Novel ABCB4 Gene Mutations in a Child with Progressive Familial Intrahepatic Cholestasis Type 3

Progressive Familial Intrahepatic Cholestasis (PFIC) is a heterogeneous group of liver disordersof autosomal recessive inheritance, caused by defect in bile secretion and present with intrahepatic cholestasis, usually in infancy or early childhood and resulting End Stage Liver Disease (ESLD) and death or liver transplantation in infancy to adulthood. This is the first report of PFIC type 3 with novel compound heterozygous mutation in Georgia. The patient was presented at the age of 3,5 years with direct hyperbilirubinemia, elevated transaminases and high GGT, Alkaline phosphatase levels. On physical examination, palmar erythema, spider angioma and mild splenomegaly was observed. Abdominal magnetic resonance imaging revealed liver cirrhosis, portal hypertension, splenomegaly, and cholestasis. These findings are going with the diagnosis Progressive Familial Intrahepatic Cholestasis (PFIC3). Genetic testing (sequencing by Sanger method) of this patient revealed novel compound heterozygous mutations (c.537-6T>G and c.3768_3769del p.(Arg1256Serfs*?)) in the ABCB4 gene. Treatment with ursodeoxycholic acid was started while diagnoses by genetical analysis was confirmed and in 2-month liver function tests were reevaluated and were within normal limits. Severity of cholestasis, the time of presentation and the favorable response to UDCA therapy seems to depend on the degree of penetrance of the genetic defect. In PFIC 3, regular administration of UDCA normalizes liver function tests and improves clinical parameters in up to 50% of the patients. The therapeutic effect appears to be dependent on the type of mutation, with premature stop codons leading to a truncated protein being associated with nearly no response to therapy. UDCA should therefore be the first choice in the initial therapeutic management of patients with ABCB4 deficiency, especially when a missense mutation in the corresponding gene is found.