The Hematologist

May-June 2008, Volume 5, Issue 3

Clinical Penetrance of HFE Hereditary Hemochromatosis, Serum Ferritin Levels, and Screening Implications: Can We Iron This Out?

Michael Linenberger, MD

Published on: May 01, 2008

Allen KJ, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358:221-30.

Waalen J, Felitti VJ, Gelbart T, et al. Screening for hemochromatosis by measuring ferritin levels: a more effective approach. Blood. 2008;111:3373-6.

Since the discovery of the homozygous C282Y mutation of the HFE gene as the major cause of hereditary iron overload in Caucasians of Northern European descent, numerous studies have attempted to define the risk of iron-overload-related disease and a practical rationale for screening. The interpretation of cross-sectional population and family-based studies has been controversial,1,2 related to concerns about ascertainment bias, observer bias, insufficient control groups, and variable definitions of disease penetrance. Longitudinal cohort studies have involved relatively few HFE homozygotes and mostly women, thus raising issues about gender bias and other confounding variables. The U.S. Preventive Services Task Force recommendation against genetic screening cited the need for more information on the clinical penetrance of HFE-associated disease, factors affecting phenotypic expression, and outcomes from prospective follow-up and therapeutic intervention trials.3

Allen, et al. analyzed 12-year biochemical and clinical data on 1,438 adults of Northern European ancestry (99 percent 40 to 69 years old) participating in a longitudinal health study. The 203 C282Y homozygotes and matched controls with other HFE genotypes or no mutations underwent baseline and follow-up interviews, blinded physical exams, and laboratory studies. Liver biopsies were performed on 16 of 33 men and one of seven women HFE homozygotes who had at least one serum ferritin >1,000 µg/L. Among those with documented iron overload, clinical disease occurred in 21 of 74 men (28.4 percent) and one of 84 women (1.2 percent); including hepatocellular carcinoma (n=2), liver fibrosis or cirrhosis (n=12), elevated transaminases (n=6), abnormal metacarpophalangeal joints (n=5), or other hemochromatosis-related symptoms (n=11). Serum ferritin ≥1,000 µg/L was significantly associated with fatigue, liver disease, use of arthritis medication at baseline, and elevated transaminases, but not associated with diabetes or joint arthropathy. One non-C282Y homozygote had clinical disease. Waalen, et al. observed a serum ferritin level >1,000 µg/L in 59 of 29,699 white adults (0.2 percent) in the Scripps-Kaiser hemochromatosis study, including 20 C282Y homozygotes and four with other HFE genotypes, only one of whom had liver cirrhosis. (The number of biopsies was not reported.) Hyperferritinemia in 30 of the 35 without HFE mutations (86 percent) was attributable to excess alcohol, cancer, liver disorders, or hemolytic anemia. The researchers concluded that a single serum ferritin determination could serve as a cost-effective screen for the most threatening HFE mutation-associated complication (liver cirrhosis). Ferritin was also valuable in identifying non-HFE disorders, similar to observations among multi-ethnic populations.4

The report by Allen, et al. supports prior observations that iron-overload-related disease, when broadly defined, affects roughly a quarter of male HFE C282Y homozygotes.1 Both reports confirm data from others that liver cirrhosis develops at a serum ferritin >1,000 µg/L. Importantly, however, pre-cirrhotic fibrosis is found in 28 percent of asymptomatic C282Y homozygotes with a ferritin of 500 to 1,000 µg/L (mostly middle-aged males) and phlebotomy reverses this process.5 Thus, using a ferritin of >1,000 µg/L for screening, rather than the conventional thresholds of >200 µg/L for premenopausal women and >300 µg/L for other adults, may fail to identify some high-risk homozygotes before irreversible liver injury develops. Despite new understanding, a risk-adapted screening and management approach to HFE hemochromatosis still awaits answers to the following questions:

  • How do genetic, lifestyle, and other co-factors affect progression or "nonexpression" of iron overload and liver disease?

  • Are other tissues (joint, endocrine, cardiac) at risk? If so, by what mechanisms?

  • What clinical and/or biochemical parameters (e.g., ferritin level) should be used to initiate therapeutic phlebotomy?

  1. Ajioka RS and Kushner JP. Clinical consequences of iron overload in hemochromatosis homozygotes. Blood. 2003;101:3351-3.

  2. Beutler E. Rebuttal to Ajioka and Kushner. Blood. 2003;101:3354-7.

  3. U.S. Preventive Services Task Force. Screening for hemochromatosis: recommendation statement. Ann Intern Med. 2006;145:204-8.

  4. Adams PC, Reboussin DM, Barton JC, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005;352:1769-78.

  5. Powell LW, Dixon JL, Ramm GA et al. Screening for hemochromatosis in asymptomatic subjects with or without a family history. Arch Intern Med. 2006;166:294-301.

Conflict of Interests

Dr. Linenberger indicated no relevant conflicts of interest. back to top