Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00005541 |
| Other study ID # |
5083 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
May 25, 2000 |
| Last updated |
April 13, 2016 |
| Start date |
January 2000 |
| Est. completion date |
January 2006 |
Study information
| Verified date |
April 2009 |
| Source |
National Heart, Lung, and Blood Institute (NHLBI) |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Federal Government |
| Study type |
Observational
|
Clinical Trial Summary
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.
Description:
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).
