Ferritin >1000: grand for hemochromatosis screening?

In this issue of Blood, Waalen and colleagues describe one-time screening using serum ferritin (SF) greater than 1000 μg/L to detect HFE hemochromatosis and increased risk of cirrhosis in non-Hispanic white individuals.

HFE C282Y homozygosity occurs in 0.44% to 0.48% of non-Hispanic white individuals in North America, and is the predominant hemochromatosis genotype.^1-3  In hemochromatosis patients diagnosed via routine medical care, cirrhosis and other complications are common.³  Until recently, it was believed that population screening using transferrin saturation, with or without HFE genotyping, would detect undiagnosed persons with iron overload (IO), allowing timely iron depletion to prevent organ damage as compared with delayed diagnosis and institution of phlebotomy when relying only on routine medical care. Ironically, few C282Y homozygotes discovered in screening have severe IO or cirrhosis.^1,2  Except for liver abnormalities, disease manifestations in screened C282Y homozygotes are no more prevalent than in control subjects.^3,4  The United States Preventive Services Task Force concluded that benefits do not outweigh risks and costs of phenotype or genotype screening for HFE hemochromatosis.⁵ 

The present novel screening proposal is based on accepted principles: (1) cirrhosis is the most common, serious IO complication of HFE hemochromatosis; and (2) an SF level greater than 1000 μg/L predicts increased risk of cirrhosis.³  Waalen et al reviewed other characteristics of C282Y homozygotes pertinent to one-time SF screening: (1) the development of severe IO is uncommon and cannot be detected prospectively; (2) SF does not usually rise substantially over long intervals; (3) most subjects 30 years of age or younger have SF levels less than or equal to 1000 μg/L; (4) cirrhosis is rare among those with SF levels less than 1000 μg/L; and (5) some develop cirrhosis due to non-IO causes. In 29 699 white individuals,²  Waalen and colleagues detected SF levels above a “grand” in 59, including 19 men and 5 women with C282Y homozygosity or other HFE genotypes lacking wild-type alleles. The Hemochromatosis and Iron Overload Screening (HEIRS) Study findings are similar.^2,3  Waalen et al discovered only one screen-positive C282Y homozygote with cirrhosis (and alcoholism), but did not routinely perform liver biopsy in screen-positive subjects.

No practical screening strategy can detect all C282Y homozygotes whose risk of cirrhosis is increased, especially those with alcoholism, viral hepatitis, or hepatic steatosis. Such persons may also benefit less from iron depletion than those with hepatic injury due to IO alone, although hepatic fibrosis sometimes resolves after iron depletion.³  The authors state that one-time SF screening would be more cost-effective than other strategies, but provide no formal support for their assertion. Screening white populations often detects persons with elevated SF levels less than or equal to 1000 μg/L caused by various liver disorders or other conditions, and detects subnormal SF levels resulting from iron deficiency.^1-3  If all abnormal screened SF values were reported to participants or their physicians, the costs of screening and investigating “positives” could exceed informal estimates, regardless of the SF cut point.

The “grand” SF strategy warrants prospective evaluation in a study designed to define optimal venues and subpopulation targets for screening, provide liver biopsies and treatment for persons discovered to have HFE hemochromatosis and SF levels greater than or equal to 1000 μg/L, conduct follow-up evaluations of untreated C282Y homozygotes with substantially elevated SF levels (≤1000 μg/L) or non-IO liver disorders, and assess screening benefits, risks, and costs.