Unusual Cystic Fibrosis Transmembrane Conductance Regulator Mutations and Liver Disease: A Case Series and Review of the Literature.

Cystic fibrosis (CF) is caused by a mutation in the CF transmembrane conductance regulator (CFTR) gene, deranging the activity of chloride channels on the epithelial cell surface. Herein we describe end-stage liver disease in 3 infants with rare CFTR gene mutations; 2 of them were heterozygous. Case 1 was a premature male infant with negative CF screening at birth who developed a small bowel obstruction in the neonatal period requiring an ileostomy, with subsequent cholestatic liver disease and portal hypertension. In addition, he was noted to have frequent respiratory infections prompting a sweat test, which was positive. Genetic testing revealed that he was heterozygous for P.1177F. He then underwent a successful liver transplant. Case 2 was a female infant who developed progressive cholestasis with poor weight gain and was found to have neonatal hepatitis on liver biopsy. A sweat test was negative and genetic testing revealed she was heterozygous for CFTR and PEX26 gene mutations. She subsequently developed pneumatosis involving the cecum that was treated conservatively, followed by a successful liver transplant. Case 3 was a male infant who developed progressive liver disease, with liver biopsy showing neonatal hepatitis. He was extensively investigated but had a negative sweat test on repeated studies. Genetic testing revealed that the patient was heterozygous P.K186N-variant in the AKRID1 gene and homozygous P.R75Q-variant in the CFTR gene. Unfortunately, he succumbed to an acute upper gastrointestinal hemorrhage. Rare and unusual CFTR mutations, even in the heterozygous form, may be a feature in otherwise undiagnosed end-stage liver disease of infancy.

Expansion of transplanted hepatocytes during liver regeneration.

BACKGROUND: Successful clinical application of hepatocyte transplantation has been limited by poor engraftment of the recipient liver by transplanted hepatocytes. METHODS: To address the hypothesis that liver regeneration induced by an acute hepatotoxic injury promotes expansion of transplanted hepatocytes, we injected beta-galactosidase-labeled hepatocytes intrasplenically into mice 24 hr after treatment with carbon tetrachloride (CCl4) and into untreated controls. RESULTS: Macroscopic examination of whole liver segments identified clusters of transplanted hepatocytes uniformly spread on the capsular surface of the recipient liver and in the liver core following the distribution pattern of portal vein branches. Frozen sections showed that although the degree of initial engraftment of transplanted hepatocytes was similar in CCl4-treated and control livers, there was a fourfold increase of engrafted hepatocytes in CCl4-treated livers 10 days after transplantation which persisted to 28 days. CONCLUSIONS: We conclude that the number of transplanted hepatocytes increases in response to regeneration signal triggered by an acute hepatocyte-specific liver injury.