Outcomes of 38 patients with PFIC3: Impact of genotype and of response to ursodeoxycholic acid therapy
Emmanuel Gonzales,
Antoine Gardin,
Marion Almes,
Amaria Darmellah-Remil,
Hanh Seguin,
Charlotte Mussini,
Stéphanie Franchi-Abella,
Mathieu Duché,
Oanez Ackermann,
Alice Thébaut,
Dalila Habes,
Bogdan Hermeziu,
Martine Lapalus,
Thomas Falguières,
Jean-Philippe Combal,
Bernard Benichou,
Sonia Valero,
Anne Davit-Spraul,
Emmanuel Jacquemin
Affiliations
Emmanuel Gonzales
Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France; Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
Antoine Gardin
Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France; Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
Marion Almes
Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France; Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
Amaria Darmellah-Remil
Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
Hanh Seguin
Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France
Charlotte Mussini
Pathology, Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France
Stéphanie Franchi-Abella
Pediatric Radiology, Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France
Mathieu Duché
Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France; Pediatric Radiology, Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France
Oanez Ackermann
Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France; Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
Alice Thébaut
Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France; Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
Dalila Habes
Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France; Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
Bogdan Hermeziu
Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France; Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
Martine Lapalus
Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
Thomas Falguières
Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
Jean-Philippe Combal
Vivet Therapeutics, Paris, France
Bernard Benichou
Vivet Therapeutics, Paris, France
Sonia Valero
Vivet Therapeutics, Paris, France
Anne Davit-Spraul
Biochemistry; Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, University Paris-Saclay, Le Kremlin-Bicêtre, France; Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France
Emmanuel Jacquemin
Pediatric Hepatology and Liver Transplantation, National Reference Centre for Biliary Atresia and Genetic Cholestasis, FILFOIE, ERN RARE LIVER, France; Inserm U1193, Hepatinov, University Paris-Saclay, Orsay, France; Corresponding author. Address: Service d’Hépatologie et de transplantation hépatique pédiatriques, Hôpital Bicêtre, 78, rue du Général Leclerc, Le Kremlin-Bicêtre, 94275 cedex, France. Tel.: +33 1 45 21 31 68, fax: +33 1 45 21 28 16.
Background & Aims: Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare liver disease caused by biallelic variations in ABCB4. Data reporting on the impact of genotype and of response to ursodeoxycholic acid (UDCA) therapy on long-term outcomes are scarce. Methods: We retrospectively describe a cohort of 38 patients with PFIC3 with a median age at last follow-up of 19.5 years (range 3.8–53.8). Results: Twenty patients presented with symptoms before 1 year of age. Thirty-one patients received ursodeoxycholic acid (UDCA) therapy resulting in serum liver test improvement in 20. Twenty-seven patients had cirrhosis at a median age of 8.1 years of whom 18 received a liver transplant at a median age of 8.5 years. Patients carrying at least one missense variation were more likely to present with positive (normal or decreased) canalicular MDR3 expression in the native liver and had prolonged native liver survival (NLS; median 12.4 years [range 3.8-53.8]). In contrast, in patients with severe genotypes (no missense variation), there was no detectable canalicular MDR3 expression, symptom onset and cirrhosis occurred earlier, and all underwent liver transplantation (at a median age of 6.7 years [range 2.3–10.3]). The latter group was refractory to UDCA treatment, whereas 87% of patients with at least one missense variation displayed an improvement in liver biochemistry in response to UDCA. Biliary phospholipid levels over 6.9% of total biliary lipid levels predicted response to UDCA. Response to UDCA predicted NLS. Conclusions: Patients carrying at least one missense variation, with positive canalicular expression of MDR3 and a biliary phospholipid level over 6.9% of total biliary lipid levels were more likely to respond to UDCA and to exhibit prolonged NLS. Impact and implications: In this study, data show that genotype and response to ursodeoxycholic acid therapy predicted native liver survival in patients with PFIC3 (progressive familial intrahepatic cholestasis type 3). Patients carrying at least one missense variation, with positive (decreased or normal) immuno-staining for canalicular MDR3, and a biliary phospholipid level over 6.9% of total biliary lipids were more likely to respond to ursodeoxycholic acid therapy and to exhibit prolonged native liver survival.
