disorders of bile acid synthesis

Abstract

This chapter summarises the treatment of inbornerrors of bile acid synthesis in patients that present in infancy or childhood with cholestatic liver disease and malabsorption of fat and fat-soluble vitamins. Synthesis of chenodeoxycholic acid and cholic acid is essential for activating bile solute pumps (via nuclear receptors such as the farnesoid X receptor) and for fuelling bile flow. Transport of bile acids leads to the flow of water. Abnormal bile acids may actually inhibit the canalicular bile salt pump; thus impaired bile flow (cholestasis) and an increased plasma concentration of conjugated bilirubin commonly occur in bile acid synthesis defects. The cholestasis, in infants at least, is usually associated with signs of hepatocyte damage (raised transaminases, a giant cell hepatitis on biopsy). In most bile acid synthesis defects, the liver function tests and biopsy appearances can be normalised by treatment with chenodeoxycholic acid and/or cholic acid. In some, liver damage progresses, requiring liver transplantation. Reducedsecretionof chenodeoxycholic acidandcholic acid intothe intestine impairs the digestion and absorption of fats and fat-soluble vitamins. Thus inborn errors of bile acid synthesis can present dramatically in infancy with bleeding due to vitamin K deficiency, or fits due to hypocalcaemia caused by severe rickets. More insidious presentations in infancy include failure to thrive, with steatorrhoea and rickets or progressive intrahepatic cholestasis. Fat-soluble vitamins are usually only required in the early stages of treatment; once the bile acid deficiency is corrected, a supplement is not required. Indeed care should be taken not to give high doses of vitamin D for a prolonged period after bile acid replacement therapy has been started or hypercalcaemia will ensue. In several of the peroxisomal disorders, there is impaired bile acid synthesis and some impairment of liver function. However, other pathways are often impaired and neurological disease usually predominates. These disorders are considered elsewhere, with one exception: α-methyl-acyl-CoA racemase deficiency can present with neonatal cholestasis and is considered in this chapter. After infancy the major route for catabolismof cholesterol occurs via a bile acid synthesis pathway that starts with the conversion of cholesterol to 7α hydroxycholesterol. This rate-limiting step for the pathway is subject to feedback inhibitionbybile acids. Defects in cholesterol 7α-hydroxylasehave recently been shown to lead to hypercholesterolaemia. Cholesterol and its saturated analogue cholestanol accumulate in tissues in cerebrotendinous xanthomatosis (CTX), giving rise to tendon xanthomata, atheroma and dementia. The defect is in cholesterol 27-hydroxylase, which is important both in the neutral pathway for bile acid synthesis, which starts with conversion of cholesterol to 7α-hydroxycholesterol, and in the acidic pathway, which starts with conversion of cholesterol to 27-hydroxycholesterol. The reasons for accumulation of cholesterol and cholestanol in the tissues are complex. Conversion of cholesterol to oxysterols and C27 bile acids may represent a significant route for elimination of cholesterol from extrahepatic tissues. However, there is also evidence of conversion of 7α-hydroxycholesterol to cholestanol. Other intermediates along the cholesterol 7α-hydroxylase pathway are converted to bile alcohol glucuronides and excreted in the urine in CTX. Treatment with chenodeoxycholic acid reduces the rate of synthesis of cholestanol and the urinary excretion of bile alcohols. One mechanism is likely to be inhibition of cholesterol 7α-hydroxylase. Certainly ursodeoxycholic acid, which does not inhibit cholesterol 7α-hydroxylase, is ineffective in reducing bile alcohol excretion. Chenodeoxycholic acid also reduces cholesterol synthesis in CTX. This may be due to its ability to inhibit HMG-CoA reductase. Whatever the exact mechanisms of action of chenodeoxycholic acid are, what is observed clinically is a reversal of the patient's neurological disability,with clearing of the dementia, improved orientation, a rise in intelligence quotient and enhanced strength and independence. The magnetic resonance (MR) images of the brain may not show any improvement, and osteoporosis, another feature of CTX, also appears to be resistant to chenodeoxycholic acid treatment.