High iron in Asians, South Sea Islanders

[Guest guest]

Can't find this in PubMed, maybe because it will be published in

NEJM tomorrow. Just general interest. I wonder if Okinawans were

included? Here it is:

UAB and international scientists studying iron-overload disorders

have made the unexpected discovery that Asians and Pacific Islanders

have the highest levels of iron in their blood of all racial/ethnic

groups who were screened.

Individuals who develop hemochromatosis/iron overload absorb an

excessive amount of iron from food and supplements ingested. The

abnormality affects many people worldwide, is prevalent in the

South, and sometimes causes organ damage when severe iron deposition

occurs due to inadequate control of iron absorption by the small

intestine.

The first major report of findings in the five-year, 100,000-person

study will be published tomorrow, April 28, in The New England

Journal of Medicine (NEJM). The University of Alabama at Birmingham

received $3.1 million of study funds to screen 20,000 people for the

group of disorders called hemochromatosis and iron overload.

T. Acton, Ph.D., professor of microbiology and director of

the UAB Immunogenetics Program, is principal investigator for the

Birmingham Field Center that did the screening. C. Barton,

M.D., director of the Southern Iron Disorders Center and UAB

clinical professor of medicine, is co-principal investigator. They

exceeded the goal of screening 10,000 African-Americans and 10,000

whites for blood iron levels or the presence of mutations in a gene,

called the HFE gene, which evidence suggests regulates iron

absorption.

" Hemochromatosis and iron overload are easily treatable if diagnosed

early, but the simple blood test that could detect these conditions

is not performed as part of routine medical exams, " said Acton.

Delaying treatment – the weekly removal of a pint of blood by

phlebotomy – can permit the progressive accumulation of iron

deposits in target organs that may result in complications such as

cirrhosis of the liver, liver cancer, arthritis, diabetes, impotence

and heart failure.

" The finding that Asians and Pacific Islanders have high levels of

iron in the blood is surprising because they also have the lowest

prevalence of the particular gene mutation that is found in

Caucasians with the typical form of hemochromatosis, " he said. " This

may mean that the Asians and Pacific Islanders have a different

genetic mutation that has not yet been discovered, or that they do

not, for some reason, develop hemochromatosis/iron overload despite

their high blood levels of iron. "

He said that the NEJM paper is the first report from analysis of the

massive data arising from the study, called the Hemochromatosis and

Iron Overload Screening (HEIRS) Study. The study is funded by the

National Heart, Lung and Blood Institute and the National Human

Genome Research Institute.

The other HEIRS Study Field Centers were located at University of

California, Irvine; London Health Sciences Centre, Ontario, Canada;

University, Washington, D.C.; and Kaiser Permanente Center

for Health Research (Oregon and Hawaii). Wake Forest University in

Winston-Salem, N.C. coordinated the Study, and the Study's Central

Laboratory is located at the University of Minnesota in Minneapolis.

At the beginning of the study in 2000, it was known that most cases

of hemochromatosis in Caucasians resulted from common mutations in

the HFE gene, first discovered in 1996. At that time, little was

known about the causes of iron overload in other racial/ethnic

groups.

Major findings of the study include:

· Caucasians had the highest prevalence of persons who had two

copies of the C282Y mutation of the HFE gene (4.4 per 1,000 people).

· Prevalence of two copies of the C282Y mutation of the HFE gene in

other racial/ethnic groups were: Native Americans (1.1 per 1,000),

Hispanics (2.7 per 10,000), African-Americans (1.4 per 10,000),

Pacific Islanders (1.2 per 10,000) and Asians (3.9 per 10 million).

· Most participants who had two copies of the C282Y mutation of the

HFE gene also had elevated levels of iron in their blood.

· Men who had two copies of the C282Y mutation of the HFE gene were

more likely to report a history of liver disease than participants

without HFE mutations.

" Our findings in Caucasians confirm reports from previous smaller

studies, " said Acton. " Our findings in non-Caucasians help everyone

understand the prevalence of these conditions in other racial/ethnic

groups. "

He added that many white Alabamians have Celtic origins, with some

counties reporting Irish ancestry in 17 percent of the

population. " The hemochromatosis C282Y mutation is thought to have

occurred among Celtic or Scandinavian populations 1,500-3,000 years

ago, and the mutation may have helped them survive iron-poor diets. "

Hemochromatosis or iron overload occur in 0.3-0.5 percent of white

persons of northern, central, and western European descent. In fact,

a health-screening program conducted by Barton and Acton at an

Alabama forest products mill detected the disorder in 0.39 percent

of all white participants, and 0.53 percent of white men.

Acton and Barton said they hope that results of the study will

prompt more primary care physicians to consider hemochromatosis and

iron overload as a diagnosis. Nationwide studies indicate it takes

an average of nine years and three physicians to obtain a correct

diagnosis, partly because physicians incorrectly believe that such

disorders are rare, or that they affect only older men. A previous

UAB study found that primary care physicians provided fewer than 70

percent correct responses about screening at-risk populations for

hemochromatosis, iron overload, and associated abnormalities.

As the HEIRS Study shows, iron overload was mistakenly believed to

be a disorder that is limited to Caucasians, said Acton. He, Barton,

and others have begun studying the role of iron overload and HFE

mutations in the development of type 2 diabetes in persons of

various racial/ethnic groups.

[Guest guest]

Hi All,

Many CRers do have lower iron, and some CRers have hemochromatosis.

The pdf for the New Engl J Med main paper is available.

Common iron overload disorder often misdiagnosed, studies show

Last Updated Wed, 27 Apr 2005 18:42:49 EDT

CBC News

LONDON, ONT. - An iron disorder is the most common genetic defect in North

America,

but is often misdiagnosed and undertreated, according to a new Canadian-led

study

that puts a spotlight on the condition.

Hemochromatosis leads to a build-up of iron in the blood. It can be deadly and

is

often misdiagnosed as arthritis or diabetes.

The treatment for hemochromatosis can be as simple as giving blood.

Dr. , a hematologist at London Health Sciences Centre, led an

international study on the little-known condition that touches many Canadians of

white European descent.

" We have shown in the study that one in 227 have the condition, yet this is

considered to be uncommon, " said .

The study is published in this week's issue of the New England Journal of

Medicine.

People with hemachromatosis don't metabolize all the iron in their bodies

properly,

leading to what can be fatal levels or serious liver scarring.

The treatment can be as simple as donating blood regularly to remove the extra

iron.

The problem is, it can be difficult to diagnose, since the symptoms are often

vague,

such as fatigue, aching joints or a bronze tinge to the skin.

Many more cases would be found if more people were screened either for iron

buildup

or the disease that causes the disease, or the gene that causes it, suggests a

second study published in this week's issue of medical journal The Lancet.

" There's a definite advantage to catching it pre-symptomatically. If not,

certainly

when the early signs manifest, " said Somerville, an assistant professor

of

genetics at the University of Alberta. " The hope is, you can simply stop it from

getting worse. "

The disorder is easier and cheaper to treat if diagnosed before complications

begin.

Test options

Neither the genetic test nor the iron test is foolproof. A positive genetic test

doesn't always mean someone will go on to develop the disease, and there are

fears

it could harm a person's ability to buy insurance or get a job.

Higher iron levels in the blood don't necessarily mean someone has

hemachromatosis,

since conditions such as hepatitis or inflammation may also show elevated

levels.

recommends general practitioners should be more open to ordering iron

tests,

particularly for those likely at highest risk: Caucasian men.

Marjorie Lounder's husband, Jim, was a doctor, but he never considered the

possibility of iron overload.

" He was treated for diabetes and arthritis but he never really investigated them

that much so it slipped through the cracks, " said the Ottawa resident. Her

husband

died at age 69 of liver failure without knowing the blood disorder caused his

chronic tiredness and other problems.

It's estimated as many as 100,000 Canadians may be at risk for hemachromatosis.

New Engl J Med 352:1741-1744 April 28, 2005 Number 17

Orchestration of Iron Homeostasis

R. E. Fleming and B. R. Bacon

Related Article by , P. C.

The number of newly identified genes participating in the regulation of iron

homeostasis has increased at a remarkable pace. The characterization of these

genes

has led investigators to challenge previous models of the regulation of iron

homeostasis in health and its dysregulation in disease. There is now substantial

evidence that the liver plays a central role in determining how much iron is

absorbed from the gut and in influencing the release of iron from sites of

storage.

The discovery of the iron regulatory hormone hepcidin has provided a cohesive

theory

to explain the pathophysiology of such common disorders as hereditary

hemochromatosis and the anemia of inflammation (also known as the anemia of

chronic

disease). The most important cellular targets for hepcidin appear to be the

villus

enterocyte, the reticuloendothelial macrophage, and the hepatocyte (see

diagram).

In the duodenal enterocyte, dietary iron is reduced to the ferrous state by

duodenal ferric reductase (Dcytb), transported into the cell by divalent metal

transporter 1 (DMT1), and released by way of ferroportin into the circulation.

Hephaestin facilitates enterocyte iron release. Hepatocytes take up iron from

the

circulation either as free iron or transferrin-bound iron (through transferrin

receptor 1 and transferrin receptor 2). Transferrin receptor 2 may serve as a

sensor

of circulating transferrin-bound iron, thereby influencing expression of the

iron

regulatory hormone hepcidin. The hepcidin response is also modulated by HFE and

hemojuvelin. Hepcidin is secreted into the circulation, where it down-regulates

the

ferroportin-mediated release of iron from enterocytes, macrophages, and

hepatocytes

(dashed red lines).

There are no substantial physiologic mechanisms that regulate iron loss.

Accordingly, iron homeostasis is dependent on regulatory feedback between body

iron

needs and intestinal iron absorption. Several factors have been found to

influence

the rate of iron absorption, including the body's iron stores, the level of

erythropoietic activity in bone marrow, the blood hemoglobin concentration, the

blood oxygen content, and the presence or absence of inflammatory cytokines.1

More

than one of these factors may act simultaneously, and some are interrelated.

Intestinal iron absorption increases with decreased iron stores, increased

erythropoietic activity, anemia, or hypoxemia. Conversely, intestinal iron

absorption decreases in the presence of inflammation — a process that

contributes to

the anemia of inflammation. Excess iron absorption relative to body iron stores

is

the hallmark of hereditary hemochromatosis.2

Nearly all absorption of dietary iron occurs in the duodenum. Several steps

are

involved, including the reduction of iron to a ferrous state, apical uptake,

intracellular storage or transcellular trafficking, and basolateral release.

Molecular participants in each of these processes have been identified3 (see

diagram). The reduction of iron from the ferric to the ferrous state occurs at

the

enterocyte brush border by means of a duodenal ferric reductase (Dcytb). Ferrous

iron is then transported across the apical plasma membrane of the enterocyte by

divalent metal transporter 1 (DMT1). Iron taken up by the enterocyte may be

stored

intracellularly as ferritin (and excreted in the feces when the senescent

enterocyte

is sloughed) or transferred across the basolateral membrane to the plasma. This

iron

is transferred out of the enterocyte by the basolateral transporter ferroportin

— a

process that is facilitated by the ferroxidase activity of the ceruloplasmin

homologue hephaestin. The expression of each of the genes involved in these

steps is

subject to regulation. Changes in the expression of each of the identified

molecules

that participate in iron absorption have been examined in various conditions.

The

best characterized of these conditions is anemia caused by dietary iron

deficiency,

in which the up-regulation of duodenal DMT1, Dcytb, and ferroportin messenger

RNA

and protein is observed.

Iron released into the circulation binds to transferrin and is transported to

sites of use and storage. Production of hemoglobin by the erythron accounts for

most

iron use. High-level expression of transferrin receptor 1 in erythroid

precursors

ensures the uptake of iron into this compartment. Hemoglobin iron has

substantial

turnover, as senescent erythrocytes undergo phagocytosis by reticuloendothelial

macrophages. Iron export from macrophages is accomplished primarily by

ferroportin,

the same iron-export protein expressed in the duodenal enterocyte.

Hepatocytes serve as a storage reservoir for iron, taking up dietary iron

from

portal blood and, at times of increased demand, releasing iron into the

circulation

by way of ferroportin. The ferroportin-mediated release of iron from

enterocytes,

macrophages, and hepatocytes is recognized as an important determinant of iron

homeostasis. The discovery of hepcidin revealed the important role of the

hepatocyte

in sensing the body iron status and modulating the ferroportin-mediated release

of

cellular iron.

Hepcidin is a 25-amino-acid peptide that was first identified in urine and

plasma

during a search for novel antimicrobial peptides.4 However, its role in

influencing

the systemic iron status has been discovered to be paramount, and hepcidin is

now

considered to be the principal hormone involved in iron regulation.

Each of the previously mentioned factors regulating intestinal iron

absorption

(iron stores, erythropoietic activity, hemoglobin, oxygen content, and

inflammation)

also regulates the expression of hepcidin by the liver. When each of these

factors

undergoes a change, intestinal iron absorption varies inversely with liver

hepcidin

expression. Hepcidin decreases the functional activity of ferroportin by

directly

binding to it and causing it to be internalized from the cell surface and

degraded.5

In the enterocyte, this action would be expected to decrease basolateral iron

transfer and thus dietary iron absorption. In the reticuloendothelial macrophage

and

the hepatocyte, hepcidin would lead to a decrease in iron export and thus an

increase in stored iron.

Abnormalities in hepcidin regulation have now been implicated in two

important

clinical conditions: hereditary hemochromatosis and the anemia of inflammation.

The

abnormalities of iron homeostasis seen in hereditary hemochromatosis are the

converse of those seen in the anemia of inflammation. Hepcidin expression is

inappropriately low in patients with the former condition, whereas it is

increased

in patients with inflammatory conditions. In hereditary hemochromatosis, there

is

increased dietary iron absorption, relative sparing of iron in

reticuloendothelial

macrophages, and increased iron saturation of circulating transferrin.

Hepatocytes

become iron-loaded in this setting, presumably because the uptake of iron from

the

circulation exceeds their ferroportin-mediated iron export. Conversely, in the

anemia of inflammation, iron retention by duodenal enterocytes and

reticuloendothelial macrophages leads to markedly low transferrin saturation,

iron-restricted erythropoiesis, and mild-to-moderate anemia. Thus, hepcidin

offers a

unifying explanation for the abnormalities in iron metabolism observed in these

two

common clinical conditions.

Most patients with hereditary hemochromatosis are homozygous for the C282Y

mutation in the HFE gene. In this issue of the Journal, et al. (pages

1769–1778) report the results of a large population screening study examining

the

prevalence and consequences of the C282Y mutation in various racial and ethnic

groups. The authors found that although most persons who are homozygous for this

mutation have elevations of the mean ferritin level and transferrin saturation,

individual variability is great. Moreover, the differences observed among racial

and

ethnic groups in these iron-related variables could not be accounted for by

differences in the HFE genotype. These data indicate that although the HFE

mutation

is the most important heritable cause of iron overload, basal iron status is

significantly influenced by other genetic factors, environmental factors, or

both.

The contribution of genetic factors is probably substantial, as suggested by

data

from strains of inbred mice.

Genes other than HFE have been identified that, when mutated, lead to

decreased

hepcidin expression and clinical hereditary hemochromatosis. One of these genes

(TFR2) encodes transferrin receptor 2, a homologue of the classic transferrin

receptor that is highly expressed by hepatocytes. It has been postulated that

transferrin receptor 2 may act as a " sensor " of circulating iron and thereby

influence hepcidin expression. Another such gene is hemojuvelin (HJV), which is

mutated in most persons with juvenile hereditary hemochromatosis. These

observations

suggest that HFE, TFR2, and HJV participate in a pathway that regulates hepcidin

expression. Polymorphisms in these genes might contribute to the observed

variation

in basal iron status.

Although much has been learned regarding the regulation of iron homeostasis,

many

important questions remain. The molecular mechanisms by which HFE, TFR2, and HJV

influence hepcidin expression are unknown. HFE expression in cell types other

than

hepatocytes (e.g., reticuloendothelial cells or duodenal crypt cells) may also

influence iron homeostasis. Moreover, additional gene products involved in iron

metabolism — for instance, the dietary heme transporter and proteins that

participate in intracellular iron trafficking — have yet to be identified. There

may

be therapeutic potential for hepcidin antagonists in the treatment of the anemia

of

inflammation, or for exogenous hepcidin in the treatment of hemochromatosis.

Investigations focused on these unanswered questions will continue to expand our

understanding of how iron absorption and distribution are regulated in health

and

dysregulated in certain diseases.

Hemochromatosis and Iron-Overload Screening in a Racially Diverse Population

P. C. and Others

New Engl J Med 352:1769-1778 April 28, 2005 Number 17

ABSTRACT

Background Iron overload and hemochromatosis are common, treatable

conditions.

HFE genotypes, levels of serum ferritin, transferrin saturation values, and

self-reported medical history were studied in a multiethnic primary care

population.

Methods Participants were recruited from primary care practices and

blood-drawing

laboratories. Blood samples were tested for transferrin saturation, serum

ferritin,

and C282Y and H63D mutations of the HFE gene. Before genetic screening,

participants

were asked whether they had a history of medical conditions related to iron

overload.

Results Of the 99,711 participants, 299 were homozygous for the C282Y

mutation.

The estimated prevalence of C282Y homozygotes was higher in non-Hispanic whites

(0.44 percent) than in Native Americans (0.11 percent), Hispanics (0.027

percent),

blacks (0.014 percent), Pacific Islanders (0.012 percent), or Asians (0.000039

percent). Among participants who were homozygous for the C282Y mutation but in

whom

iron overload had not been diagnosed (227 participants), serum ferritin levels

were

greater than 300 µg per liter in 78 of 89 men (88 percent) and greater than 200

µg

per liter in 79 of 138 women (57 percent). Pacific Islanders and Asians had the

highest geometric mean levels of serum ferritin and mean transferrin saturation

despite having the lowest prevalence of C282Y homozygotes. There were 364

participants in whom iron overload had not been diagnosed (29 C282Y homozygotes)

who

had a serum ferritin level greater than 1000 µg per liter. Among men, C282Y

homozygotes and compound heterozygotes were more likely to report a history of

liver

disease than were participants without HFE mutations.

Conclusions The C282Y mutation is most common in whites, and most C282Y

homozygotes have elevations in serum ferritin levels and transferrin saturation.

The

C282Y mutation does not account for high mean serum ferritin levels and

transferrin

saturation values in nonwhites.

--- mikesheldrick <mike@...> wrote:

> Can't find this in PubMed, maybe because it will be published in

> NEJM tomorrow. Just general interest. I wonder if Okinawans were

> included? Here it is:

Al Pater, PhD; email: old542000@...

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