Iron Loading and Disease Surveillance
Eugene D. Weinberg
Indiana University, Bloomington, Indiana, USA
|Iron is an oxidant as well
as a nutrient for invading microbial and neoplastic
cells. Excessive iron in specific tissues and cells
(iron loading) promotes development of infection,
neoplasia, cardiomyopathy, arthropathy, and various
endocrine and possibly neurodegenerative disorders. To
contain and detoxify the metal, hosts have evolved an
iron withholding defense system, but the system can be
compromised by numerous factors. An array of behavioral,
medical, and immunologic methods are in place or in
development to strengthen iron withholding. Routine
screening for iron loading could provide valuable
information in epidemiologic, diagnostic, prophylactic,
and therapeutic studies of emerging infectious diseases.
Excessive iron in specific tissues (iron loading) promotes
infection, neoplasia, cardiomyopathy, arthropathy, and a profusion
of endocrine and possibly neurodegenerative disorders (1-5).
An array of behavioral, medical, and immunologic methods are being
developed to decrease iron loading or its detrimental effects.
Routine screening for iron loading in populations exposed to certain
diseases can provide valuable epidemiologic, diagnostic,
prophylactic, and therapeutic information.
Hazards of Iron Loading
Iron can contribute to disease development in several ways.
Excessive amounts of the metal in specific tissues and cells can
hinder the ability of proteins, such as transferrin and ferritin, to
prevent accretion of free iron. Moreover, in infectious diseases,
inflammatory diseases, and illnesses that involve ischemia and
reperfusion, iron causes reactions that produce superoxide radicals
Nonprotein bound ferric ions are reduced by superoxide, and the
ferrous product is reoxidized by peroxide to regenerate ferric ions
and yield hydroxyl radicals, which attack all classes of biologic
macromolecules. Hydroxyl radicals can depolymerize polysaccharides,
cause DNA strand breaks, inactivate enzymes, and initiate lipid
Iron can also increase disease risk by functioning as a readily
available essential nutrient for invading microbial and neoplastic
cells. To survive and replicate in hosts, microbial pathogens must
acquire host iron. Highly virulent strains possess exceptionally
powerful mechanisms for obtaining host iron from healthy hosts (7).
In persons whose tissues and cells contain excessive iron, pathogens
can much more readily procure iron from molecules of transferrin
that are elevated in iron saturation. In such cases, even microbial
strains that are not ordinarily dangerous can cause illness.
Markedly invasive neoplastic cell strains can glean host iron more
easily than less malignant strains or normal host cells (3).
Moreover, iron-loaded tissues are especially susceptible to growth
of malignant cells (Table
| Table 1.
Iron loading in specific tissues and
increased risk for disease
||Gonadal and growth
||Aorta; carotid and
||Viral hepatitis, cirrhosis,
||Acinar and beta cell
||Plasma and lymph
How Microbes Acquire Iron: A Determinant of Host Range and of
The number of infectious disease agents whose virulence is
enhanced by iron continues to increase (Table
2). To obtain host iron, successful pathogens use one or more of
four strategies: binding of ferrated siderophilins with extraction
of iron at the cell surface; erythrocyte lysis, digestion of
hemoglobin, and heme assimilation; use of siderophores that withdraw
iron from transferrin; and procurement of host intracellular iron.
Microbial strains that use siderophilin binding often have a very
narrow host range (7).
Bacterial receptors recognize siderophilins generally from a single
or closely related host species. Strains of Haemophilus somnus,
for example, form receptors for bovine but not for human transferrin;
these bacteria are virulent for cattle but not for humans (9).
The human pathogen, Neisseria meningitidis, can bind ferrated
transferrins from humans and such hominids as chimpanzees, gorillas,
and orangutans, but not from monkeys or nonprimate mammals (10,11).
Actinobacillus pleuropneumoniae synthesizes a swine-specific
transferrin receptor and causes pneumonia only in hogs (12).
Each of the above three pathogens, as well as other organisms
that use siderophilin binding, can often obtain iron from heme.
Helicobacter pylori, for instance, first obtains iron from human
ferrated lactoferrin in the gastric lumen. Then, as it migrates into
intercellular junctions of epithelial cells in the gastric wall, its
sole source of iron is heme. This pathogen binds neither bovine
ferrated lactoferrin nor human, bovine, or equine ferrated
However, not every pathogen that uses siderophilin binding has a
narrow host range. For example, Staphylococcus aureus can be
virulent for a variety of mammalian species. Strains of this
organism can bind human, rat, and rabbit transferrins and, much less
efficiently, bovine, porcine, and avian transferrins (14).
Moreover, isolates of S. aureus also may produce siderophores
These small molecules can withdraw iron from transferrins
synthesized by a variety of host species. The siderophore,
staphyloferrin A, removes iron from both human and porcine
transferrin; thus, the metal can be available to invading cells in
humans and in hogs. Erythrocyte lysis, digestion of hemoglobin, and
heme assimilation are available to strains of S. aureus.
Bacterial hemolysins generally are active against erythrocytes from
several, although not from all, potential host species.
Microbial genera with strains whose growth in body fluids,
and intact vertebrate hosts is stimulated by excess iron (8)
Virulent streptococci are examples of bacteria that neither bind
siderophilins nor produce siderophores yet proficiently invade and
replicate in many tissues in diverse host species. The cellulytic
activities of these pathogens enable them to access such
intracellular sources of host iron as hemoglobin, myoglobin,
catalase, and ferritin (17).
The remarkable versatility for host species shown by Listeria
monocytogenes illustrates the adeptness of this organism in
procuring iron. Although mainly a saprophyte that lives in the
plant-soil environment, L. monocytogenes can be acquired by
humans and other mammals through ingestion of undercooked tissue of
other mammals, birds, fish, and Crustacea, as well as from raw
vegetables. Unable to bind siderophilins or form siderophores, L.
monocytogenes obtains iron by using either exogenous
siderophores of other microorganisms or natural catechols, such as
dopamine and norepinephrine, in host tissues. The pathogen expresses
a cell surface ferric reductase that recognizes the siderophoric
chelated iron site; the metal is then reduced and assimilated (18).
Furthermore, in contrast to saprophytic strains, systemic pathogenic
strains of L. monocytogenes are hemolytic.
To grow within host cells, pathogens apparently are not required
to synthesize siderophilin binding sites or form siderophores. For
instance, unlike the wild type, siderophore-minus mutants of
Salmonella Typhimurium cannot grow in extracellular compartments
of the host. However, both the wild and mutant strains replicate
within host cells (19).
Possible sources of intracellular iron are heme, iron released from
transferrin at pH 5.5-6, and ferritin.
For at least two pathogens, Francisella tularensis and
Legionella pneumophila, the host intracellular niche is
obligatory. Like the mutant strain of S. Typhimurium, these
organisms are unable to access iron in extracellular fluids and
tissues. Culturing these bacteria in laboratory media requires
markedly elevated concentrations of iron (20,21).
In host intracellular niches, growth of microbial pathogens is
stimulated by elevation and depressed by decrease of iron. Indeed,
at least one bacterial pathogen, Ehrlichia chaffeensis,
induces elevation of iron in its host cells; intracellular
inclusions of the organism cause the host cell to upregulate
expression of the transferrin receptor mRNA (22).
Iron Withholding Defense System
Hosts use several mechanisms (Table
3) to withhold iron from invading microbial and neoplastic
cells: stationing of potent iron binding proteins at sites of
impending microbial invasion; lowering iron levels in body fluids,
diseased tissues, and invaded cells during invasion; and
synthesizing immunoglobulins to the iron acquisition antigens of
|Table 3. The iron
withholding defense system (1,8)
Transferrin in plasma, lymph, cerebrospinal fluid
Lactoferrin in secretions of lachrymal and
mammary glands and of respiratory, gastrointestinal,
and genital tracts
Ferritin within host cells
|Processes induced at time of invasion
Suppression of assimilation of 80% of dietary irona
Suppression of iron efflux from macrophages that have
digested effete erythrocytes to result in 70% reduction
in plasma irona
Increased synthesis of ferritin to sequester withheld
Release of neutrophils from bone marrow into
circulation and then into site of infectiona
Release of apolactoferrin from neutrophil granules
followed by binding of iron in septic sites
Macrophage scavenging of ferrated lactoferrin in
areas of sepsis and of tumor cell clusters
Hepatic release of haptoglobin and hemopexin (to bind
extravasated hemoglobin and hemin, respectively)
Synthesis of nitric oxide (from L-arginine) by
macrophages to disrupt iron metabolism of invadersb
Suppression of growth of microbial cells within
macrophages via downshift of expression of transferrin
receptors and enhanced synthesis of Nrampl (23)
by the host cellsb
Induction in B lymphocytes of synthesis of
immunoglobulins to iron-repressible cell surface
proteins that bine either heme, ferrated siderophilins,
or ferrated siderophores
|aActivated by interleukin-1 or -6 or
by tumor necrosis factor-.
bActivated by interferon-g.
High concentrations of iron not only benefit invading cells, they
may also mediate antimicrobial activities of defense cells. In in
vitro studies, 150 µM iron augmented macrophage killing of
Brucella abortus (24)
and, without altering phagocytosis, 250 µM iron enhanced
anti-Candida activity of microglia (25).
In the latter system, the metal suppressed synthesis of nitric oxide
but not of tumor necrosis factor A. By generating oxidant-sensitive
mediators, iron may focus influx of neutrophils to sites of
Iron loading of staphylococci increased their killing by peroxide,
macrophages, and neutrophil-derived cytoplasts but not by
Certain conditions can impair iron withholding (Table
4); numerous studies have presented evidence that risk for
infection or neoplasia is increased significantly in persons with
|Table 4. Conditions that
can compromise iron
|Excessive intake of iron through intestinal absorption
Behavioral and nutritional factors
Accidental ingestion of iron tablets
Adulteration of processed foods with inorganic
iron or blood
Excessive consumption of red meats
Excessive intake of alcohol (HCl secretion
Folic acid deficiency
Ingestion of ascorbic acid with inorganic iron
Use of iron cookware
Genetic and physiological factors
Asplenia (mechanism unknown)
Pancreatic deficiency of bicarbonate ions
Porphyria cutanea tarda
Regulatory defect in mucosal cells in
Thalassemia, sicklemia, other
Intramuscular and intravenous iron saccharate
Multiple transfusions of whole blood or erythrocytes
Exposure to amosite, crocidolite, or tremolite
Exposure to urban air particulates
Mining iron ore, welding, grinding steel
Painting with iron oxide powder
Tobacco smoking (1-2 µg iron inhaled per cigarette
|Release of body iron from compartments into plasma
Efflux of erythrocyte iron in hemolytic diseases
Efflux of hepatocyte iron in hepatitis
|Deficit in iron withholding
Lack of dietary amino acids in kwashiorkor or
in jejunoileal bypass
Decreased activity in acidosis
Substitution of bovine milk or milk formula for
human milk in nursling nutrition
Decreased synthesis in persons with haplotype
Detection of Iron Loading
Screening of large populations for iron loading can be
accomplished with inexpensive, noninvasive methods. A useful
indicator of iron loading is marked elevation of serum ferritin
(sFt). However, sole reliance on this measurement can be misleading
because sFt increases moderately during inflammatory episodes.
Accordingly, concurrent determination of the percentage of iron
saturation of serum transferrin (%TS) provides useful information (29).
In iron loaded persons, hyperferritinemia generally is accompanied
by an elevation in %TS. In contrast, in patients with an
inflammatory process, hyperferritinemia generally is accompanied by
a reduction in %TS.
Iron loading is associated also with moderate depression of a
third variable, serum transferrin receptor (sTfR). The ratio of
sTfR/sFt, apparently independent of inflammation, is significantly
reduced in persons with high levels of iron (5).
Strengthening the Iron Withholding Defense
A considerable array of behavioral, medical, and immunologic
methods are in place or in development for strengthening iron
Additional precautions are indicated for persons who are known to be
(or have a tendency to become) iron loaded. For example, persons
with elevated iron due to either hemochromatosis or alcoholism are
cautioned to avoid eating raw oysters, which may contain Vibrio
Another pathogen that likewise causes severe systemic infection in
hosts with elevated iron is Capnocytophaga canimorsis.
Accordingly, persons who have hemochromatosis, alcoholism, or
asplenia are advised to receive prompt antibiotic therapy if they
are exposed to a dog bite (31).
De-ironing by phlebotomy is effective in lowering risk for
cardiovascular diseases (32,33)
and various neoplasms (34),
as well as in therapy for hepatitis C (35).
Interfering with iron metabolism by administering gallium can be
useful in suppressing growth of lymphoma and bladder cancer cells (36).
The antineoplastic action of monoclonal antibodies against ferrated
transferrin receptors has been examined (37).
Combinations of the iron chelator, deferoxamine, with gallium or
with antibodies against ferrated transferrin receptors increase
effectiveness against tumor cells.
The natural iron scavenger, lactoferrin, has been shown to remove
free iron from synovial fluid aspirated from joints of rheumatoid
arthritic patients (38).
Recombinant human lactoferrin, which is indistinguishable from
native breast milk lactoferrin with respect to its iron binding
properties, is now available (39)
and could become a very useful addition to our array of de-ironing
A recently discovered integral membrane phosphoglycoprotein,
Nrampl, is expressed exclusively in macrophages and is localized to
phagolysosomes. The protein suppresses replication of
intramacrophage microbial invaders apparently by altering iron
A second protein, Nramp2, is involved in enhancement of intestinal
iron absorption (40).
Future research might develop useful medical procedures for
modulation of the actions of these proteins.
Potential vaccines that incorporate iron acquisition antigens of
pathogens in the families Neisseriaceae and
Pasteurellaceae are being developed by several research groups.
For example, in Moraxella catarrhalis, the recombinant
transferrin binding protein B (TbpB) has been shown to elicit
bactericidal antibodies (41)
In N. meningitidis, antisera to TbpA and TbpB were
bactericidal for both homologous and heterologous strains (42,43).
Because the antigenic proteins function at the cell surfaces of the
pathogens, the receptors are potentially ideal vaccine candidates.
For synthesis of the receptors, the organisms must be cultured in
Methods of strengthening the iron withholding defense system
|Reduction of excessive intake of ingested
Decreased consumption of red meats (heme iron)
Avoidance of processed foods that have been
adulterated with inorganic iron or with blood
Decreased consumption of alcohol and ascorbic acid
Elimination of iron supplements unless an iron
deficiency has been correctly diagnosed
|Reduction of excessive intake of parenteral
Inject iron saccharates only if unequivocally
Transfuse blood or erythrocytes only if unequivocally
Substitute erythropoietin (+ minimal amount of iron)
for whole blood transfusions when possible
|Reduction of excessive inhalation of iron
Eliminate use of tobacco
Use iron-free chrysotile in place of iron-loaded
amosite, crocidolite, tremolite varieties of asbestos
Use mask to avoid inhalation of urban air
Use mask and protective clothing when mining or
cutting ferriferous substances
|Reduction of iron burden by regular
depletion of whole blood or erythrocytes
Avoidance of premature hysterectomy
Routine ingestion of aspirin
Regular donations of whole blood or erythrocytes
|Increased use of iron chelators
Use human milk (high in lactoferrin, low in iron)
rather than milk formula (lacking in lactoferrin, high
in iron) in nursling nutrition
Use tea (iron-binding tannins) and bran (iron-binding
Continue research and development (R&D) of potential
iron chelator drugs (e.g., recombinant human
lactoferrin; hydroxpyridones; pyridoxal isonicotinoyl
|Initiation of prompt therapy of chronic
infections and neoplastic diseases to forestall saturation
of iron withholding defense system
Continued R&D of cytokines such as interferon g that
induce cellular iron withholding
Continued R&D of passive and active methods of
immunization against surface receptor proteins used by
microbial and neoplastic cells to obtain iron
Perspectives and Conclusions
There is growing awareness that transmissible agents are involved
in diseases not earlier suspected of being infectious (44-46).
A recent review contains a list of 34 degenerative, inflammatory,
and neoplastic diseases associated in various ways with specific
infectious agents (44).
Other chronic inflammatory diseases, such as sarcoidosis,
inflammatory bowel disease, rheumatoid arthritis, systemic lupus
erythematosus, Wegener granulomatosis, diabetes mellitus, primary
biliary cirrhosis, tropical sprue, and Kawasaki disease may also
have infectious etiologies (45).
Excessive iron is correlated with synovial damage in rheumatoid
and with impaired glucose metabolism in diabetes (48).
The association of Chlamydia pneumoniae (49)
and excessive iron (5)
with cardiovascular disease is well established. Growth of this
pathogen is strongly suppressed by iron restriction (50).
Proving the role of infection in chronic inflammatory diseases
and cancer presents challenges (46).
The means by which pathogens suppress, subvert, or evade host
defenses to establish chronic or latent infection have received
little attention. However, the association and causal role of
infectious agents in chronic inflammatory diseases and cancer have
major implications for public health, treatment, and prevention (44-46).
Iron loading is a risk factor in these illnesses, as well as in
classic infectious diseases. Because the prevalence of iron loading
in various populations can be remarkably high, routine screening of
iron values in host populations could provide valuable information
in epidemiologic, diagnostic, prophylactic, and therapeutic studies
of emerging infectious diseases.
Dedicated to Jerome L. Sullivan, pioneer and leader
in our awareness of the role of iron in cardiovascular disease.
Support for this review was provided by the Office
of Research and the University Graduate School, Indiana University,
Bloomington, IN, USA.
Dr. Weinberg is professor emeritus of microbiology
in both the College of Arts and Sciences and the School of Medicine
at Indiana University, Bloomington, IN. His studies on iron were
initiated in 1952. Since retiring from teaching in 1992, he has
devoted full time to research.
Address for correspondence: E.D. Weinberg, Jordan
Hall 142, Indiana University, Bloomington, IN 47405, USA; fax:
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