Double Heterozygous Mutation Causing PFIC2 with Synchronic Hepatocellular Carcinomas before Two Years of Age

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IntroductionBile salts are exclusively synthesized in the liver. The bile salt export pump (BSEP), an adenosine triphosphate (ATP)-dependent transporter, is exclusively located in the hepatic canalicular membrane, and exports the bile salts into the canaliculus against a concentration gradient. Mutations in the ABCB11 gene alter BSEP and cause progressive intrahepatic familial cholestasis (PFIC2) type 2. This disease is characterized by low GGT hepatitis and early onset of cholestasis and pruritus; these patients are at increased risk of developing hepatocellular carcinoma (HCC) or cholangiocarcinoma.AimTo communicate a case or PFIC 2 with early development of synchronic HCC, with two ABCB11 heterozygous mutations, one of them not described before.Case ReportThis is a female referred to this center at 3 months of age due to cholestasis and coagulopathy. Coagulation corrected after vitamin K administration; hepatocellular enzymes and bilirubin persisted elevated with normal GGT. Further workup was done, ruling out viral hepatitis, biliary atresia and cystic fibrosis. Alpha-fetoprotein and bile serum salts were markedly elevated. A percutaneous liver biopsy was remarkable for giant cell hepatitis with moderate activity, portal and periportal fibrosis with incomplete bridges. PFIC was suspected and a molecular analysis was requested. Two heterozygous mutations were identified: p.Glu297Gly already reported in association to PFIC2 and p.Arg303Met previously not identified as related with this disease. The patient remained clinically stable, with progression of cholestasis and pruritus that was managed medically. At 17 months of age she presented sustained increase of Alpha-fetoprotein. A liver ultrasound showed a 7 mm nodule that was confirmed by CT hepatic angiography. She was promptly evaluated for liver transplant; extra hepatic lesions were excluded. Three weeks later the patient was transplanted with a split liver. The transplant was uneventful and she was discharged home 10 days after the surgery. The explanted liver showed cirrhosis and 4 nodules of poorly differentiated HCC measuring less than 1 cm each. The Alpha-fetoprotein decreased to normal values three weeks after TX and it has remained normal. The patient is now 14 months post TX with a functioning graft and showing no lesions of HCC.ConclusionPFIC type 2 is one of the few entities that might present HCC at a very early age. It is important to perform an adequate follow up in order to make the appropriate diagnosis and to perform a timely adequate liver transplant. It is of great interest for the medical community that newly identified mutations are reported, in order to enrich the medical knowledge.

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