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Abstract
This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage—transferrin, transferrin receptor, and ferritin—have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the "Stimulator of Fe Transport" (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation.
In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation.
In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on the implications for clinical practice.
In Section III, Dr. Brissot and colleagues discuss how the diagnosis and management of hereditary hemochromatosis has changed following the identification of the gene, HFE, that is mutated in most patients with hereditary hemochromatosis, and the subsequent development of a genotypic test. The current understanding of the molecular effects of HFE mutations, the usefulness of genotypic and phenotypic approaches to screening and diagnosis and recommendations for management are summarized.
I. Advances in the Laboratory Evaluation of Iron Deficiency and Iron Overload
Gary M. Brittenham, M.D.*
Our understanding of the molecular and cellular mechanisms underlying the absorption, transport, utilization and storage of iron in the body provides the foundation for the use of laboratory means to detect iron deficiency, iron overload and other abnormalities of iron metabolism. Recent rapid progress in studies of iron has led to the characterization of newly identified key proteins, shown in Table 1, that interact with the familiar proteins long known to be participants in iron metabolism—transferrin, transferrin receptor, and ferritin—and greatly refined our appreciation of the intricacies of iron physiology.1 While a variety of new laboratory measures are likely to be developed using these and other still to be recognized proteins or genes of iron metabolism, two are already available for routine clinical use and will be discussed in more detail: (i) measurement of the concentration of the soluble fragment of transferrin receptor in serum in the diagnosis of anemia associated with enhanced erythropoiesis and with tissue iron deficiency, and (ii) detection of mutations in the HFE gene in the diagnosis of the iron overload of hereditary hemochromatosis.
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Iron metabolism
The metabolic roles of the proteins in
Table 1 are described in detail
in
reviews1,2,3
or
reports4,5,6,7,8
elsewhere and will only be summarized here. The major pathway of internal iron
exchange is a unidirectional flow from plasma transferrin to the erythron
(defined as the totality of erythroid elements at all stages of development)
to the macrophage and back to plasma
transferrin.3 About
four-fifths of the iron passing through the transferrin compartment each day
is flowing to and from the erythron. Physiologically, immature erythroid cells
acquire iron from transferrin through a specific transferrin receptor located
on the surface membrane.
HFE,9 the
hemochromatosis gene, produces a protein that binds to the transferrin
receptor; this protein may have a role in determining receptor affinity for
ferric transferrin but its full role in iron metabolism is still incompletely
understood (see below). The iron-transferrin—transferrin
receptor-[±HFE] protein complex is internalized within an endosome,
which undergoes acidification followed by the release of iron and its
transport across the endosomal membrane via the divalent metal transporter 1
(DMT1). Most of the internalized iron is used for hemoglobin synthesis and
then enters the circulation in erythrocytes, but small quantities of iron may
be stored intracellularly in the iron storage protein ferritin.
Within developing erythroid and other cells, the iron-regulatory proteins
IRP-1 and IRP-2 act to control iron availability by translational control of
the synthesis of transferrin receptor (increasing iron uptake by the cell) and
of ferritin (increasing iron storage). IRPs are cytoplasmic RNA-binding
proteins that function in a trans-acting manner on mRNAs that contain
an iron-responsive element (IRE), a cis-acting regulatory structure.
Functional IREs are found in the 3' untranslated region of mRNAs for the
transferrin receptor, in one of the two isoforms of DMT1, and in the 5'
untranslated region of mRNAs for ferritin, for the erythroid-specific form of
-aminolevulinic acid synthase, and for mitochondrial
aconitase. IRPs function as a nexus connecting intracellular iron availability
with cellular iron utilization, erythropoiesis, mitochondrial energy
metabolism and cellular responses to inflammation and oxidative
stress.10 A homolog
of the transferrin receptor, identified as transferrin receptor 2, lacks an
IRE; a homozygous nonsense mutation in the gene that encodes transferrin
receptor 2 is found in some patients with a form of non-HFE-related
hemochromatosis.11
Senescent erythrocytes are phagocytized by specialized macrophages in the spleen, bone marrow, and liver. Within macrophages, the inducible heme oxygenase 14 catabolizes heme, releasing ferrous iron to a Fe-ATPase iron transporter,5 which seems to be responsible for intracellular transmembrane iron transport. The exact means of iron exit from the macrophage is uncertain but may involve ferroportin 1.6,7,8 Ceruloplasmin may be required for the mobilization of iron from macrophages and other tissues and for its oxidation and incorporation into ferric transferrin. Whatever the route and means, macrophages return most of the catabolized erythroid iron to the transferrin compartment, where the cycle recommences. The phagocytosis of aged erythrocytes and flawed immature red cells accounts for almost all of the storage iron found in the macrophages of the liver, bone marrow, and spleen; none or almost none of the storage iron is derived from transferrin. By contrast, the parenchymal cells of the liver may either take iron from or give iron to plasma transferrin.
The remaining one-fifth of iron movement to and from transferrin consists mostly of iron shifted between the plasma and extravascular transferrin compartments, exchanged between extravascular transferrin and parenchymal tissues, or moved to and from hepatocytes. Under certain circumstances, iron may enter cells through transferrin-independent pathways via passive perfusion, fluid-phase endocytosis, or membrane-based transport systems that are still poorly characterized. In some cells, another protein termed SFT for "stimulator of Fe transport" seems to enhance both transferrin and nontransferrin-bound iron transport. Frataxin, a mitochondrial protein expressed in neuronal and cardiac tissue, and ATP-binding cassette 7 (ABC7), a mitochondrial protein expressed in neuronal and erythroid tissue, both seem to be involved in mitochondrial iron homeostasis.
Under normal physiologic conditions, less than 0.05% of the total body iron is acquired or lost each day. DMT1 also serves as the intestinal iron transporter that moves iron from the lumen of the gastrointestinal tract through the apical surface of duodenal enterocytes. Hephaestin is a transmembrane-bound ceruloplasmin homolog that is apparently required for the passage of iron through the intestinal enterocyte. Ferroportin 16,7,8 is also expressed at the basolateral surface of duodenal enterocytes and seems to transport iron into the portal circulation. Ceruloplasmin may also be needed for the mobilization of iron from enterocytes and its oxidation and incorporation into ferric transferrin. This synopsis of the current state of understanding of the proteins involved in iron metabolism is intended to serve as back-ground for the discussions of laboratory assessment of body iron status, the anemia of chronic disease and hereditary hemochromatosis that follow.
Soluble fragment of transferrin receptor
The soluble transferrin receptor is a truncated form (Mr 85,000)
of the tissue transferrin receptor that consists of the N-terminal cytoplasmic
domain that has probably been proteolytically released from the cell
membrane.12 The
contribution of the newly recognized transferrin receptor 2 to the plasma pool
has not been reported. Commercial immunoassays that can detect the soluble
truncated form of the transferrin receptor in human plasma have been approved
by the FDA and are now clinically available. The soluble form of the receptor
that circulates in the plasma reflects the total body mass of cellular
transferrin
receptor.13
Because, in normal subjects, over 80% of the mass of cellular transferrin
receptor is located in the erythroid marrow, the concentration of circulating
soluble transferrin receptor is primarily determined by erythroid marrow
activity. Accordingly, decreased levels of circulating soluble transferrin
receptor are found in patients with erythroid hypoplasia (aplastic or
hypoplastic anemia, chronic renal failure). Increased levels are present in
patients with erythroid hyperplasia (thalassemia major, sickle cell anemia,
chronic hemolytic anemia). Iron deficiency is the other principal cause of
elevated concentrations of soluble transferrin receptor because, as noted
above, with intracellular lack of iron, the iron regulatory proteins direct
increased synthesis of transferrin receptor, which is eventually shed into the
plasma. In the absence of other conditions causing erythroid hyperplasia, an
increase in concentration of plasma transferrin receptor provides a sensitive,
quantitative measure of tissue iron deficiency. Most importantly, the plasma
transferrin receptor concentration is not increased with infection or
inflammation, unlike plasma ferritin. As a result, measurement of the plasma
transferrin receptor concentration may be especially helpful in the task of
differentiating between the anemia of iron deficiency and the anemia
associated with chronic inflammatory disorders, the "anemia of chronic
disease."12,14,15,16
The most sensitive means available to distinguish between the anemia of iron
deficiency and the anemia of chronic disease is a combination of plasma
transferrin receptor and plasma ferritin concentrations, the
"transferrin receptor-ferritin index," i.e. the transferrin
receptor concentration divided by the plasma ferritin concentration (or, in
some studies, by the log of the plasma ferritin
concentration).12,14,15,16
Mutations in HFE in Patients with Hereditary
Hemochromatosis
First identified in 1996, HFE, the protein that is defective in most
patients with hereditary hemochromatosis, is structurally similar to major
histocompatibility complex (MHC) class I
proteins.9 HFE is a
single polypeptide with a short cytoplasmic tail, a membrane-spanning region,
and three extracellular domains. The exact role of HFE in iron metabolism and
the means whereby mutations result in the increased iron absorption found in
hereditary hemochromatosis are still unknown, but a number of potentially
relevant observations have been
made.3 In the
endoplasmic reticulum, newly synthesized HFE forms a 1:1 complex with
ß2-microglobulin, and the HFE/ß2-microglobulin
heterodimer is targeted to the plasma membrane. At neutral pH, the
HFE/ß2-microglobulin heterodimers form a stable complex with
the transferrin receptor and apparently decrease the affinity of the
transferrin receptor for transferrin. HFE is abundantly expressed in the crypt
cells of the duodenal mucosa, and some evidence suggests that levels of HFE
and DMT1 may be reciprocally related in intestinal cells. Missense mutations
in the HFE gene are responsible for about 85% of cases of hereditary
hemochromatosis in the United
States15; elsewhere
the proportion ranges from about 60 to 100%. The most prevalent (homozygous in
83% of patients in the US) is a C282Y mutation. A second mutation in HFE,
H63D, was enriched in patients who were compound heterozygotes for the C282Y
substitution. Recently, a third relatively common mutation, S65C, has been
identified17 and
several other isolated or rare mutations have been
reported.18,19
Importantly, in the US 10 to 15% of the patients examined have none of the
three mutations (C282Y, H63D, S65C) but are indistinguishable clinically from
the others.
II. Advances in the Diagnosis and Management of the Anemia of Chronic Disease
Günter Weiss, M.D.*
The anemia of chronic disease is the most common cause of anemia in hospitalized patients. This form of anemia typically develops in patients suffering from chronic inflammatory disorders that involve activation of cellular immunity, such as patients with chronic infections, autoimmune diseases or neoplasia. The anemia of chronic disease can usually be easily diagnosed although the underlying mechanisms are not fully understood. A variety of processes have been shown to be involved in the pathogenesis of the anemia of chronic disease, including a diversion of iron traffic from the serum to stores within the reticuloendothelial system, diminished erythropoiesis, a blunted response to erythropoietin, and possibly erythrophagocytosis and a decreased red cell survival. Overall, the anemia of chronic disease seems to be the product of an activated immune system using a defensive strategy of withholding iron, an essential growth factor, from invading pathogens while increasing the efficacy of cell-mediated immunity.
Diagnosis of the Anemia of Chronic Disease
The anemia of chronic disease is generally a normochromic or slightly
microcytic anemia, which can be readily diagnosed by laboratory studies of
iron status. Patients with the anemia of chronic disease are clinically
characterized by reduced plasma iron concentrations and transferrin
saturation, while iron stores, as reflected by plasma ferritin levels, are
normal or even increased. Transferrin concentrations are at the lower limit of
normal or reduced, and reticulocyte counts are usually decreased despite the
presence of
anemia.1,2,3,4
As noted in the preceding section, the differential diagnosis between iron
deficiency anemia and the anemia of chronic disease can now be readily made by
measurement of the plasma transferrin receptor concentration and, ideally,
determination of the plasma transferrin receptor-ferritin index (i.e. the
transferrin receptor concentration divided by the plasma ferritin
concentration or, in some studies, by the log of the plasma ferritin
concentration). Characteristic findings of laboratory measures of iron status
in the anemia of chronic disease and in iron deficiency anemia are shown in
Table 2.
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Pathophysiology of the Anemia of Chronic Disease
A variety of mechanisms have been identified that contribute to the
pathogenesis of the anemia of chronic disease.
Diversion of iron traffic from erythropoiesis to storage sites
The induction of hypoferremia by increased iron retention and storage
within the reticuloendothelial system, thereby limiting iron availability to
the erythron, is a central feature of the development of the anemia of chronic
disease. These alterations in iron metabolism are primarily produced by
cytokines and their metabolic products. Almost twenty years ago, treatment of
mice with the proinflammatory (Th-1-derived) cytokines IL-1 and TNF-
was shown to induce both hypoferremia and
anemia.5,6
These cytokines stimulate ferritin synthesis in macrophages and in hepatocytes
via both transcriptional and translational
pathways.7,8
Interestingly, not only pro-inflammatory but also anti-inflammatory cytokines
play a major role in iron regulation in inflammatory conditions. In activated
murine macrophages, IL-4, IL-10 and IL-13 modulate iron metabolism by two
different
pathways9: first,
by opposing IFN-
-mediated activation of IRP, thereby increasing
ferritin translation, and second, by augmentating transferrin receptor mRNA
expression, most likely by reversing the inhibitory effect of IFN- on
transferrin receptor transcription. Thus, anti-inflammatory (Th-2-derived)
cytokines are able to increase iron retention in activated macrophages and may
also contribute to the development of anemia.
Apparently, both pro- and anti-inflammatory cytokines participate in the induction of hypoferremia and hyperferritinemia in chronic inflammatory disorders. Part of the action of these cytokines is indirect, via the activation or deactivation of processes involved in the generation of nitric oxide, hydrogen peroxide or superoxide anion. The latter substances affect iron homeostasis via their influence on posttranscriptional regulation of ferritin and transferrin receptor expression by modulating the avidity of iron-regulatory proteins for iron-regulatory elements (IREs) within the untranslated region of ferritin mRNA and transferrin receptor mRNA.
Inhibition of erythroid progenitor proliferation and
differentiation
Apart from modulating iron homeostasis, cytokines directly affect
erythropoiesis by inhibiting the growth of erythroid progenitors. As we know
from the work of Means and
Krantz3 and others
a number of cytokines, such as TNF-, IFN- and Type I
interferons, block BFU-E and CFU-E colony formation. IFN- appears to be
the most potent inhibitor of erythropoiesis in directly blocking CFU-E
proliferation,10
probably accounting for the inverse correlation of IFN- levels with
hemoglobin concentrations and reticulocyte
counts.11 The
inhibitory effects of TNF- or IFN- on erythropoiesis may also be
related to their ability to induce the formation of nitric oxide. Nitric oxide
can directly block erythropoiesis by retarding the proliferation of erythroid
progenitor cells in the bone
marrow,12 an action
mediated, in part, by inhibitory effects of nitric oxide on heme
biosynthesis.
Blunted erythropoietin response
Plasma erythropoietin concentrations in patients with the anemia of chronic
disease are normal or even increased when compared to healthy subjects. While
some studies have suggested that erythropoietin levels are nonetheless low
when the degree of anemia is taken into
account,13 others
(e.g. in juvenile chronic arthritis) have found no significant
differences.14
These results suggest that erythropoietin concentrations may vary with the
disorder responsible for the anemia of chronic disease. Moreover,
erythropoietin responsiveness may also be related to the severity of disease
and the amounts of circulating cytokines. Data in vitro have shown that
greater amounts of erythropoietin are needed to restore CFU-E colony formation
with high concentrations of IFN- or
TNF-.15
Erythrocyte survival
In mice, administration of sublethal doses of TNF- or endotoxin not
only decreased the incorporation of iron into red blood cells and induced
hypoferremia but also decreased red cell
survival.16 In
humans, the extent to which a decrease in red cell survival contributes to the
anemia of chronic disease is uncertain. Erythrophagocytosis by macrophages
could potentially contribute to the destruction of circulating red blood cells
and could help explain the development of splenomegaly and the observations of
increased amounts of erythrocyte-derived iron in splenic macrophages and
Kupffer cells in inflammatory
conditions,17,18
but definitive evidence of increased red blood cell destruction in the anemia
of chronic disease is lacking.
Advantages of the Anemia of Chronic Disease
The high prevalence of the anemia of chronic disease suggests that the
development of this form of anemia might have some benefits for those with
chronic inflammation. Two major advantages may be postulated. First, iron is
an essential element for all living and proliferating organisms, being
required for enzymes in the citric acid cycle, for mitochondrial respiration,
for DNA synthesis and for oxygen transport systems. Thus, withdrawal of iron
by increased storage of the metal within the reticuloendothelial system acts
to limit the availability of iron to microorganisms or tumor cells and thereby
inhibit their growth and proliferation. In addition, decreased formation of
hemoglobin by withholding iron from the erythron and by cytokine-mediated
inhibition of erythropoiesis reduces the oxygen transport capacity of the
blood and decreases the overall oxygen supply, which may primarily affect
rapid proliferating (malignant) tissues and micro-organisms. Second, iron
strongly affects cell-mediated immune function. In addition to the role of
iron in the proliferation and differentiation of lymphocyte
subsets,19 iron
directly inhibits the activity of
IFN-.20 This
crucial pro-inflammatory cytokine is centrally involved in the co-ordination
of cell-mediated immune effector mechanisms against invading pathogens.
Iron-loaded macrophages exhibit diminished IFN- responsiveness,
decreased TNF- production, reduced formation of nitric
oxide,20,21,22
and an impaired immune defense against various intracellular pathogens and
viruses.23
Therefore, withdrawal of metabolically active iron from the circulation and
storage of the metal, as occurs in the anemia of chronic disease, may act to
strengthen the immune response via stimulation of
IFN--mediated immune effector
mechanisms.24
Therapy for the Anemia of Chronic Disease
The optimal treatment for the anemia of chronic disease is cure of the
underlying disorder. Even when cure is not possible, immunological therapies
such as the use of anti-TNF-antibodies may improve the anemia of chronic
disease by counteracting the detrimental effects of TNF- on
erythropoiesis and iron metabolism.
For patients with the anemia of chronic disease associated with chronic infection or malignancy, supplementation of iron should be strictly avoided. First, supplementation of iron may counteract the iron-withholding strategy of the body and favor the growth and proliferation of microbes and tumor cells. Second, iron therapy may weaken cell-mediated immune effector mechanisms and promote progression of the underlying disease.4 Third, most of the administered iron will be diverted to the reticuloendothelial system and little is likely to reach the erythron.
In contrast, iron supplementation could conceivably benefit patients with
the anemia of chronic disease associated with auto-immune or rheumatic
disorders. In this setting, an iron-induced weakening of cell-mediated
immunity might help to reduce disease activity and improve the anemia of
chronic disease by counteracting TNF- or IFN- activity, thereby
improving erythroid progenitor proliferation, improving endogenous
erythropoietin formation and responsiveness, and enhancing the delivery of
iron to the erythron by amelioration of disturbances of iron metabolism.
Conversely, some investigators have evaluated the use of iron chelation with
deferoxamine for treatment of the anemia of chronic disease in rheumatic
disorders, despite a low serum iron concentration. In one report, iron
chelation therapy was associated with a rise in hemoglobin levels, which was
attributed to stimulation of erythopoietin
production25 via
induction of hypoxia regulatory factors in the erythopoietin promoter.
Blood transfusion has been used to correct the anemia of chronic disease,
especially in cancer patients where other mechanisms (e.g. bone marrow
suppression following chemotherapy, bone marrow infiltration) may contribute
to the anemia. Recombinant erythropoietin may also be used for the management
of the anemia of chronic
disease,26 but
response rates vary and are often
low.27 We need to
better define therapeutic endpoints and aims of treatment for the use of
recombinant erythropoietin in the anemia of chronic disease. We also need to
develop new models for choosing those patients most likely to benefit from
recombinant erythropoietin and for predicting the likelihood for a response to
treatment; these might include not only measures of iron homeostasis but also
soluble markers reflecting activated cell-mediated immune function in vivo,
such as ß2-microglobulin, neopterin or
IFN-.28,29
III. Advances in the Diagnosis and Management of Hereditary Hemochromatosis
Pierre Brissot, M.D.,* Fabrice Lainé, Anne Guillygomarc'h, Dominique Guyader, Romain Moirand, and Yves Deugnier
Hereditary hemochromatosis1 is one of the most frequent genetic diseases in Caucasian populations, affecting approximately one in three hundred people.2 The discovery, in 1996,3 of the HFE gene that is mutated in most patients with hereditary hemochromatosis has rapidly provided a powerful diagnostic genotypic test. The availability of this genetic test has radically transformed the diagnostic strategy and overall management of the disease.
Strategy for the Diagnosis of Hereditary Hemochromatosis
This strategy should rest upon the following three successive
steps4
(Figure 1).
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First Step: Suspect the Diagnosis from Early Clinical
Manifestations
Suspecting hemochromatosis is easy with the "classical"
clinical picture of the disease: A middle-age man presenting with i) diffuse
hyperpigmentation (melanodermia), often with a metallic grey or
"bronze" rather than a brown discoloration; ii) hepatomegaly, with
the liver markedly enlarged, firm and sharp to palpation but without signs of
hepatocellular insufficiency (no palmar erythema, no spider nevi, no bruises,
normal prothrombin time) or of portal hypertension; and iii) diabetes
mellitus, often requiring insulin. When this classical triad of "bronzed
cirrhosis with diabetes" is present, the diagnosis may be immediately
suspected, especially if there are also signs of cardiomyopathy. This
presentation occurs only when complications are irreversible and the prognosis
is already poor, so that making the diagnosis at this stage is far too late
and must be considered a diagnostic failure.
Earlier signs and symptoms that may allow an earlier diagnosis include:
Second Step: Screen for Biochemical Abnormalities of Iron Metabolism
with the Serum Transferrin Saturation
Normal transferrin saturation (< 45%) rules out the iron overload of
hereditary hemochromatosis in the absence of a coexisting inflammatory
syndrome (as reflected, for example, by an increased serum C-reactive protein
[CRP]). Nonetheless, a normal transferrin saturation is compatible
with the two types of iron overload not related to hereditary
hemochromatosis:
An increased transferrin saturation reflects the basic metabolic abnormality of hereditary hemochromatosis and is the most sensitive single test for phenotypic detection of the disease. Edwards and Kushner10 have shown that the transferrin saturation is usually above 60% in men and 50% in women and remains high throughout the day11 in these patients. Although a sensitive marker, an elevated transferrin saturation is not specific for hereditary hemochromatosis. An increased transferrin saturation can be found in other iron overload syndromes of hematological origin where the major mechanisms responsible for iron excess are dyserythropoiesis, with or without red blood cell transfusions. With these conditions, the key differential feature with respect to hereditary hemochromatosis is the presence of chronic anemia, although the anemia may be very mild. The transferrin saturation can also be elevated in the absence of any iron excess in case of hepatic cytolysis (as indicated by increased levels of serum transaminases) especially when associated with hepatic failure (resulting in decreased transferrin synthesis) and with excessive alcohol consumption.
Third Step: Prove the Diagnosis of Hereditary Hemochromatosis
Confirmation of the diagnosis may be obtained with a single blood test for
the HFE mutation C282Y. Three situations occur:
T,16 which
has been reported in association with severe phenotypic expression of
hemochromatosis, the S65C
mutation17
associated with a mild phenotype, and the I105T
mutation.18 In practice, whenever there is a strong suspicion of pronounced iron overload and the patient is not C282Y +/+, one must remain a "clinician" and resort to a liver biopsy for a diagnostic purpose, accordingly to the "pre-HFE" diagnostic strategy. Indeed, in this situation, hepatic histology is essential in many diagnostic aspects: i) to confirm iron overload; ii) to identify a predominantly periportal and hepatocytic distribution; iii) to provide a semi-quantitative evaluation of iron excess using a special grading system22; iv) to permit the determination of hepatic iron concentration (HIC), which is closely correlated with the level of iron stores23 and can be performed in deparaffinized liver biopsy specimens.24 Furthermore, given the age of the patient, the hepatic iron index (ratio of hepatic iron concentration to age) can be calculated. Prior to the HFE era, a value of the hepatic iron index greater than 1.9 was highly suggestive of homozygous hemochromatosis,25 provided other kinds of iron overload (especially of hematological origin) had been excluded. Finally, v) liver biopsy is able to detect associated lesions (e.g. steatosis).
Management of Hereditary Hemochromatosis
Two aspects of the management of hereditary hemochromatosis will be
considered: curative management and preventive
management.26
Curative management
Apart from the symptomatic treatment of visceral and metabolic
complications for the disease, which will not be reviewed here due to their
lack of specificity, the major curative challenge is the elimination of iron
excess.
Venesection therapy is the key tool. The removal of one unit of blood per
week, resulting in the loss of 200-250 mg of iron, should be conducted until
the serum ferritin is 
50 µg/L and the transferrin saturation is
20%, provided hemoglobin levels do not drop below 110 g/L. Thereafter,
maintenance phlebotomies must be performed throughout the patient's life to
keep serum ferritin 50 µg/L and transferrin saturation 35% (a
level that usually corresponds to the disappearance of non-transferrin bound
iron,27 a
potentially toxic iron
species28). The
efficacy of venesections is excellent. The life expectancy returns to normal,
provided neither cirrhosis nor diabetes were present at the time of the
diagnosis.29 Even
with cirrhosis, the prognosis is far better than for other types of cirrhosis,
especially of alcoholic origin. With regard to the various syndromes of the
disease, the efficacy of phlebotomies is variable: i) Good for asthenia, skin
pigmentation, and hypertransaminasemia; ii) Inconstant for arthralgia (which
may even worsen during—and sometimes after—the iron depletion
treatment), for glucose abnormalities, and for non-cirrhotic fibrosis (which
can stablize or decrease); iii) Poor for impotence; iv) Ineffective for two
types of lesions: a) cirrhosis, which is an irreversible process, and b)
hepatocellular carcinoma, which may develop in cirrhotic patients despite
adequate iron elimination by phlebotomies.
Dietary recommendations are useful for counteracting iron excess: alcoholic beverages should be avoided, supplemental iron and supplemental vitamin C are contra-indicated, and tea is beneficial.
In the following cases, venesection is contra-indicated:
Preventive management
Preventive management of hereditary hemochromatosis has greatly evolved
since the discovery of the HFE gene.
Family Screening: The preventive strategy has been considerably modified and simplified by HFE testing. Starting from a C282Y proband, it is now possible to evaluate "immediately" the hemochromatosis risk among the family members. In brief, C282Y +/+ subjects are homozygous for the HFE gene and either already expressing the disease or are at high risk of developing it. C282Y +/- individuals are heterozygous for the HFE gene. They will not develop the disease but can transmit the gene to their offspring. Due to the high prevalence of the HFE gene in the general population, the probability for a heterozygote to marry another heterozygote is approximately 10%. It is therefore important to inform the family of this possibility in a "smooth and positive" way. With respect to young family members, specific screening is not justified because no treatment is indicated during infancy and adolescence. A phenotypic evaluation (including clinical examination, serum transferrin saturation and ferritin) can be performed at 15 years of age and genetic testing postponed until 18 years of age.
Population screening: Several arguments can be put forward in favor of general screening in Caucasian populations: i) the high frequency of the disease; ii) the severity of the disease both in terms of morbidity and mortality; iii) the possibility, from now on, of establishing the diagnosis on the basis of non-invasive investigations; and iv) the efficacy and simplicity of the treatment (venesections), which not only improves the quality of life but restores normal life expectancy provided the diagnosis is sufficiently early in the course of the disease.
The screening strategy could be based on the assessment of serum transferrin saturation in adults aged 18 or more. Genetic testing testing for C282Y would be confined to individuals with transferrin saturation > 45%. This strategy would then avoid the ethical, logistical, and financial problems raised by systematic genetic testing as well as the societal impact of discovering a genetic mutation in asymptomatic persons without a disease. It is, in fact, essential that major changes occur in the attitudes towards unexpressed or slightly expressed HFE homozygosity, especially by insurers and health care administrators, to avoid any adverse genetic discrimination.
Summary
In conclusion, hemochromatosis is a striking illustration of a disease in
which immediate clinical benefit has been obtained from a basic discovery at
the molecular level. It is indeed a paradoxical disease, connecting a
treatment worthy of the middle ages with a diagnostic procedure of the
21st century.
Footnotes
* Department of Pediatrics, Columbia University, College of Physicians & Surgeons, Harkness Pavilion HP550, 630 West 168th Street, New York, NY 10032
Acknowledgements: This work was supported, in part, by research grants from
the National Institutes of Health (HL62882, HL57594 and DK49108). 
* Department of Internal Medicine, University Hospital Innsbruck, Anichstrsse 35, A-6020 Innsbruck, Austria
Acknowledgments: Support by the Austrian Research Funds FWF 14215 is
gratefully acknowledged.
* Clinique des Maladies du Foie and Liver Research Unit, INSERM U-522,
University Hospital Pontchaillou, 35033 Rennes, France
I. New Insights into the Pathophysiology of Disorders of Iron and Heme Metabolism
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