(usually leading to a Cys282Tyr mutation in the gene
product) and characterized by a slow and progressive in-
crease in plasma iron content, which, in adults, may lead
hepatocytes) and, eventually, to organ disease. In rare
a similar syndrome. The term was coined by von Reck-
linghausen in 1889 to describe the association at autopsy
of widespread tissue injury, usually cirrhosis, with in-
creased tissue staining for iron.1Sheldon, in his review of
all published cases, linked this term to an inherited disor-
mon in males and sometimes has a familial incidence.2A
breakthrough in the history of the disease came with the
recognition of its autosomal recessive nature and the lo-
cation of the pathogenic gene on the short arm of chro-
identification of an iron-regulating gene, now named
HFE,5that is mutated in hemochromatosis.
Once the HFE gene was identified, it immediately ap-
peared to be clear that not all patients with an inherited
tations in the HFE gene. This was particularly evident in
southern European countries.6,7Therefore, the term
‘non-HFE hemochromatosis’ was coined to define hered-
itary iron overload in patients without pathogenic muta-
tions in the HFE gene.8Like ‘non A-non B hepatitis’,
based on the ignorance of the genetic basis of the under-
lying disorders. Since then, unprecedented progress in
animal and human iron genetics has led to the identifica-
he term ‘hemochromatosis’ refers to an autoso-
mal recessive disorder of iron metabolism associ-
ated with two mutant alleles of the HFE gene
tion of new forms of primary iron overload caused by
mutations in other genes involved in iron metabolism.
overload, or ferroportin disease), epidemiology, natural
corresponding characteristics in HFE hemochromatosis.
diagnosis and screening. Other disorders share patho-
genic mechanisms, clinical presentation characteristics,
juvenile-associated iron overload) with classic hemochro-
matosis. In this context, these disorders might be consid-
ered different forms of the same clinicopathologic
syndrome. Therefore, the term ‘non-HFE hemochroma-
tosis’ probably should be restricted to TFR2 and juvenile-
hemochromatosis and ferrorportin disease, they define
the group of ‘primary iron-overload disorders’, i.e., disor-
ders due to a defect in a gene primarily involved in iron
rare forms of aceruloplasminemia9,10and atransferrine-
mia.11In the former, the lack of ferroxidase activity of
plasma ceruloplasmin leads to defective iron release from
tissues; the clinical picture is dominated by a neurological
syndrome. In the latter, the lack of transferrin leads to
increased iron absorption and excessive iron influx in pa-
clinical manifestation. A unique pedigree in which iron
overload is associated with a mutation in the iron-regula-
tory element of the H-ferritin gene also has been de-
A distinction should be made between primary iron-
in which iron overload is secondary to specific diseases
(e.g., thalassemia or other iron-loading anemias, porphy-
ria, etc.) or acquired factors (e.g., alcohol exposure, liver
Ferroportin disease (also known as ferroportin-associ-
ated iron overload) is an autosomal dominant inherited
disorder of iron metabolism that results from pathogenic
mutation of the SLC40A1 gene, previously called
SLC11A3. The first description of the disease was pub-
lished in 1999, when an autosomal dominant form of
hereditary iron overload similar to classic hemochroma-
Abbreviations: RE, reticuloendothelial; mRNA, messenger RNA; IRE, iron-re-
From the Center for Hemochromatosis and Hereditary Liver Diseases, Depart-
ment of Internal Medicine, University of Modena and Reggio Emilia, Modena,
Received July 25, 2003; accepted November 7, 2003.
Supported in part by EU Grant QLK1-2001-00444 and by the Ministero
dell’Universita ` e Ricerca Scientifica e Tecnologica.
del Pozzo 71, 41100 Modena, Italy. E-mail: email@example.com;
Copyright © 2004 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
tosis but not linked to chromosome 6p was reported.13
Distinctive features included tissue iron accumulation
predominantly in reticuloendothelial (RE) cells, steadily
increasing serum ferritin levels, which were dispropor-
ginal anemia, and mild organ disease.13
Genetics, Epidemiology, and Molecular Pathogen-
provided evidence of linkage with respect to markers on
2q32.14A candidate gene, SLC40A1, was identified in that
region, and all affected patients were heterozygous for a
230C3A substitution; which resulted in replacement of
a large, negatively charged amino acid; within a predicted
another group reported that a form of non-HFE hereditary
ferroportin mutation (N144H) in a Dutch pedigree.15
Ferroportin disease now has been reported in many
countries, and, at variance with the distribution of the
C282Y mutation in the HFE protein, it is distributed
worldwide regardless of ethnicity. A common mutation
involves three sequential bases in exon 5 and predicts the
loss of one of three valine residues at positions 160–162.
It probably is due to a slipped-strand mispairing and has
been found in pedigrees from the United Kingdom, Aus-
have been reported in French, French Canadian, and
Asian families with hyperferritinemia.20–22
In 2000, ferroportin 1/IREG1/MTP1 protein was
identified independently by three different laboratories
and was shown to play a role in the export of iron in frog
oocytes and in cell lines.23–25It is expressed in cells that
play a critical role in mammalian iron metabolism, in-
cluding placental syncytiotrophoblasts, duodenal entero-
cytes, hepatocytes, and RE macrophages. In the human
intestine, this protein is expressed strongly under condi-
tions of enhanced iron absorption, such as anemia or
hemochromatosis.26,27It is involved in the pathogenesis
of the hypoferremia associated with anemia of chronic
disease, characterized by iron trapping in reticuloen-
doethelial (RE) cells and reduced intestinal iron trans-
Ferroportin expression is responsive to iron and in-
(mRNA) possesses an iron-responsive element (IRE) in
the 5? untranslated region that binds iron-regulatory pro-
ment with this model, the ferroportin promoter is
various promoter fragments does not eliminate iron-de-
pendent regulation, whereas removal of the IRE leads to
be important in controlling ferroportin expression, par-
ticularly in the duodenum, in response to stimuli such as
hypoxia or erythron demands.33
According to consensus structural predictions, ferro-
portin has 9 or 10 transmembrane helices.16,23,24Al-
though the reported mutations span the entire protein,
the majority involve the region between the first and
be involved in iron binding and/or transport activity or
may define a functional binding site for a circulating pro-
tein (possibly serum ceruloplasmin or hepcidin) that is
important for export of iron from the cell.
The proposed function of the gene product of
SLC40A1 in iron export is consistent with the phenotype
of the disease and with the original hypothesis of a selec-
tive disturbance of iron recycling in RE cells.13The find-
ing that different mutations in the same protein lead to
the same disorder, characterized by iron accumulation in
macrophages, is more consistent with a loss of protein
function14than with a gain of protein function.15None-
theless, no experimental proof of the functional effects of
various ferroportin mutations has been provided yet. A
loss-of-function mutation might cause impairment of
iron export from cells, and mainly RE cells, which nor-
mally must process and release a large quantity of iron
derived from the lysis of senescent erythrocytes (Fig. 2).
This leads to tissue iron accumulation (which is responsi-
availability of iron for circulating transferrin (reflected in
low transferrin saturation), which may be responsible for
marginal anemia. Progressive tissue iron loading may re-
and hepatocytes and from increased iron influx following
the compensatory activation of iron absorption due to
marginal anemia. Lack-of-function mutations may be
rophage iron metabolism but less important in iron ex-
port from the intestine and from hepatocytes, for which
other systems may overcome the functional deficiency.
Nonetheless, it is possible that different mutations
throughout the protein may affect iron transfer capability
differently or involve protein domains that are important
in interactions with cell-specific molecular partners.
These mutations also may have different effects on pro-
tein function depending on the specific cellular context.
At the molecular level, it is likely, but not proven, that a
mutated allele exerts a dominant negative effect over the
Clinical Features. The earliest biochemical abnor-
mality, appearing in the first decade of life, is high serum
ferritin levels with normal or low transferrin saturation.13
22PIETRANGELO HEPATOLOGY, January 2004
Serum ferritin levels, as well as tissue iron loading, in-
crease with age. In young females, hypochromic anemia
may be reported and may require oral iron supplementa-
tion. In the fourth and fifth decades, the level of trans-
ferrin saturation also may increase, but it rarely reaches
100%, as it does in classic HFE hemochromatosis (Table
1). The biochemical penetrance of the genetic defect is
complete, as all documented patients to date have exhib-
ited hyperferritinemia. Clinically, according to available
reports, the picture appears more heterogeneous, ranging
of symptoms and signs that are typical of hemochroma-
tosis.15In general, the phenotype appears to be mild, and
in spite of severe iron burden, liver disease is limited to
signs of fibrosis, primarily sinusoidal. This is consistent
with the typical pattern of hepatic iron distribution (Fig.
Fig. 1. Positions along the protein backbone of known ferroportin
mutations associated with hereditary iron overload. The software predic-
tion of ferroportin membrane organization is adapted from Devalia
et al.16Copyright American Society of Hematology, used with permission.
Fig. 2. Pathogenesis of primary iron-overload diseases. Inactivation of genes primarily involved in iron metabolism, such as HFE, TFR2, and
hepcidin, leads to uncontrolled release of iron from intestinal and macrophage cells and expansion of the circulating iron pool (transferrin-bound and
non–transferrin-bound iron). Subsequently, increased iron influx into parenchymal cells is responsible for cell damage and organ toxicity. If the rapidity
and extent of expansion of the circulating iron pool are high, as in the case of hepcidin-associated iron overload, endocrine and cardiac damage
will dominate clinical presentation. The opposite occurs in the case of inactivation of HFE or TFR2. In ferroportin disease, defective release of iron
from storage sites (particularly, reticuloendothelial macrophages) is primarily responsible for tissue iron overload. In ferroportin disease, reduced
transferrin saturation may lead to inadequate iron supply to bone marrow and marginal anemia. Late in the disorder, progressive saturation of
transferrin with iron also occurs, while the continuing iron retention in organs progresses.
HEPATOLOGY, Vol. 39, No. 1, 2004PIETRANGELO 23
3) and with the notion that non–parenchymal cell
(Kupffer cell) iron overload is better tolerated and less
fibrogenic than parenchymal cell iron overload.34In fact,
histologically, early Kupffer cell iron overload is a charac-
teristic feature of the disease; however, other studies have
confirmed the original finding that some degree of paren-
atocellular iron overload has a homogeneous lobular
distribution without the periportal-central iron gradient
that is typical of hemochromatosis. Due to the mixed
pattern of iron accumulation in parenchymal and non-
parenchymal cells, a decrease in both liver and spleen
signal intensity (due to a decrease in T2 relaxation time)
can be observed on magnetic resonance imaging study
fers from classic hemochromatosis, in which decreased
signal intensity is evident only in the liver. It is likely that
atitis infection, etc.) and genetic factors (e.g., HFE and
non-HFE gene status) may influence the final clinical
manifestation of the disease, as in classic hemochromato-
Although phlebotomy is an effective therapeutic tool,
in some individuals, a weekly phlebotomy program is not
tolerated and slight anemia and low transferrin saturation
rapidly occur despite still-elevated serum ferritin levels.
also can become iron depleted, although a therapeutic
target of serum ferritin concentration ? 30 ng/mL,
adopted for classic hemochromatosis, should be avoided,
due to the risk of anemia. Adjuvant therapy with erythro-
poietin may be beneficial. Discontinuation of phlebot-
Ferroportin disease should be suspected in all cases of
familial hyperferritinemia and in sporadic cases in the
absence of known secondary causes (e.g., infection, dys-
metabolism, inflammation, or malignancy). Differential
diagnosis also should consider the rare form of familial
which is not associated with tissue iron overload,36,37
aceruloplasminemia,9,10or dysmetabolic hepatosider-
Patients with autosomal recessive iron loading disor-
ders similar to hemochromatosis may carry mutations in
the TFR2 gene.39Until recently, only one type of trans-
ferrin receptor, transferrin receptor 1 (TfR1), had been
identified. Then, in 1999, Kawabata et al.40cloned a sec-
ond human transferrin receptor gene, TFR2, which
mapped onto chromosome 7q22, had significant se-
quence homology with TFR1, and mediated the cellular
uptake of transferrin-bound iron.
Genetics, Epidemiology, and Molecular Pathogen-
esis. The frequency of TFR2 mutations is low, and to
date, they have been detected in four Italian, one Portu-
guese, and one Japanese pedigree.39,41–43
Two transcripts of the TFR2 gene have been found in
humans: an ? form (TFR2-?), which is 2.9 kilobases
TfR2-? probably is a soluble intracellular form of TfR2.
The tissue distribution and expression level of TFR2
mRNA are distinctly different from the corresponding
characteristics in TFR1 mRNA: the former is highly ex-
pressed in liver and normal erythroid precursor cells and
Table 1. Primary Iron Overload Disorders Generically Defined as “non-HFE Hemochromatosis”
Known or Postulated
2q32Iron export from cells
Iron retention, mainly in
4°–5°Early and preferential
accumulation of iron in
Kupffer cells; at later
Sinusoidal (and periportal)
7q22Uptake of iron-bound
Unclear (possibly, increased
iron influx in parenchymal
cells following excessive
iron release from intestine
and macrophages due to
Increased iron influx in
parenchymal cells following
excessive iron release from
intestine and macrophages
iron efflux from
1°–2°Massive hepatic iron
24PIETRANGELOHEPATOLOGY, January 2004
in the liver and in all types of cells except for mature
erythroid cells. The regulation of expression of these two
genes also differs. TFR1 is regulated by cellular iron level
through the IRE–iron-regulatory protein system, as well
as by the proliferation and differentiation states of cells.45
TFR2 mRNA does not contain an IRE,44and its expres-
sion is not regulated by cellular iron levels, but it is cell
sensus sequences for GATA-1 transcription factors and
for the liver-enriched transcription factor C/EBP may be
TfR2 in the liver and in erythroid cells.47
TfR2 mediates the uptake of transferrin-bound iron,40
possibly via receptor-mediated endocytosis, similar to
TfR1, but the affinity of TfR2 for transferrin is 25–30
ferrin-iron uptake may be of major importance in hepa-
tocytes, which express low levels of TfR1. In fact, an
alternative pathway of transferrin-bound iron uptake in-
volving energy-dependent endocytosis of transferrin has
It is difficult to reconcile the preceding information,
which would predict defective tissue iron uptake follow-
ing TfR2 inactivation, with the finding that pathogenic
mutations of TFR2 in humans and Tfr2 gene deletion in
mice50lead to a hemochromatosislike phenotype. In vitro
TfR2 and HFE failed to detect a direct interaction be-
tween these two proteins.48In one study, TfR2 was not
found in intestinal crypts,51where TfR1-HFE interac-
Fig. 3. Hepatic histologic pattern of iron accumulation in primary iron-overload disorders (Perls’ Prussian blue stain). (A) Hemocromatosis.
Cirrhotic-stage disease in a patient (age, 58 years) who is homozygous for C282Y. Inset: granular iron deposits in hepatocytes. (B) Ferroportin
disease. Advanced-stage disease with massive iron overload characterized by coalescent iron deposits in Kupffer cells and macrophages (patient age,
65 years). Inset 1: early-stage disease with typical iron accumulation predominantly in Kupffer cells (patient age, 25 years). Inset 2: late-stage
disease, viewed at high magnification; both Kupffer cells and hepatocytes accumulate iron. (C) TFR2-associated hemochromatosis (patient age, 32
years). Iron is observed in Zone 1 and in parenchymal cells (inset), as in early HFE hemochromatosis. (D) Hepcidin-associated hemochromatosis
(patient age, 20 years). Massive iron overload of hepatocytes, with panlobular iron distribution, can be seen.
HEPATOLOGY, Vol. 39, No. 1, 2004 PIETRANGELO25
tions may be important for hemochromatosis pathogen-
esis.52In contrast, Griffiths and Cox53colocalized TfR2
and HFE in specific subcellular compartments of crypt
Hypothetically, because TfR2 and hepcidin both are
synthesized in the hepatocytes, TfR2 expression or iron
uptake by a TfR2-mediated process may regulate the ex-
iron retention (Fig. 2).
Clinical Features. Clinical descriptions of hereditary
sidering the available information, the clinical phenotype
appears to be similar to that of hemochromatosis. In all
accumulates preferentially in periportal hepatocytes (Fig.
3C). In one study, disease with unusually early onset was
observed in a patient age 14 years, while another patient
venile hemochromatosis’ was raised.54Surprisingly, in
two female patients, spontaneous reduction of hepatic
iron stores was observed over time, with no signs of fibro-
sis. In another pedigree, affected individuals presented
with marked hepatic iron overload; mild hypochromic
matosis); and, in one young male patient, hypogonad-
ism.42Finally, in a Japanese family, massive hepatic iron
TfR2 is an important protein in iron homeostasis;
however, the epidemiologic impact of hereditary iron
overload associated with TfR2 mutations is low. The
TFR2 gene is relatively large, spanning 21 kilobases and
including 18 exons; thus, detection of new TFR2 muta-
tions in individual patients remains cumbersome. Analy-
sisof TFR2 mutations
consideration for individuals with non-HFE hepatic iron
overload who come from families with high levels of con-
Hepcidin- and HFE2-Associated
Hemochromatosis and the Juvenile
In recent years, a rather vague term, ‘juvenile hemo-
chromatosis’, has been used to refer to a form of heredi-
tary iron overload that affects men and women equally
and develops in a pattern resembling that of hemochro-
was recognized in 1979.55Because of the rate of iron
loading and the increased susceptibility of tissue to the
present with cardiomyopathy and endocrinopathy, in-
cluding reduced glucose tolerance, than with severe liver
disease (Fig. 2).
Genetics, Epidemiology, and Molecular Pathogen-
is clear that juvenile hemochromatosis is genetically het-
erogeneous. It is likely that pathogenic mutations in pro-
teins that are of primary importance in the regulation of
In fact, homozygous mutations in hepcidin have been
reported in individuals with a clinical condition that re-
tosis.56Another gene (or multiple genes) responsible for a
similar syndrome is located on chromosome 1q.57Re-
cently, a candidate gene named HFE2 was cloned in this
region.58The possibility also exists that a second gene is
ceptually, if both TfR2 and HFE influence the synthesis
and/or function of hepcidin, combined mutations in
TFR2 and HFE should give rise to a similar juvenile iron
Hepcidin, the product of the HAMP gene, is a circu-
lating antimicrobial peptide produced in the hepatocytes
in response to inflammatory stimuli and to iron.59–61
stimulatory factor 2 or in C/EBP?, both of which are
required for hepcidin transcriptional control, have a
hemochromatotic phenotype.62,63Transgenic animals
that overexpress hepcidin die perinatally, due to severe
iron overload.64In addition, hepcidin appears to be the
main mediator of hypoferremia associated with chronic
diseases, characterized by iron sequestration in macro-
phages and decreased intestinal iron absorption.65There-
fore, hepcidin is the primary negative regulator of iron
release from intestinal, macrophage, and placental cells,
and possibly from other cells as well. In HFE hemochro-
matosis, production of this peptide appears to be abnor-
mally low,66,67and it may be responsible for the chronic
release of iron from macrophages and intestinal cells
overload.68This finding demonstrates that hepcidin may
blunt the iron-loading effect of mutated HFE, but it does
not prove that underexpression of hepcidin plays a direct
role in the pathogenesis of hemochromatosis. Nonethe-
less, hepcidin plays a dominant role in cellular iron traf-
ficking. Its absence may give rise to a dramatic release of
iron from storage sites and from the intestine into the
iron pool and to the overflow of iron in parenchymal cells
26 PIETRANGELOHEPATOLOGY, January 2004
via receptor-dependent or -independent mechanisms
Clinical Features. The most common symptom at
presentation is hypogonadism, which, at the end of the
second decade, may be present in all cases (Fig. 2; Table
1).69–71In sporadic cases, abdominal pain and cardiac
disease also are common findings, and cirrhosis seems a
delayed event in the course of the disorder. Patients with
of hypogonadism or cardiopathy before cirrhosis suggests
that endocrine organs and the heart have a particular sus-
ceptibility to iron toxicity. Rapid iron accumulation in
these organs may be less tolerated than in the liver, which
is physiologically more protected against iron toxicity.
Conclusions and Perspectives
The liver holds a central position in the regulation of
and storage proteins (i.e., transferrin and ferritin) and the
iron hormone hepcidin are synthesized and in which the
iron regulator HFE and the iron transporters TfR2 and
ferroportin are preferentially expressed (Fig. 4). Conse-
quently, the liver also has a central role both in the patho-
other primary iron-overload disorders (Fig. 5). Genetic
defects that are responsible for the inactivation of these
proteins may cause enhanced influx (HFE, TfR2, and
hepcidin) or reduced export (ferroportin) of iron in the
liver. This invariably will lead to hepatic iron accumula-
tion and, potentially, organ disease. In the case of hemo-
chromatosis, the faulty protein, HFE, is not an iron
tion; instead, it modulates the function of other iron-
related proteins, such as the receptors for transferrin and
hepcidin.52Therefore, it is not surprising that in hemo-
chromatosis, several decades are needed for the genetic
defect to translate into a clinically evident disorder. In
contrast, in other primary iron-overload disorders in
which a direct iron carrier or a major regulator of body
iron trafficking is involved, the phenotypic expressivity
appears at earlier stages (in ferroportin- and hepcidin-
associated iron overload) and, in the case of hepcidin-
associated iron overload, is far more severe than in classic
hemochromatosis (Figs. 2,3; Table 1).
Ferroportin, TfR2, and hepcidin are important pro-
teins in metabolism, and their recognition has been
greatly informative in understanding the regulation of
iron trafficking; however, with the possible exception of
ferroportin-associated disease, the global epidemiologic
impact of hereditary iron overload associated with muta-
theless, it is believed that polymorphisms or heterozygote
modulation of these genes may have a significant impact
on the phenotypic penetrance of other diseases, such as
classic hemochromatosis. Individuals with heterozygote
mutations in HFE may have an unusually severe pheno-
Fig. 4. The liver in iron homeostasis. Key proteins in iron metabolism
are either synthesized (hepcidin and TfR2 in hepatocytes) or preferen-
tially expressed (ferroportin and HFE in Kupffer cells) in the liver. HFE is
depicted in Kupffer cells, but expression in hepatocytes also has been
reported. The most important iron compartment in humans (the ‘erythron
compartment’) also is represented. In this compartment, iron continu-
ously recycles through reticuloendothelial macrophages, where it is freed
by the breakdown of senescent red cells, to the circulating iron carrier
transferrin and to bone marrow, where it is incorporated into the hemo-
globin of erythroid precursors. A limited amount of iron is absorbed daily
to compensate for losses and to maintain a constant total iron pool.
Fig. 5. The liver as the central organ in the pathogenesis of primary
iron-overload disorders. The main pathogenic pathways involved in var-
ious primary iron-overload disorders, with emphasis on the role of
liver-specific or preferentially expressed iron genes, are listed on the
HEPATOLOGY, Vol. 39, No. 1, 2004PIETRANGELO27
type. These individuals could carry additional abnormal-
ities in genes that share common pathogenic pathways
other hand, ferroportin, the main protein responsible for
the intestine, may aid in setting the individual levels of
circulating iron and (indirectly) hemoglobin. In this re-
gard, it is noteworthy that a polymorphic change in fer-
roportin recently was found to be associated with a
levels in African and African American populations.72
During the past few years, we have witnessed dramatic
progress in the field of iron research—progress that has
The liver, which is the main storage organ for iron, the
main source of iron regulators, and the main site for fun-
damental homeostatic function in iron metabolism,
stands at the center of the complex pathways that govern
iron metabolism and trafficking in health and in disease.
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