Ask the Hematologist January-February 2007

A 74-year-old African-American woman was found to have a serum ferritin concentration of 2010 ug/L and transferrin saturation of 33 percent on screening blood tests. She was on anti-hypertensive and cholesterol-lowering medications and multivitamins with iron, but had no history of blood transfusions or blood donations. She did not drink alcohol. Repeat blood testing revealed ferritin 2012 ug/L, transferrin saturation 34 percent, hemoglobin concentration 13.2 g/dL, and mean corpuscular volume 91 fL. Testing for hepatitis B surface antigen, antibody to hepatitis C, the C282Y and H63D mutations in the HFE gene, and the Q248H mutation in the ferroportin gene was negative. Apart from a slightly elevated gamma glutamyl transferase concentration of 43 U/L, liver function tests were normal. A diagnostic needle liver biopsy revealed grade 3 hepatocellular iron in a periportal distribution, the presence of macrophage iron, minimal portal inflammation, and otherwise normal hepatic architecture. The patient was advised to discontinue multivitamins with iron and to undergo a weekly phlebotomy program with the endpoint of serum ferritin <20 ug/L, but the patient complied with the program only sporadically.

Infectious and other inflammatory processes, hepatic disorders such as alcoholic and viral hepatitis and non-alcoholic steatohepatitis, increased body-iron stores resulting from multiple blood transfusions, anemias characterized by ineffective erythropoiesis, and mutations in HFE or other iron pathway-related genes are all potential causes of increases in serum ferritin concentration. In addition, any acquired anemia that is not due to blood loss or iron loss is associated with an increase in macrophage stores and serum ferritin, because iron formerly present in hemoglobin enters storage during development of anemia. Inflammatory processes are typically characterized by reduced transferrin saturation in association with increased serum ferritin concentration. On the other hand, patients with elevated iron stores or hepatic disorders tend to have transferrin saturations above the population mean in association with increased serum ferritin concentration.

Homozygosity for HFE C282Y, the most commonly recognized cause of primary increases in body-iron stores in persons of European ancestry, has a prevalence of about 440/100,000 in Caucasians but only 14/100,000 in African-Americans. About 90 percent of male and about 55 percent of female C282Y homozygotes have elevated serum ferritin concentrations, at least to a mild degree, but the occurrence of organ damage is far lower. The ferroportin Q248H mutation seems to be unique to persons of African ancestry. Heterozygosity for ferroportin Q248H occurs in about 10 percent of African-Americans and has been associated with increased iron stores in a minority of individuals. Mutations in a number of other genes, including those for transferrin receptor 2, hemojuvelin, and hepcidin, are associated with increased iron stores but rare in the population. Iron overload on a dietary basis is well described in sub-Saharan Africa and may be associated with an as-yet-undefined genetic predisposition. Whether taking multivitamins with iron contributed to increased iron stores in the patient presented here is not clear. Frequently, increased iron stores, usually of mild degree, are documented in patients of various ethnic groups without a history of blood transfusions and without the presence of HFE mutations. In a recent analysis, serum ferritin concentration >200 µg/L for women or >300 µg/L for men in combination with transferrin saturation >29 percent for women or >35 percent for men occured in 6.7 percent of more than 27,000 African-American primary care patients > 25 years of age, and these patients were at increased risk for elevated body iron stores and/or liver disease.

Clearly, heavily iron-loaded patients are at risk for cirrhosis, hepatoma, and heart failure and iron should be removed by phlebotomy therapy if anemia is not present and by iron chelation if phlebotomy is not possible. Heavy iron loading associated with these complications occurs in only a small minority of HFE C282Y homozygotes, ferroportin Q248H heterozygotes, and patients with primary increases in iron stores of undetermined etiology. Mild increases in iron stores are associated with symptomatic porphyria cutanea tarda, and some studies suggest such elevations may be associated with a general increased risk of cancer, the development of hepatocellular carcinoma in the absence of cirrhosis, and an increased risk of diabetes mellitus. Further studies of the proper management for various degrees of iron overload are needed. At present, we believe that in general it is prudent to remove excess body iron of even mild or moderate degrees.