Curing Iron Overload with Liver Transplantation

The role of hepcidin in iron metabolism has been described in detail.  Yet, a new study provides another line of evidence that the liver has a primary role in regulating iron absorption (Hepatology 2014; 59: 839-47, editorial 749-50).

Background: Hereditary hemochomatosis (HH) is mainly due to defects in the gene encoding the human hemochromatosis protein (HFE), particularly the C282Y mutation.  Initially, HH was thought to be related to the role of HFE in regulation iron absorption at the intestinal crypt.  However, the discovery of hepcidin, which is mainly secreted by the liver, was shown to regulate iron absorption through its interaction with ferroportin, the cellular iron exporter. With HH, inappropriately low hepcidin was associated with excessive iron absorption.

Despite this understanding, many questions remain, especially regarding the fact that some C282Y homozygotes have a normal serum ferritin and transferrin saturation.  In addition, whether liver transplantation prevents further iron overload in patients transplanted for HH is not entirely certain.

Methods: This study evaluated 18 liver transplant (LT) patients with HH and who were homozygous for C282Y mutations.  16 of these patients had HCC.  All patients underwent iron evaluations (iron, hepcidin, hepatic iron concentrations) prior to LT and most (n=11) had evaluations following LT with a median followup of 57 months.

Key findings:

  • After LT, no patients received iron depletion therapy (eg. phlebotomy).  9 of 11 had no iron overload based on bloodwork (normal transferrin saturation) and MRI without iron overload.
  • One patient with hereditary spherocytosis continued to have iron overload, and one patient with metabolic syndrome had mild iron overload.
  • Hepcidin was normal (11.12 nmol/L) in 10 patients at the end of followup and low in one patient with iron deficiency anemia; prior to LT, serum hepcidin levels were low in all patients (mean 0.54 nmol/L)

Bottomline: This study shows that LT corrects hepcidin dysregulation caused by the HFE mutation and that post-LT HH patients do not require phlebotomy.  Thus, HH is clearly a liver disease and not an intestinal disease.

Related blog post: Help with hepcidin | gutsandgrowth (with annotated references)

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