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Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 1076-1082
Evidence of Genetic Transmission in African Iron Overload
By
Victor M. Moyo,
Eberhard Mandishona,
Sandra J. Hasstedt,
Innocent
T. Gangaidzo,
Zvenyika A.R. Gomo,
Hlosukwazi Khumalo,
Thokozile Saungweme,
Clement F. Kiire,
Alan C. Paterson,
Peter Bloom,
A. Patrick MacPhail,
Tracey Rouault, and
Victor R. Gordeuk
From the Departments of Medicine and Chemical Pathology and the
Clinical Epidemiology Unit, University of Zimbabwe School of Medicine,
Harare, Zimbabwe; Departments of Medicine and Anatomical Pathology,
University of the Witwatersrand, Johannesburg, South Africa; Department
of Human Genetics, University of Utah Medical Center, Salt Lake City,
UT; Ormskirk and District General Hospital, Ormskirk, Lancashire,
England; Cell Biology and Metabolism Branch, National Institute of
Child Health and Human Development, Bethesda, MD; and Department of
Medicine, The George Washington University Medical Center, Washington,
DC.
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ABSTRACT |
Iron overload in Africa was previously regarded as purely due to
excessive iron in traditional beer, but we recently found evidence that
transferrin saturation and unsaturated iron binding capacity may be
influenced by an interaction between dietary iron content and a gene
distinct from any HLA-linked locus. To determine if serum ferritin
follows a genetic pattern and to confirm our previous observations, we
studied an additional 351 Zimbabweans and South Africans from 45 families ranging in size from two to 54 members. Iron status was
characterized with repeated morning measurements of serum ferritin,
transferrin saturation, and unsaturated iron binding capacity after
supplementation with vitamin C. For each measure of iron
status, segregation analysis was consistent with an interaction between
a postulated iron-loading gene and dietary iron content
(P < .01). In the most likely model, transferrin saturation
is 75% and serum ferritin is 985 µg/L in a 40-year-old male
heterozygote with an estimated beer consumption of 10,000 L, whereas
the saturation is 36% and serum ferritin is 233 µg/L in an
unaffected individual with identical age, sex, and beer consumption.
This segregation analysis provides further evidence for a genetic
influence on iron overload in Africans.
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INTRODUCTION |
IRON OVERLOAD of a severity to cause
damage to the liver is common among sub-Saharan Africans, with a
prevalence in some communities that is over 10 times that of the
homozygous state for HLA-linked hemochromatosis in populations derived
from Europe.1 Although increased dietary iron from
traditional home-brewed beer has been regarded as the sole cause of
iron overload in Africa,2 we recently conducted a study of
36 Zimbabwean and Zambian pedigrees that suggested a gene, distinct
from any gene linked to the HLA region on chromosome 6, may be
implicated in the pathogenesis of this condition.3 In that
study, likelihood analysis was used to test for an interaction between
a gene (the hypothesized iron-loading locus) and an environmental
factor (increased dietary iron) that would determine the levels of
transferrin saturation and unsaturated iron binding capacity, two
indirect measures of iron status.
Our original study3 had some potential limitations in the
measurement of iron status: (1) Serum ferritin was not used in the
genetic analysis. Because serum ferritin reflects body iron stores,4 this measure would be expected to display a
genetic pattern in African iron overload as it does in HLA-linked
hemochromatosis.5 (2) Single determinations of transferrin
saturation and unsaturated iron binding capacity were made on blood
samples obtained from nonfasting subjects at various times of the day
rather than repeated determinations on specimens obtained in the
morning from fasting subjects. Because serum iron has a diurnal
variation,6,7 the transferrin saturation and unsaturated
iron binding capacity may vary markedly according to the time of day.
Furthermore, ingestion of an iron-rich food or beverage within 6 hours
of venesection could conceivably increase transferrin saturation and
decrease unsaturated iron binding capacity8,9 (3) The
vitamin C status of the subjects was unknown, and they did not receive
vitamin C supplementation before venesection. Serum iron and
transferrin saturation may be inappropriately decreased and unsaturated
iron binding capacity inappropriately increased in iron-loaded subjects with vitamin C deficiency.10 (4) The subjects were not
asked to abstain from alcohol before venesection. Simultaneous
ingestion (within 6 hours) of alcohol in the form of traditional beer
might substantially increase the serum iron and transferrin saturation and decrease the unsaturated iron binding capacity because of the iron
content of the beverage, as mentioned, and recent ingestion (within
days) of substantial amounts of alcohol of any type might increase
serum iron and transferrin saturation levels and decrease unsaturated
iron binding capacity through bone marrow suppression and impaired
folate metabolism.11,12
We now report the results of a study of 45 additional pedigrees that
was designed to address the potential limitations of our original
investigation. Iron status was measured in a detailed manner in these
families, and serum ferritin was included in the segregation analysis.
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SUBJECTS AND METHODS |
Study sample.
Written informed consent was obtained from all study subjects. The
sample consisted of 351 black Africans older than 12 years of age: 150 from five of Zimbabwe's 10 provinces and 201 from one of South
Africa's nine provinces. The research subjects were predominantly
rural dwellers of Shona, Swazi, and Shangaan ethnic origin, and none
had European ancestry. We ascertained 21 pedigrees, ranging in size
from six to 54 members and comprising a total of 271 subjects, through
index subjects exhibiting iron overload (hepatocellular iron grade, 2 to 4)13,14 on diagnostic liver biopsy specimens. To
maximize the sample size and to strengthen the estimates of the
parameters of the genetic model and of the gene frequency, we included
an additional 24 pedigrees, ranging in size from two to 13 members,
that were not ascertained through index subjects with iron overload but
comprised 70 subjects who were rural traditional beer drinkers. We
visited the villages of the study participants and determined precise
relationships within the pedigrees in interviews.
Estimation of traditional beer consumption.
Traditional beer was defined as a beverage that is brewed at home in
nongalvanized iron drums and is known to have a high iron
content.2 In 48 samples of this beverage collected from the
subjects' households, the mean ± SD alcohol concentration was 3.2% ± 0.4% and the mean iron content was 46 ± 17 mg/L. Each subject
was asked to estimate his or her consumption of traditional beer: the
amount ingested on a typical day, the number of days in a typical month
the beverage was consumed, the year the subject began drinking
traditional beer, and if no longer drinking, the year he or she
stopped. The estimate only provides a broad approximation of lifetime
traditional beer consumption, because consumption was probably not
uniform over time and information was obtained by recollection.
Collection of blood samples.
To confirm that elevated serum iron levels were not a sporadic
event,15 venous blood samples were obtained on 3 separate days in 322 (92%) of the subjects. In the remaining 29 subjects, blood
samples were collected on 1 or 2 days. The blood samples were obtained
in the morning to avoid the effect of diurnal variation in serum
iron.4,5 Samples were drawn from fasting individuals to
avoid the transient increase in serum iron potentially seen after
ingestion of an iron-rich meal.6 Because serum iron and serum ferritin may be inappropriately decreased in iron-loaded subjects
with vitamin C deficiency,8 1.0 or 2.0 g vitamin C were
given orally to each subject 24 hours before collection of the second
and third blood samples. To minimize alcohol-related increases in serum
iron and ferritin,9,10,16 the subjects were asked to
abstain from drinking any alcoholic beverage for at least 24 hours
before collection of the first blood sample and to continue to abstain
throughout the study period.
Laboratory tests.
The serum iron level and total iron binding capacity were determined by
methods modified from those recommended by the International Committee
for Standardisation in Haematology.17,18 The serum ferritin
level was measured using an enzyme immunoassay (Ramco, Houston, TX).
Full blood cell counts (Coulter, Hialeah, FL), reticulocyte counts, and
erythrocyte sedimentation rates (Westergren) were determined. Liver
function tests were performed with a Cobas Bio autoanalyzer (Roche
Diagnostic Systems, Montclair, NJ) using reagents from Roche Diagnostic
Systems (Johannesburg, South Africa). Hepatitis B and hepatitis C
markers were screened using enzyme immunoassay techniques (Abbott
Laboratories, North Chicago, IL). Leukocyte ascorbic acid levels were
determined by a method modified from Dennson and
Bowers.19,20 Leukocyte ascorbic acid levels were determined
on all 3 days in 298 of the subjects; in the remainder, samples were
lost during transport or processing.
Indirect measures of iron status.
Transferrin saturation was calculated as the serum iron divided by the
total iron binding capacity times 100, with a maximum value of 100%.
Unsaturated iron binding capacity was calculated by subtracting the
serum iron from the total iron binding capacity, with a minimum value
of 0 µg/dL. Where possible, we averaged transferrin saturation,
unsaturated iron binding capacity, and serum ferritin measurements
obtained on 2 different days (days 2 and 3) following vitamin C
supplementation. The ratio of serum ferritin to aspartate aminotransferase (AST) was calculated by dividing the serum ferritin on
day 1 by the AST measured on day 1, with the minimum value for AST set
at the upper limit of normal of our assays (30 to 35 IU/L) and a
minimum value for the ratio set at 1.0.
Statistical analysis.
The effect of vitamin C supplementation on leukocyte ascorbic acid
levels and on indirect serum measures of iron status was examined with
repeated-measures analysis of variance. In subjects other than index
cases, variables were compared according to whether traditional beer
was consumed by the Student t-test, Mann-Whitney U
test, or Fisher's exact test. Measures of iron status were compared according to whether subjects were first-degree relatives of index cases using analysis of variance with adjustment for age, sex, and
estimate of lifetime traditional beer consumption. Values for ferritin,
the ratio of ferritin to AST, and estimated traditional beer
consumption were logarithmically transformed for the analysis of
variance procedures.
Segregation analysis of families.
We eliminated trait values for 16 individuals including seven probands
because anemia (hemoglobin <13 g/dL for men and <12 g/dL for
women)21,22 could not be excluded as the cause of elevations in transferrin saturation and the ratio of ferritin to AST.
We followed the example of an assessment of iron nutritional status in
the US population23 and regarded an increased serum ferritin as greater than 150 µg/L in women 20 to 44 years of age, greater than 200 µg/L in men aged 20 to 44 and women aged 45 to 65 years, greater than 300 µg/L in men aged 45 to 64 and women over 64 years, and greater than 400 µg/L in men aged over 64 years. The
corresponding elevated ferritin to AST ratio would be the indicated
serum ferritin divided by a minimum AST of 30 or 35. In a conservative
application of the definition of iron overload recommended by Dr C.A.
Finch24 and used in the US nutritional survey, we
designated as affected the 21 probands and 25 other individuals with a
high serum ferritin and a transferrin saturation greater than 80%. We
designated as unaffected 50 individuals who had consumed at least 1,000 L homemade beer yet had a serum ferritin that was not elevated and a
transferrin saturation less than 42%, or who had consumed at least
10,000 L beer and had a serum ferritin that was not elevated. A
transferrin saturation of 42% is about 2 standard deviations above the
mean for African-Americans in the second National Health and Nutrition
Examination Survey.23 Adult/postmenopausal age was computed
as the years exceeding 20 for men and the years exceeding 50 for women.
Trait values for three individuals were eliminated because they had
serum ferritin levels over 10,000 µg/L, extreme elevations that would
more likely reflect hepatocellular necrosis or secretion by a tumor
rather than body iron stores.25 Lifetime beer consumption,
serum ferritin, and the ferritin to AST ratio were each natural
logarithmically transformed because of positive skew. Transferrin
saturation and unsaturated iron binding capacity were eliminated in 12 individuals because of a serum ferritin greater than 400 µg/L and a
ferritin to AST ratio less than 11.4 µg/IU; with the combination of
an elevated ferritin and a normal ratio, an elevated transferrin saturation may represent hepatocellular damage rather than iron stores.
We applied segregation analysis to transferrin saturation, unsaturated
iron binding capacity, serum ferritin, and the ferritin to AST ratio.
Each segregation analysis was a bivariate analysis of a quantitative
trait measured on 332 individuals and affection status designated on 96 individuals. Likelihoods26 of the genetic model were
computed using the Pedigree Analysis Package27 and the
maxima obtained with Non-linear Programming: Systems Optimization Laboratory (NPSOL).28 Correction was made for the
ascertainment of each of 21 pedigrees selected through a proband with
increased hepatic iron by dividing the likelihood by the probability of affection for each proband. Tests of hypotheses compared the maximized likelihood of a general model with the maximized likelihood of a
submodel formed by restricting parameters. Negative two multiplied by
the natural logarithm of the ratio of the submodel likelihood to the
general model likelihood approximates a chi-square distribution if
certain assumptions hold. Briefly, the approximation requires a large
number of independent and identically distributed observations. The
degrees of freedom for the chi-squared test equal the difference in the
number of parameters estimated in the general model and the submodel.
We assumed that a single major locus with two alleles determined both
affection status and the quantitative trait. The prevalence of
affection was fixed at 0.059. This prevalence is based on our previous
community survey in rural Zimbabwe and is the average of the proportion
of iron overload in men and in women.29 A recent survey of
iron status in a South African population gives a similar estimated
prevalence of iron overload of 0.05.30 Affection status was
assumed to reflect an underlying quantitative liability scale; the
difference between mean values for the two homozygotes was fixed at 10 within-genotype standard deviations. Each quantitative trait was
transformed as part of the analysis using power
transformation.31 Natural logarithmically transformed
lifetime beer consumption and adult/postmenopausal age were each
assumed to have a linear effect on the mean transformed quantitative
trait level. Genotype-specific effects were assumed for beer
consumption, and a single effect was assumed for age. The liability
scale and each quantitative trait, after transformation and correction
for lifetime beer consumption and age, were each assumed to be
distributed as a mixture of normal densities with the mixture
proportions equal to the genotype frequencies. Within major locus
genotypes, the variation was attributed to polygenes and random
environmental effects specific to the individual; we assumed a
within-genotype correlation of .9 between the quantitative trait and
affection status. Differences between the present analysis and our
previuos study3 include the following: traditional beer
consumption modeled as a continuous rather than a categorical variable,
the designation of affection status in certain individuals, and fixing
the prevalence of affection at 5.9%.
The parameters of the model included allele frequency (q), transmission
probabilities ( 1, 2, and
3), mean level of the trait (µ1,
µ2, and µ3), within-genotype standard
deviation of the trait ( ), effect on the trait of beer consumption
by genotype (b1, b2, and b3),
effect on the trait of age (a), location and scale parameters of the
transformation (L and S), polygenic heritability of the trait
(ha2). Transmission probability
i represents the probability that a parent of genotype i
transmits allele 1, where genotypes i = 1, 2, and 3 correspond to
homozygotes lacking the iron-loading allele, heterozygotes, and
homozygotes with the iron-loading allele, respectively. Polygenic
heritability ht2 and
ha2 represents the proportion of
within-genotype variance attributed to polygenes. The likelihood of the
model was approximated.32
Major locus inheritance was inferred by rejecting the hypotheses of no
major locus and of environmental nontransmission, but not rejecting the
hypothesis of Mendelian transmission. The hypothesis of no major locus
(q = 0) was tested by comparing the likelihood maximized fixing q = 0, µ1 = µ2 = µ3,
b1 = b2 = b3, d = 0, 1 = 1, 2 = 1/2, 3 = 0 to the likelihood maximized with 1 = 1, 2 = 1/2, 3 = 0. The hypothesis of
environmental nontransmission (1-q = 1 = 2 = 3) was tested by comparing the
likelihood maximized fixing 1-q = 1 = 2 = 3 to the likelihood maximized with no constraints. The
hypothesis of Mendelian transmission (1 = 1,
2 = 1/2, 3 = 0) was tested by
comparing the likelihood maximized fixing 1 = 1, 2 = 1/2, 3 = 0 to the likelihood
maximized with no constraints.
The mode of inheritance was inferred by rejecting either the hypothesis
of recessive inheritance, the hypothesis of dominant inheritance, or
both. The hypothesis of recessive inheritance (µ1 = µ2,
b1 = b2, d = 0) was tested by comparing the
likelihood maximized fixing µ1 = µ2,
b1 = b2, d = 0, 1 = 1, 2 = 1/2, 3 = 0 to the likelihood
maximized with 1 = 1, 2 = 1/2,
3 = 0. The hypothesis of dominant inheritance
(µ2 = µ3,
b2 = b3, d = 1) was tested by comparing the
likelihood maximized fixing µ2 = µ3,
b2 = b3, d = 1, 1 = 1, 2 = 1/2, 3 = 0 to the
likelihood maximized with 1 = 1, 2 = 1/2, 3 = 0.
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RESULTS |
Administration of vitamin C led to significant increases in leukocyte
ascorbic acid levels, but had no effect on indirect measures of iron
status (Table 1). Table
2 summarizes the clinical characteristics
of 21 index subjects who were chosen because of a liver biopsy
demonstrating grade 2+ to 4+ hepatocellular iron. These patients had
markedly abnormal values for the indirect measures of iron status, and
they had some evidence of hepatic dysfunction. Table
3 presents the clinical characteristics of
other study subjects according to whether there was any history of
traditional beer consumption. The indirect measures of iron status were
significantly different between drinkers and nondrinkers. Table
4 presents iron measures according to
whether the research subjects were first-degree relatives of the index
cases with liver biopsy-proven iron overload. The mean values for serum
ferritin and the ratio of ferritin to AST were significantly higher in
first-degree relatives, and the transferrin saturation tended to be
higher and unsaturated iron binding capacity lower. Similar to our
previous study,3 the frequency distributions of transferrin
saturation and unsaturated iron binding capacity in males were bimodal
in the presence of increased dietary iron. In contrast to our previous
study,3 these frequency distributions were not obviously
bimodal for women in the presence of increased dietary iron.
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Table 1.
Effect of Vitamin C Supplementation on Leukocyte
Ascorbic Acid Levels and Indirect Serum Measurements of Iron Status
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Table 3.
Clinical Characteristics in Subjects Other Than Index
Cases According to History of Traditional Beer Consumption
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Table 5 shows that for each measure of iron
status, segregation analysis was consistent with an interaction between
a postulated iron-loading gene and dietary iron content
(P < .01). We inferred major locus inheritance by rejecting
the hypotheses of no major locus and of environmental nontransmission
while failing to reject the hypothesis of Mendelian transmission for
all four traits.
Table 6 shows that we inferred dominant
inheritance for transferrin saturation, unsaturated iron binding
capacity, serum ferritin, and the ferritin to AST ratio by rejecting
recessive but not dominant inheritance. All four traits showed
nonsignificant evidence for different parameter values in homozygotes
versus heterozygotes for the iron-loading allele. This finding could result either because homozygotes do not have more severe iron-loading than heterozygotes or because the sample includes too few homozygotes to allow us to detect a difference.
Table 7 presents the estimated mean values
for each measure by genotype, age, and lifetime beer consumption for
men and women. Only normal homozygotes and heterozygotes are included
because of the lack of support for homozygotes for the iron-loading
allele, as shown in Table 6. Nondrinking heterozygotes, although having marginally higher iron status than homozygotes, do not qualify as
iron-loaded. As little as 1,000 L traditional beer results in fourfold
differences in serum ferritin and the ratio of ferritin to AST between
the genotypes. Similarly, 1,000 L or more of traditional beer
consumption leads to marked elevations in transferrin saturation and
reductions in unsaturated iron binding capacity in heterozygotes compared with nonaffected homozygotes.
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Table 7.
Estimated Trait Means by Age and by Lifetime Beer
Consumption for Normal Homozygotes (genotype 1) and Heterozygotes
(genotype 2) for Dominant Inheritance
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Table 8 shows that the estimates of the
iron-loading allele frequency (p) ranged from 0.029 to 0.050. When
estimates of the frequencies of heterozygotes and homozygotes are
calculated from allele frequencies by the Hardy-Weinberg equation, the
summed frequency of heterozygotes (2pq or 2p[1-p]) and of homozygotes (p2) exceeds the assumed prevalence of 0.059 for
transferrin saturation and unsaturated iron binding capacity. The
segregation analysis permits different allele frequency estimates (p)
from the assumed prevalence (2pq + p2) because
affection status was assigned in only 28% of the subjects studied; in
the remainder, the probability of affection was estimated. The small
number of independent individuals in our pedigree samples does not
allow good frequency estimation of the iron-overload allele.
Pedigree Z-34 is shown in Fig 1. Purely
environmental causation of high iron levels is refuted by relatively
normal values for transferrin saturation and ferritin for individual
no. 5 despite substantial beer consumption. Individual no. 3 is the
only member of this pedigree to express iron overload in the absence of
beer consumption. He may be a homozygote for the iron-loading allele that our previous analysis3 suggests leads to iron loading in the absence of beer consumption, but more individuals are needed to
confirm this. The high frequency of the disorder is supported by the
presence of two spouses of pedigree members with iron overload.
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| Fig 1.
Pedigree Z-34. Filled symbols designate iron overload
defined from liver biopsy (individual no. 1), high transferrin
saturation and ferritin (individuals no. 8, 9, and 11), a probability
>90% of heterozygosity in the analyses of transferrin saturation and unsaturated iron binding capacity (individual no. 4), or a probability >70% in the analyses of ferritin and the ferritin to AST ratio (individuals no. 3, 4, and 7). Open symbols designate studied individuals for whom iron overload criteria were not met. Shaded symbols designate unstudied individuals. Individual no. 5 was assigned
unaffected status in the analysis because of low transferrin saturation
and ferritin to AST ratio despite consuming >1,000 L beer.
Individual no. 6 had a probability >90% of being a normal homozygote in the analyses of transferrin saturation and unsaturated iron binding capacity.
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DISCUSSION |
This segregation analysis of African pedigrees provides evidence that
in some individuals exposed to increased dietary iron, a genetic defect
allows an elevation in serum ferritin and in transferrin saturation and
a decrease in unsaturated iron binding capacity. The present findings
extend the results of our original genetic analysis of African
pedigrees,3 and are especially important because the
present study was specifically designed to address potential
shortcomings of our initial investigation. In particular, the
alterations in serum ferritin, transferrin saturation, and unsaturated
iron binding capacity observed in these pedigrees do not appear to be
explainable by purely environmental effects. Furthermore, these
indirect measures of iron status do not appear to be unduly influenced
by diurnal variations or by the presence of ascorbic acid deficiency or
anemia. According to the most likely model, a 40-year-old male
heterozygote for the postulated iron-loading locus with an estimated
beer consumption of 10,000 L would have a transferrin saturation of
75% and a serum ferritin of 985 µg/L, as compared with a transferrin
saturation of 36% and a serum ferritin of 233 µg/L in an unaffected
individual of identical age, sex, and beer consumption (Table 7).
Because the chief source of iron in these subjects is a traditional
beverage that contains alcohol,2 it was important to consider that changes in serum iron measures resulting from alcohol ingestion11,12 may have affected our results. This
potential confounding factor was addressed in two ways: (1) the
subjects were asked to refrain from alcohol ingestion for a minimum
period of 24 hours before the first venesection and to continue to
abstain throughout the study period, and (2) the ratio of ferritin to AST was calculated. This index has been shown to reflect hepatic iron
stores in the setting of acute alcohol consumption, shortly after
stopping consumption, and after prolonged abstention from alcohol.33,34
In our previous study,3 we inferred recessive inheritance
of the iron-loading gene in the absence of increased dietary iron and
dominant inheritance in the presence of increased dietary iron. The
present set of pedigrees may not include any homozygotes for the
iron-loading allele, leading to the inference of dominant inheritance
in this analysis. The sample sizes in both studies were too small to
make confident statements regarding the iron status of homozygotes for
the hypothesized iron-loading locus. In addition, the performance of
the analysis required that assumptions be made about the relationships
among age, beer consumption, and iron measures. The conclusions are
dependent on the assumptions.
Iron overload in Africans was first reported by A.S. Strachan, who
conducted an autopsy series of blacks from across southern and central
Africa and who died in Johannesburg, South Africa, in the
1920s.35 Professor Strachan found a high prevalence of iron
overload: 19% of the subjects had "very marked to marked" iron
deposition in the liver and in the spleen. Iron overload in southern
African blacks was thought initially to be the result of some metabolic
defect induced by chronic malnutrition,36 but the dietary
intake of iron was subsequently shown to be very high, with most of the
iron derived from the iron drums and cans used for brewing traditional
alcoholic beverages.2 The histologic findings were
distinctive, with the bulk of the iron being deposited in hepatocytes
and in macrophages in most subjects.37 Several direct and
indirect sequelae were documented. Direct sequelae included
micronodular cirrhosis38-41 and diabetes
mellitus,41 and indirect sequelae, ascorbic acid deficiency
and osteoporosis.42-44 More recently, associations of iron
overload in Africans with death from hepatocellular carcinoma and
tuberculosis have been described.45 Although the condition
is underrecognized or even unknown by many health care providers today,
iron overload still has a high prevalence in many areas of
Africa.1,29,46,47
The finding of a possible genetic pattern to iron overload in African
can now be put in perspective with other inherited iron overload
conditions. HLA-linked hemochromatosis is the predominant inherited
iron-loading condition in populations derived from
Europe.15,48 Thalassemia major and intermedia syndromes are
inherited anemias common in historically malarious geographic areas
that are characterized by high degrees of ineffective erythropoiesis,
increased intestinal iron absorption, and development of iron overload
even in the absence of blood transfusions.49-51 An
apparently autosomal dominant and non-HLA-linked form of iron loading
has been described in a large Melanesian family.52
Congenital atransferrinemia is a sporadic autosomal recessive condition
that leads to severe parenchymal iron overload.53 A single
nucleic acid substitution of the ceruloplasmin gene leads to
aceruloplasminemia and systemic iron overload in Japanese families in
an autosomal recessive pattern.54 The finding of different
genetically determined mechanisms for iron overload in different
populations may suggest there is some type of advantage to these
traits.
Recent studies have emphasized that primary iron overload occurs among
African-Americans, but the genetics of this condition have not been
examined.55,56 High dietary iron does not appear to be a
contributing factor. Further studies will be required to determine
whether primary iron overload in African-Americans is related in any
way to the condition in Africa.
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FOOTNOTES |
Submitted April 30, 1997;
accepted September 22, 1997.
Supported by grants from the Office of Minority Health to the Cell
Biology and Metabolism Branch, National Institute of Child Health and
Human Development (NICHD); the JF Kapnek Charitable Trust; the Research
Board of the University of Zimbabwe; the South African Medical Research
Council; and the University of the Witwatersrand; and by NICHD Contract
No. 1-HD 3-3196.
Address reprint requests to Victor R. Gordeuk, MD, Department of
Medicine, The George Washington University Medical Center, 2150 Pennsylvania Ave NW, Washington, DC 20037.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
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Abstract
Introduction
Abstract