Therapeutic Phlebotomy

Hereditary Hemochromatosis

HH is a common inherited disorder characterized by progressive accumulation of dietary iron. In the United States, the most common hemochromatosis genotype is the homozygous mutation in the HFE gene (C282Y or H63D; type 1 HH), involved in the regulation of hepcidin, the peptide hormone central to the regulation of iron metabolism. Autosomal recessive mutations in hepcidin itself and its other regulators (HJV, TfR2) as well as autosomal dominant mutations in its receptor (ferroportin) result in juvenile, type III, and type IV HH, respectively.

Serum transferrin saturation and ferritin levels are typically used for screening. Genetic testing for the most common HH-associated mutations is routinely available. Liver biopsy and noninvasive quantitative techniques (i.e., MRI) enable diagnosis of parenchymal iron overload. Life-threatening complications of iron overload include cirrhosis, hepatocellular carcinoma, diabetes, and heart disease. The severity of liver disease closely reflects the magnitude of hepatic iron deposition and is often reversible with therapy.

Therapeutic phlebotomy is the treatment of choice in patients with HH. However, the benefit of therapeutic phlebotomy has not been established for HH individuals without elevated serum ferritin or evidence of tissue iron load. In cases with evidence of frank or impending iron overload, complications and symptoms can be prevented or reversed by reducing iron overload for which therapeutic phlebotomy is an established treatment. Response rate to therapeutic phlebotomy is dependent on the individual severity of iron overload and no evidence-based guidelines are available to direct the end point of therapeutic phlebotomy. The recommendations that exist are based on (1) a theoretical argument that achieving iron deficiency is necessary to normalize tissue iron and (2) that a stated target prevents variable interpretation and practice. Thus, practice guidelines propose goals of therapy as reducing and maintaining low-normal iron stores (ferritin 50–100 ng/mL). The typical regimen is weekly phlebotomy until ferritin approximates 50 ng/mL followed by lifelong maintenance phlebotomy. Although therapeutic phlebotomy is not a cure for HH, effectively phlebotomized patients exhibit normalized tissue iron, decreased risk of liver cirrhosis, and a significantly longer median survival.