Prevalence of iron overload in the Lower Mainland of British Columbia

Hereditary hemochromatosis (HHC) is a disorder caused by uncontrolled absorption of iron from the gut. Tissue damage occurs (principally in the liver, joints, and endocrine system) when physiologic iron stores become saturated and iron is deposited in parenchymal cells.

The prevalence of iron overload and HHC is attracting considerable attention in many parts of the world because of the recent discovery of the HFE gene on the short arm of chromosome six.[1] A major consequence of this discovery has been the development of a specific diagnostic test for HHC that has virtually eliminated the need for liver biopsy during the initial evaluation of a patient with suspected iron overload. Investigators have also been prompted to revisit the subject of population screening for HHC, which is controversial because of the ethical, societal, and legal implications of a genetic screening test.[2]

HFE-related hemochromatosis is the most common genetic disorder in persons of northern European heritage,[3] and consensus is building for the screening of such populations because of the impact (including cost savings to the health care system) that early detection would have on morbidity (diabetes, cirrhosis, and arthropathy) and mortality (hepatocellular carcinoma).[4,5] Iron overload disorders resembling HHC but which are HFE-negative are also known, especially the well-documented southern European and African types.[6,7] Therefore, there is an argument for extending population screening for iron overload to diverse populations, since it is clearly established that early intervention—by means of therapeutic phlebotomy—minimizes disease-related morbidity and can be life saving (the risk of hepatocellular carcinoma in HHC is 200 times that for the general population).[8] The study described here had two principal objectives:

• To measure the prevalence of iron overload in a diverse ethnic population of male subjects (approximately 60% white, 20% southeast Asian, and 20% south Asian)

• To make recommendations regarding population screening based upon the data obtained in light of the evidence currently available in the medical literature

Methods

There were 1905 male volunteers (between the ages of 20 and 70) recruited by means of a posted notice in community-based bleeding stations to take part in the study at the time that they presented for outpatient testing. The tests would have been ordered by their primary care physicians following a clinical examination. After informed consent, a blood sample was obtained and the following additional parameters were measured: serum iron, total iron-binding capacity, and transferrin saturation.

Serum iron and total iron-binding capacity were measured by a colorimetric method employing the “ferrizyme” principle (Sigma-Aldrich Canada). Transferrin saturation was calculated from the ratio of serum iron and total iron-binding capacity. Serum ferritin was measured by an ELISA method according to the manufacturer’s instructions (Sigma). Subjects with transferrin saturation >0.55 were retested on a fasting specimen with the addition of serum ferritin. All test results were sent to the primary care physician together with an interpretive comment. Suggestions for further investigations were made for subjects with abnormal findings. Patients with persistent elevation of transferrin saturation on fasting were referred to a hematologist and/or gastroenterologist for clinical assessment and ancillary investigations including DNA analysis for the C282Y and H63D mutations of the HFE gene associated with HHC. DNA testing was carried out at the Molecular Diagnostic Laboratory at BC’s Children’s and Women’s Health Centre using the method described by Feder and colleagues.[1]

Ethics

This study was approved by the Clinical Research Ethics Board of the University of British Columbia.

Results

Transferrin saturation was elevated in 108 subjects, of which 35 normalized on a fasting repeat. The remaining 73 showed the following:

• 23 reduced total iron-binding capacity without elevation of serum iron

• Nine hepatitis C

• Six ethanol-related liver disease

• Six non-A,B,C hepatitis

• One hepatitis B

• Four inadvertent iron supplementation

• Four borderline elevations of transferrin saturation (annual follow-up is planned for these cases)

• Two nephrotic syndrome

• One thalassemia trait

The 17 unexplained cases include these categories:

• Two C282Y homozygotes

• Two C282Y heterozygotes

• One C282Y/H63D compound heterozygote

• Four H63D heterozygotes

• One H63D homozygote

• Three DNA negative

• Four appear to be lost to follow-up

The data are summarized in the table. The accompanying figures show the distributions of serum iron (Figure 1) and transferrin saturation (Figure 2) for the study population.

Interpretation

The key findings of our study are:

• Most cases of iron overload are not HFE-related. Liver disease is the principal cause and viral hepatitis and ethanol are the most common etiologies.

• Approximately one-third of subjects with elevated transferrin saturation normalize on fasting. This is most likely due to the well-known intra-individual diurnal variation and the relationship of serum iron to a recent iron-containing meal.[9] It may also reflect the tendency for a biologic measurement to regress to the mean.[10]

• Transferrin saturation may be spuriously elevated in the presence of a reduced total iron-binding capacity. These cases are of dubious clinical significance in the absence of elevated serum iron and/or ferritin.

• HFE (C282Y homozygous)-related iron overload in this population is lower than the expected three to four per thousand. This is most likely due to ethnicity and is worthy of further study in a larger cohort.

• Measurement of serum iron and total iron-binding capacity is a valuable screening tool for iron overload in an outpatient setting; in addition to picking up cases of hemochromatosis, other important causes of iron overload (which may not be known, e.g., viral hepatitis) are also identified. Coordinating follow-up via the primary care physician is a very important factor.

Summary

Biochemical evidence of iron overload is a common finding in ambulatory outpatients. Most patients will be found to have an underlying liver disease such as viral hepatitis, and this diagnosis may not have been suspected from the patient’s history and clinical examination. Perhaps the greatest value of iron screening is the early detection of HHC, which is typically asymptomatic until the fourth decade in men and the fifth decade in women; early detection of HHC can prevent serious morbidity and mortality. Consensus is building for population screening for HHC. Specific screening strategies (target populations and the most appropriate test or tests) are the subjects of active investigation. The Guidelines and Protocols Advisory Committee (BCMA and BC Ministry of Health) has recently developed guidelines for the “Investigation and Management of Iron Overload.” This document provides useful information for physicians in the province and will help to increase awareness of iron overload states, especially HFE-related hemochromatosis.

Competing interests

Dr Krikler is a board member of the Canadian Hemochromatosis Society.

Acknowledgments

The authors wish to thank the directors and employees of BC Biomedical Laboratories for their generous assistance during the course of this study.

Transferrin saturation data summary

Samuel H. Krikler, MB, ChB, FRCPC and John C. Heathcote, MD, FRCPC

Dr Krikler is the director of Laboratory Hematology, South Fraser Valley Health Region and clinical assistant professor in the Department of Pathology and Laboratory Medicine, University of British Columbia. Dr Heathcote is medical director of BC Biomedical Laboratories in Surrey, BC.