Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial
Cite this as: BMJ 2012;344:e3799
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We thank Drs Benelli and Ventura for their comments on our recent paper.(1) However, we did not conclude that the benefit from UDCA treatment would be too small to recommend it. Rather we stated that the extent of the improvement in pruritus may be too small for most doctors to recommend it or for women to want to take it, and that women and doctors will differ in their view. This conclusion related specifically to pruritus. We also demonstrated a reduction in maternal ALT and AST and in meconium stained-liquor; this latter finding in particular raises the prospect that UDCA confers fetal benefit. An important additional conclusion of the study is that the overall risks and benefits of UDCA to the fetus should be evaluated in a larger trial, which we believe is feasible.
With regard to the biliary transport proteins that are mutated in progressive familial intrahepatic cholestasis, namely ABCB4, ABCB11 and ATP8B1, we agree that genetic variation will be of relevance to disease severity, and likely to treatment response, in some ICP cases. However, we are not aware of any evidence that UDCA is specifically efficacious in pregnancies where the mother carries the above mutations and this was not the focus of the PITCH trial. Previous studies by our group and others have demonstrated that some women with ICP have genetic variation in these transporters.(2) Heterozygous mutations in ABCB4 and ABCB11 occur in approximately 10% of ICP cases and the identification of common variants with a smaller effect upon disease risk is ongoing.(3) We consider it appropriate to perform a more detailed analysis of a large ICP cohort to establish the proportion of cases that have underlying genetic variation (both rare and common variants) in these biliary transport proteins in conjunction with an assessment of the relationship between specific genetic variants, disease severity and treatment response.
(1) Chappell LC, Gurung V, Seed PT, Chambers J, Williamson C, Thornton JG; on behalf of the PITCH Study Consortium. Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial. BMJ. 2012 Jun 13;344:e3799. doi: 10.1136/bmj.e3799.
(2) Dixon PH and Williamson C. The molecular genetics of intrahepatic cholestasis of pregnancy. Obstetric Medicine. 2008; 1(2): 65-71
(3) Dixon PH, van Mil SWC, Chambers J, Strautnieks S, Thompson RJ, Lammert F, Kubitz R, Keitel V, Glantz AG, Mattsson LA, Marschall HU, Molokhia M, Moore GE, Linton KJ, Williamson C. Contribution of Variant Alleles of ABCB11 to Susceptibility to Intrahepatic Cholestasis of Pregnancy. Gut. 2009; 58(4): 537-44.
Competing interests: JC is the founder of Obstetric Cholestasis Support UK, a support group for women and families affected by obstetric cholestasis. All other authors declare no competing interests
King's College London, London SE1 7EH
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We have read with interest the paper by Chappell et al. “Ursodeoxycholic acid versus placebo and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial” (BMJ 2012, 344: 3799). The Authors’ conclusion is that ursodeoxycholic acid reduces pruritus, but the size of the benefit is too small to recommend it. The Authors, however, didn’t consider the possibility that some patients who entered the study could be heterozygous for progressive familiar intrahepatic cholestasis (PFIC), a condition that can be effectively treated by UDCA therapy i. This disease is characterised by recurrent bouts of cholestasis, jaundice and severe pruritus, that could be triggered by infectious, fever and also pregnancyii. PFIC type 2 is caused by mutations in the ABCB11 gene, encoding a canalicular ATP-dependent bile acid transporter and it’s characterised by normal serum GGT; PFIC 3 instead results from defects in a canalicular phospholipidis flippase MDR3 (ABCB4) and is characterised by high levels of serum GGT.
Even if variation in ABCB4 only occurs in few women with intrahepatic cholestasis of pregnancy, heterozygosity for ABCB11 appears in 1% of European intrahepatic cholestasis of pregnancy iii .
Considering that the heterozygous mutations in ABCB can cause other liver diseases that could be prevented by correct management of the cholestatic attacks with ursodeoxycholic acid, we think that genetic testing of the ABCB4 and ABCB11 should be considered in all women with intrahepatic cholestasis of pregnancy (IECP), that represents, as reported by the Authors, only the 0,7% of all pregnancy in UK.
i.Maggiore G, de Giacomo C. Efficacy of ursodeoxycholic acid in preventing cholestatic episodes in a patient with benign recurrent intrahepatic cholestasis, Hepatology. 1992 Aug;16(2):504
ii. Wendy L. van der Woerd, Saskia W.C. van Mil, Janneke M. Stapelbroek, Leo W.J. Klomp,Stan F.J. van de Graaf, Roderick H.J. Houwen, Familial cholestasis: Progressive familial
cholestasis, benign recurrent intrahepatic intrahepatic cholestasis of pregnancy. Best Practice & Research Clinical Gastroenterology 24 (2010) 541–553.
iii. Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F, Kubitz R, Keitel V, Glantz A, Mattsson LA, Marschall HU, Molokhia M, Moore GE, Linton KJ, Williamson C., Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut. 2009 Apr;58(4):537-44
Competing interests: None declared
Institute for Maternal and child health Burlo Garofolo, University of Trieste., via dell'Istria, Triestre ITALY
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