Hepcidin in hemochromatosis: The message or the messenger?
Authors: Paul C. Adams
Journal: Hepatology (2013)

Despite the discovery of the hemochromatosis gene (HFE) in 1996,1 the pathogenesis of hemochromatosis remains elusive. Typical patients are homozygous for the C282Y mutation of the HFE gene. This mutation causes a convolutional change in the HFE protein which impairs cellular trafficking.2 A cascade of changes in iron-related proteins results in a low serum hepcidin in most patients with hemochromatosis. Hepcidin is primarily produced in the liver and is a major regulator of iron balance in the body3 and this dysregulation of hepcidin is our current theory for the pathogenesis of hemochromatosis.4 In this issue of Hepatology, Bardou-Jacquet et al.5 report a meticulous follow-up of 18 C282Y homozygous patients transplanted for hemochromatosis. The concept is that a liver transplant from a non-C282Y homozygote donor would replenish the supply of hepcidin, which would then decrease the intestinal iron hyperabsorption that is typical in hemochromatosis. The patients had serum iron, serum hepcidin, and hepatic iron concentrations determined before liver transplantation and at the end of follow-up (median 57 months). Survival was compared to that of the overall patient population that received liver transplantation. Prior to liver transplantation, serum hepcidin levels were low (0.54 ± 2.5 nmol/L; normal range: 4-30 nmol/L). After liver transplantation, 11 patients had iron evaluations; none received iron depletion therapy and all had a normal transferrin saturation. Although C282Y homozygotes are common (1 in 227 Caucasian patients), liver transplantation is uncommon for hemochromatosis. Liver failure is unusual in hemochromatosis and hepatocellular carcinoma with cirrhosis may be the most common indication in a C282Y homozygote. Many patients are overdiagnosed with hemochromatosis prior to liver transplantation because of the common elevations in iron tests in many other chronic liver diseases. The observations in this study are consistent with transplant experiments in animals.6 Transplantation of a normal liver (wild-type) into an HFE knockout mouse reduced intestinal iron absorption and normalized or improved serum, spleen, and enterocyte iron. Transplantation of an HFE knockout liver into a normal mouse led to a high transferrin saturation and liver iron accumulation.7, 8 Would the transplantation of a C282Y homozygous donor liver into a nonhomozygous recipient in humans result in iron overload? There have been multiple cases reported of C282Y homozygous livers being transplanted inadvertently into patients with other liver diseases and most of these cases have not documented iron overload after the transplant.9, 10 In one case report an elevated serum hepcidin was reported when a low level was anticipated.11 This may be related to an increase in hepcidin with transplantation or suggest extrahepatic production of hepcidin. The simultaneous transplant of a liver and small intestine from a C282Y homozygote has been reported to cause progressive iron overload,12 which raises the question of the potential importance of the HFE defect in an affected intestinal graft. This study seems to confirm that hemochromatosis patients will not require phlebotomy after transplantation and also that their outcome is similar to other patients. It is possible in this study that the pretransplant iron depletion has reduced the risks of postoperative cardiac dysfunction and sepsis previously reported.13 Serum hepcidin assays have not been widely used in clinical medicine at the present time. There is biological variability and noniron-related factors that may affect serum levels.14 When serum insulin was first measured, many considered that it would become the diagnostic test for diabetes and yet it has not replaced serum glucose as the diagnostic tool for diabetes.15 It is likely that this will also apply to serum hepcidin and iron tests and it may remain a test of special interest to researchers. Clinicians also need a better understanding on how to interpret a serum hepcidin level within different clinical settings such as iron deficiency, hemochromatosis, thalassemia, anemia, hepatitis, steatohepatitis, inflammation, and cirrhosis. A low serum hepcidin has been reported in alcoholic liver disease and chronic hepatitis C and may be related to severity of liver disease.16, 17 There may be more clinical interest in serum hepcidin in conditions associated with an elevated serum hepcidin such as the anemia of chronic disease. In this study, the investigators used the serum hepcidin/ferritin ratio to interpret the results in relationship to body iron stores, but in many other clinical scenarios the serum ferritin is not elevated from iron overload and the ratio may be deceptive. A low serum hepcidin as the cause of hemochromatosis raises the possibility of hepcidin analogs as treatments for hemochromatosis.6, 18 However, the costs of a parenteral peptide therapy would need to be compared to the simple and low-cost phlebotomy therapy. It is for these same reasons that oral iron chelators have not become commonly used for the treatment of hemochromatosis.19 Will hepcidin dysregulation be the last word on the pathogenesis of hemochromatosis? It does not appear that hepcidin is the primary defect in hemochromatosis. Is it the message or the messenger? Hepcidin mutations are extremely rare and may cause severe iron overload. In most patients, it seems to be a cascade of events starting with the HFE mutation that leads to the hepcidin dysregulation. There are new iron regulatory peptides being discovered like erythroferrone that can regulate hepcidin.20 We are still searching for the reasons why some C282Y homozygotes have a normal serum ferritin and transferrin saturation while other patients have severe iron overload. Comodifying genes such as TMPRSS6 have been discovered in genome-wide association studies (GWAS) and in referred patients21 and there will likely be more genes and proteins discovered that contribute to the heterogeneity of clinical expression. Paul C. Adams, M.D. Department of Medicine, University Hospital, London, Ontario, Canada