Can liver transplantation improve our understanding of the pathophysiology of iron overload?

Abstract

We observed the development of phenotypic hereditary haemochromatosis in a non-hereditary haemochromatosis liver transplant recipient, following transplantation with a liver from a C282Y heterozygous donor. No cause for secondary iron overload was identified. Subsequent sequencing of the HFE gene of both donor and recipient revealed a strong candidate for a novel pathogenic HFE mutation. In the recipient, heterozygosity for a single base substitution in exon 1, g.18 G>C, resulting in the substitution of arginine by serine at codon 6 (R6S), was detected. This R6S variation is likely to represent a novel pathogenic missense mutation of the HFE gene. An interaction between R6S heterozygosity in the recipient and C282Y heterozygosity in the donor liver is the most likely explanation for the development of iron overload in this patient. The report suggests that an hepatic defect is CommentsHereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism characterized by increased intestinal absorption of iron with deposition in the liver, pancreas, and multiple other parenchymal organs. HH is the most common, single-gene inherited disorder in U.S. Caucasians, with a homozygote frequency of approximately .5% and a heterozygote frequency of 10%. In the United States, approximately 85% of patients with HH are homozygous for the C282Y mutation. Despite being a common disorder, HH is an uncommon indication for orthotopic liver transplantation (OLT). Although iron overload is frequently observed in patients with end-stage liver disease, most do not have HH. 1 In the United States, less than 1% of all liver transplants are performed for HH. These findings are consistent with recent studies that have concluded that only a small percentage of C282Y homozygotes develop clinical manifestations of HH. 2 OLT provides life-saving treatment to many patients with end-stage liver disease. An added benefit of OLT is that it cures certain metabolic disorders such as Wilson disease, familial amyloid polyneuropathy, oxalosis, and hemophilia. It has long been assumed that iron overload in HH is caused by an intestinal defect. A recent case report by Wigg and colleagues casts doubt on this theory and suggests that HH may be due to a combined liver and intestinal defect. 3 The authors report a case of a 54-year-old Caucasian male who underwent OLT for alcoholic cirrhosis. A pretransplant liver biopsy demonstrated cirrhosis with minor (grade 1) siderosis and a normal hepatic iron concentration and hepatic iron index. The patient had an uneventful postoperative course and did well for 4 years following OLT. He underwent incisional hernia repair 49 months following transplant. At that time a liver biopsy was taken and unexpectedly demonstrated severe explant hemosiderosis with grade 4 iron deposition, hepatic iron concentration of 252 mol/g dry weight (normal Ͻ40), and hepatic iron index of 5.0 (normal Ͻ1.0). A repeat liver biopsy confirmed these findings. The patient initiated therapeutic phlebotomy and had 6 gra...

Hepatic Iron Overload following Liver Transplantation from a C282Y/H63D Compound Heterozygous Donor

“…Strong arguments against this hypothesis were presented in early 2000s, with claims that if HH is due to an intestinal defect, liver transplantation would not cure the hemochromatosis and iron would be expected to reaccumulate [ 10 ]. Yet, a number of studies failed to observe any long-term (up to 12 years) reaccumulation of iron after liver transplantation for HH [ 11 – 13 ].…”