Hereditary Hemochromatosis Missed Diagnosis or Misdiagnosis?

SUMMARY: It is estimated that 1-6 individuals per 100 in the United States have Iron overload syndrome as measured by random elevated Iron Saturation level. Hereditary Hemochromatosis (HH) is an inherited, Autosomal Recessive, iron storage disease and in the US usually occurs as a result of HFE gene mutations. This is more prevalent among persons of European origin and the HFE gene is located on the short arm of chromosome 6 and modulates iron uptake. Two mutations on the HFE gene, C282Y and H63D, account for the majority of the cases of Hereditary Hemochromatosis, in the United States. The authors in this provocative study reviewed the electronic medical records of patients seen at a tertiary referral center, to evaluate the accuracy of diagnosis of Hereditary Hemochromatosis (HH). HFE genotyping helps differentiate HH from secondary causes of Iron overload syndromes. This differentiation is relevant because of the lack of established guidelines with regards to management of individuals with abnormal iron studies, secondary to liver disease. It is however well known that HH and iron overload related to transfusions, can cause organ damage and this could be prevented by removing the excess iron. In this study, the authors investigated the diagnostic approach, when elevated iron studies were noted, interpretation of HFE genotyping results by physicians in order to accurately diagnose HH and factors contributing to misdiagnosis. Their review conducted between January 2002 and May 2012, demonstrated that of the 601 patients with disorders of iron metabolism, only 62% were genotyped for mutations in the HFE gene. Of those genotyped, 54% had genotypes consistent with HH (Homozygotes – C282Y/C282Y or Compound Heterozygotes – C282Y/H63D) and the rest of the 46% had non-hereditary hemochromatosis genotypes (C282Y heterozygotes, H63D homozygotes and heterozygotes, etc). One half of these non-hereditary hemochromatosis genotype patients were misdiagnosed as Hereditary Hemochromatosis and a third of these patients underwent phlebotomy. Of those who were not genotyped for mutations in the HFE gene, a third of these patients were diagnosed to have Hereditary Hemochromatosis and majority of these patients underwent phlebotomy. More than two third of the patients misdiagnosed to have Hereditary Hemochromatosis in fact had liver disease and 5% had other hematological conditions. The authors concluded that C282Y heterozygotes as well as H63D homozygotes and heterozygotes do not have Hereditary Hemochromatosis and a majority of patients with iron overload are misdiagnosed to have Hereditary Hemochromatosis. Aggressive phlebotomy in the absence of an appropriate Hereditary Hemochromatosis genotype, is not indicated and can be potentially harmful, delaying more appropriate therapy. Cherfane CE, Hollenbeck RD, Go J, et al. The American Journal of Medicine 2013;126:1010-1015.