To determine the prevalence, genetic and environmental determinants, and potential clinical,
      personal, and societal impact of iron overload and hereditary hemochromatosis, in a
      multi-center, multiethnic, primary care-based sample of 100,000 adults. The study is
      conducted by the Division of Epidemiology and Clinical Applications of the NHLBI, the
      Division of Blood Diseases and Resources of the NHLBI, and the Ethical, Legal, and Social
      Implications (ELSI) Research Program of the NHGRI.

Hemochromatosis and Iron Overload Screening Study (HEIRS)

Blood Disease

Hemochromatosis

Iron Overload

BACKGROUND:

      Hereditary iron overload, or hemochromatosis, is a common inherited disorder among
      Caucasians, with an estimated prevalence of 0.25-0.50 percent, though it is mistakenly
      believed by many to be quite rare. The disease is insidious in onset, and many or even most
      individuals diagnosed with this disorder are not identified until advanced organ damage is
      present. However, in the absence of anemia, which can be caused by tissue damage from iron in
      late stages of the disease, it is relatively easy to treat the disorder by removing the
      excess iron through repeated phlebotomy. Evidence suggests that early diagnosis and treatment
      can prevent disease manifestations and enable normal life expectancy The discovery of the HFE
      C282Y and H63D variants in the HLA gene region on chromosome 6 provides an opportunity for
      early and rapid genetic identification of individuals at risk for development of hereditary
      hemochromatosis. Much remains to be learned about the penetrance and expression of these
      alleles, including their relevance to the full spectrum of clinical disease. To date, the HFE
      alleles appear predominantly associated with disease mainly in populations of Caucasian
      descent. While 80-90 percent of Caucasian hemochromatosis patients have HFE abnormalities,
      there are hetero- and homozygotes that do not manifest any evidence of disease, or manifest
      disease at different ages and with different outcomes, implying the existence of other
      genetic or environmental factors. Similarly, not all hemochromatosis patients have HFE
      abnormalities. Other genes yet to be discovered are also likely to be involved in
      pathogenesis of iron overload and familial hemochromatosis in non-Caucasian populations as
      well. This project is intended to examine the genetic and environmental determinants and
      correlates of iron overload and hereditary hemochromatosis in diverse populations.

      Increases in body iron may be due to increased absorption (hemochromatosis), increased oral
      intake of non-therapeutic iron, unneeded iron therapy, or multiple blood transfusions in the
      absence of bleeding. The excess iron is deposited in body tissues, and can reach toxic levels
      leading to organ damage. The toxicity can affect most tissues and organs, but particularly
      the liver, causing cirrhosis; the endocrine system, causing diabetes, hypogonadism, and
      sometimes hypoparathyroidism; and the heart, causing arrhythmias and cardiomyopathy.

      Iron overload and hereditary hemochromatosis have not been as extensively studied in
      non-Caucasian racial/ethnic groups as they have in Caucasians. The toxicity of excess iron in
      non-Caucasians appears to be similar to that in Caucasians, but the prevalence of iron
      overload is unknown and while a genetic contribution to that overload is suspected it has not
      been proven in all groups. It has long been assumed that iron storage disease in populations
      of sub-Saharan Africa is due to increased iron absorption from beer brewed in iron pots, but
      more recent information suggests there is also a hereditary component to that accumulation of
      iron. However, iron overload among Africans does not appear to be due to HFE abnormalities,
      nor to other genes in the HLA region at all. Primary iron overload has been reported in
      African Americans but it remains to be determined whether or not this is linked to HFE or
      other genetic factors. Iron overload has been reported in Asian populations, but the
      frequency and genetic contributions (if any) are not known. In some studies where HFE
      variants have been found in non-Caucasians, additional genetic testing has suggested that
      Caucasian admixture may have been involved. Hispanic-Americans appear to have a frequency of
      iron overload similar to non-Hispanic Caucasians, although further study of the genetic and
      environmental correlates is warranted. There has been almost no study of iron overload and
      hereditary hemochromatosis in Native American populations.

      Hemochromatosis may be suitable for detection and intervention through primary care or
      population-based screening strategies because: 1) it is relatively common; 2) it is
      asymptomatic in its early stages; 3) screening methods are reliable; 4) standard diagnostic
      methods are widely available in developed countries and relatively inexpensive; 5) it is
      easily treatable; and 6) if untreated, the subsequent burden of morbidity and mortality is
      substantial. The feasibility and benefits of such programs remain to be assessed, however,
      since the prevalence of the disorder and the factors related to its phenotypic expression
      (such as the optimal age for reliable detection and effective intervention) are unknown.
      Other questions needing to be addressed include public acceptability of screening and
      testing; sensitivity and specificity of the screening methods, particularly in
      non-Caucasians; optimal timing and setting of screening and testing; as well as the benefits
      and costs and/or other burdens associated with screening and testing.

      A major objective of the project is to gather information needed to develop recommendations
      regarding possible primary care- or population-based screening for hemochromatosis.
      Estimating the burden of preventable illness from unrecognized hemochromatosis is one of the
      most important of these needs. Comparing the relative value and acceptability of diagnosis
      and screening by genotype vs phenotype is also important. In particular, differences by
      racial/ethnic group, age and other characteristics will need to be examined. Some of these
      issues, such as appropriate thresholds for transferrin saturation screening, may be resolved
      during the proposed study's planning phase, while others will constitute key research
      questions to be addressed by the study itself.

      DESIGN NARRATIVE:

      The Hemochromatosis and Iron Overload Screening Study is a multi-center epidemiological study
      of the prevalence and genetic and environmental determinants of iron overload and hereditary
      hemochromatosis in a diverse and representative primary care-based sample of men and women
      aged 25 and older. Over 101,000 patients undergoing routine screening or testing involving a
      blood draw were recruited from five Field Centers and screened for transferrin saturation
      levels. Cost-effective population-based strategies for recruitment was also considered. A
      repeat fasting transferrin saturation screen in conjunction with a serum ferritin assay was
      used to identify potential 'case' participants with confirmed elevated transferrin saturation
      levels and matched random 'control' participants with confirmed non-elevated transferrin
      saturation levels.

      In order to obtain data on the prevalence of genetic factors in a routine care population, a
      random subgroup of approximately 20-40 percent of the 101,000 screenees will be genotyped for
      known variants, such as HFE C282Y and H63D, related to iron metabolism and overload. The
      panel of genotypes to be assayed will reflect the state of knowledge at the time this phase
      of the study is conducted. In particular, any newly discovered variants related to iron
      overload and hemochromatosis in non-Caucasian populations, such as for iron overload among
      Africans, will be included. The results of the genotyping will not directly impact the
      selection of case and control participants; case/control selection will be based only on the
      transferrin saturation/serum ferritin screen results. It is likely that many HFE genotype
      positive persons will have confirmed elevations of transferrin saturation and thus may get
      selected as confirmed elevated transferrin saturation case participants. Genotype positive
      persons with non-elevated transferrin saturation levels, who are not randomly selected as
      controls, will constitute a third group and undergo the same intensive studies as cases and
      controls. A random sample of the individuals being recruited to participate in the genotyping
      subgroup will be surveyed to determine their knowledge and attitudes about, interest in, and
      support for such screening programs. Both qualitative and quantitative measures will be
      employed. Efforts will be made to ascertain reasons for refusal and related information from
      those who decline participation. In addition, 2,000 primary care patients will be selected to
      participate in a substudy comparing phenotype- versus genotype-based screening and testing
      methods.

      Following these transferrin and random subgroup genotyping screens, a comprehensive clinical
      examination will be conducted in the confirmed elevated transferrin saturation potential case
      participants, the genotype-positive participants, and the confirmed non-elevated control
      participants to assess iron stores, distinguish between primary and secondary causes of iron
      overload and to examine the associated hepatic, endocrinologic, hematologic and
      cardiovascular disease correlates and sequelae of hemochromatosis. A detailed family and
      medical history will be obtained. Examination participants not previously genotyped will
      undergo genotyping, with a panel of genotypes as described above, for use in association
      analyses. The genotype-positive participants will receive counseling on their results. The
      examination will also include an extended ELSI assessment of issues related to genetic
      screening and testing and diagnosis of disease. Data will be collected on the participants'
      acceptability of genetic testing, their experience with screening, their understanding and
      interpretation of their results, and on the impact this information is having on their own
      lives as well as those of their family members. Specific components of the comprehensive
      clinical examination will be determined during protocol development. Follow-up ELSI
      assessments will examine issues such as impact of the screening program on relationships with
      family members, and any experiences with stigmatization and discrimination.

      A family study, using comprehensive clinical examinees as probands, will seek to identify
      modifier genetic variants related to the expression of iron overload and hereditary
      hemochromatosis disorders via genome scanning and assessment of linkage. Identification of
      new genetic variants, particularly in minorities, is also of great interest, but it is
      possible this study will not achieve sufficient power to do so. Proposed efforts to improve
      the power, such as combining data from other studies, will be considered. The family study
      ELSI assessment will examine family members' experiences with the screening program, the
      impact of this information on their lives and relationships, and any experiences with
      stigmatization and discrimination.

      A repository of blood specimens will be established to permit additional studies of genetic
      and environmental factors relating to iron overload. This will require careful attention to
      the details of informed consent. For some later studies, the specimens may be anonymized.

      The study has five Field Centers, a Coordinating Center (which will subcontract for any
      necessary Reading Centers such as an ECG Reading Center), and a Central Laboratory (which may
      subcontract for novel assays and/or the genome-wide scan).

Hemochromatosis and Iron Overload Screening Study (HEIRS)

About this trial

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Placebo

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