Supplementation of Chenodeoxycholic Acid: the right choice of therapy in CTX

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We demonstrate the development of toxic hepatitis in an infant diagnosed with CTX shortly after birth after starting Chenodeoxycholic Acid supplementation at the advised dosage of 15 mg/kg/day. This is supported by the fact that liver
size and function rapidly normalised after cessation of Chenodeoxycholic Acid supplementation and that common causes for viral hepatitis in children were ruled out. Hepatitis A to E were not excluded, but it is highly unlikely that either one of these caused the hepatitis as neither the patient nor her mother did receive any blood products, hepatitis A and E are not endemic in The Netherlands, and no trips to foreign countries were undertaken. Furthermore, the potential hepatotoxic effect of CDCA, as well as other bile acids, is well established and has been shown to be dose dependent.
However, the hepatotoxic effect of Chenodeoxycholic Acid in our patient may have been aggravated by the accumulation of bile acid synthesis intermediates in hepatocytes. This would also explain the observed rise in plasma cholestanol with the development of hepatitis. In support of this is the observation that liver function deteriorated in an infant who presented with giant cell hepatitis and who was started on CDCA supplementation at a dosage of 10 mg/kg/day under suspicion of a bile acid synthesis defect. He was later diagnosed with CTX. Although neonatal cholestasis is part of the clinical spectrum of CTX, it is unlikely that CTX by itself caused the hepatitis as our patient only developed jaundice after initiation of CDCA supplementation.
However, we think that supplementation of Chenodeoxycholic Acid is the right choice of therapy in CTX, also in infants, as it is a more potent stimulator of the nuclear receptor FXR, thereby effectively inhibiting cholestanol formation through the cholesterol 7α-hydroxylase pathway in CTX. It has been proposed that CTX in infants may be best treated with CA supplementation because of the potential hepatotoxic effect of CDCA. We demonstrate that adequate metabolic control in an infant with CTX was achieved with Chenodeoxycholic Acid supplementation at a dosage of 5 mg/kg/day and was well tolerated. The currently advised dosage of 15 mg/kg/day of CDCA seems hepatotoxic in infants and should not be used in young children. This is relevant in view of the possible inclusion of CTX in newborn screening programs in the near future.