hemochromatosis: an endocrine liver disease

Hemochromatosis: An Endocrine Liver DiseaseAntonello Pietrangelo

This review acknowledges the recent and dramatic advancement in the field of hemochro-matosis and highlights the surprising analogies with a prototypic endocrine disease, diabe-tes. The term hemochromatosis should refer to a unique clinicopathologic subset of iron-overload syndromes that currently includes the disorder related to the C282Y homozygotemutation of the hemochromatosis protein HFE (by far the most common form of hemo-chromatosis) and the rare disorders more recently attributed to the loss of transferrin recep-tor 2, HAMP (hepcidin antimicrobial peptide), or hemojuvelin or to certain ferroportinmutations. The defining characteristic of this subset is failure to prevent unneeded iron fromentering the circulatory pool as a result of genetic changes compromising the synthesis oractivity of hepcidin, the iron hormone. Like diabetes, hemochromatosis results from thecomplex, nonlinear interaction between genetic and acquired factors. Depending on theunderlying mutation, the coinheritance of modifier genes, the presence of nongenetic hep-cidin inhibitors, and other host-related factors, the clinical manifestation may vary fromsimple biochemical abnormalities to severe multiorgan disease. The recognition of the en-docrine nature of hemochromatosis suggests intriguing possibilities for new and more effec-tive approaches to diagnosis and treatment. (HEPATOLOGY 2007;46:1291-1301.)

Few areas of medicine have witnessed discoveries asmomentous as those recently made in the field ofiron metabolism. Since 1996, the major proteins

involved in iron transport or the systemic control of ironhomeostasis have been identified, and genetic causes havebeen found for most forms of tissue iron overload. Hemo-chromatosis (HC) is no exception. Over the past decade,our definition of this disorder has been changing, evolv-ing, stretching, and twisting to accommodate an increas-ingly rich and rapid succession of discoveries, particularlythose that have emerged from genetic research. This re-view re-examines certain time-honored concepts ofhemochromatosis in light of the recent, dramatic achieve-ments in the field and offers a view of the disease based on

the current understanding of its pathophysiology, whichalso has implications for its diagnosis and management.

Homeostatic Control of the Internal MilieuThe survival of living organisms depends on their abil-

ity to maintain homeostasis, that indispensable level of“constancy in the internal milieu” conceptualized byClaude Bernard in the mid-nineteenth century. However,the organism’s inevitable interaction with the environ-ment can provoke dramatic changes in the chemical andphysical characteristics of the internal milieu, and thesemust be corrected if disease is to be averted. In mammals,the endocrine system is one of the body’s main tools formaintaining internal variables (body temperature, pH,water and ion balance, and a host of others) within thelimits compatible with life. It restores homeostasisthrough various mechanisms. One of the best known isprobably negative feedback, the mechanism by which glu-cose metabolism is regulated (Fig. 1A). This monosaccha-ride is a major source of energy; too little may lead tostarvation, but too much is toxic. Unneeded fluctuationsin blood glucose levels are therefore rapidly and efficientlycontrolled by the negative-feedback machinery con-structed around the pancreatic hormone insulin (Fig.1A,B).

Iron metabolism is regulated by surprisingly similarmechanisms (Fig. 1A,C). Like glucose, iron is an essentialnutrient. It is required for hemoglobin synthesis and vitalenzyme activities, but excess iron promotes noxious free-

Abbreviations: BMP, bone morphogenic protein; BMP-R, bone morphogenicprotein receptor; BMPr, bone morphogenic protein receptor; HAMP, hepcidin an-timicrobial peptide; HC, hemochromatosis; HJV, hemojuvelin; LIC, liver ironconcentration; MRI, magnetic resonance imaging; SF, serum ferritin; sHJV, solublehemojuvelin; SMAD4, mothers against decapentaplegic homolog 4; TfR, trans-ferrin receptor; TS, transferrin saturation.

From the Center for Hemochromatosis, Department of Internal Medicine, Uni-versity of Modena and Reggio Emilia, Policlinico, Modena, Italy.

Supported by a grant from EEC FP6 (LSHM-CT-2006-037296 EuroIron 1).Received May 28, 2007; accepted June 19, 2007.Address reprint requests to: Antonello Pietrangelo, M.D., Ph.D., Professor of

Medicine, Center for Hemochromatosis, Department of Internal Medicine, Uni-versity of Modena and Reggio Emilia, Policlinico, Via del Pozzo 71, 41100 Mod-ena, Italy. E-mail: [email protected]; fax: �39-059-4224363.

Copyright © 2007 by the American Association for the Study of Liver Diseases.Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/hep.21886Potential conflict of interest: Nothing to report.

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radical reactions. The control center that keeps blood lev-els of iron within the narrow physiological range is thehepatocyte. Here, specialized sensors respond to excessiron by stimulating the synthesis and release of the effec-tor hormone, hepcidin. This defensin-like peptide, en-coded by the hepcidin antimicrobial peptide (HAMP)gene, diffuses through the body, interacting with the iron-exporter ferroportin expressed on the surfaces of iron-richmacrophages and intestinal cells. As a result of this inter-action, ferroportin is internalized and degraded,1 and theunneeded iron remains in the cell, in which it is saved forfuture use in the form of ferritin, just as excess glucose isstored as glycogen (Fig. 1C). The diminished release ofiron restores blood levels to the nontoxic range, thus re-moving the stimulus for further hepcidin synthesis, andferroportin gradually resumes its iron-exporting activity.This mechanism ensures the maintenance of circulatingiron levels that can meet the body’s erythropoietic needswithout posing an oxidative threat to the cells.

Iron is also essential for a number of bacterial and viralpathogens, and hepcidin also plays a key role in deprivingpathogens of a required micronutrient. In this case, hep-cidin is released in response to inflammatory signals andcytokines. Its suppression of ferroportin activity preventsiron from entering the bloodstream, in which it could beused by proliferating pathogens. Later, when iron isneeded in the bone marrow for erythropoiesis (for exam-ple, during hypoxia or anemia), hepcidin expression ceas-es,2 and ferroportin is once again available to transfer ironto the circulation from enterocytes and macrophages.

Although our understanding of glucose sensing is quiteextensive, we are just beginning to dissect the mechanismsunderlying hepatocyte iron sensing (Fig. 1A). HFE andtransferrin receptor 2 (TfR2), which are thought to beinvolved in transferrin iron uptake, might play a role inconveying iron signals to the hepatocyte control center,but the details of this process are still unclear. Both areclearly important for hepcidin expression: the loss of ei-ther causes hepcidin insufficiency and iron overload inrodents and humans (discussed later). However, the mostimportant hepcidin regulator is hemojuvelin (HJV),3 acoreceptor for bone morphogenic protein (BMP) ligandsthat is essential for HAMP transcription in hepatocytes.4,5

Disruption of Homeostasis: Insulin andDiabetes, Hepcidin and Hemochromatosis

Similarities between the systems that control glucoseand iron metabolism persist when these systems breakdown. Failure to maintain physiological blood levels ofeither nutrient can have various causes, disruption canoccur at different points within the negative-feedbackloop, and the consequences range from mild to life-threat-

Fig. 1. Negative-feedback systems for the control of glucose and ironhomeostasis and their breakdown. (A) Essential components of feedbacksystems for the maintenance of homeostasis in glucose and iron me-tabolism. Each component plays a specific role in the process by whichan organism regulates its own internal environment. A sensor detectspotentially dangerous changes in the internal environment and reportsthem to a control center [bone morphogenic protein receptor (BMPr)].The latter responds by activating an effector protein, whose function is torestore homeostasis by interacting with a specific target/receptor. (B,C)Homeostatic regulation of glucose and iron metabolism. Excess glucosein the bloodstream is detected by specialized sensors in pancreatic betacells, and the control center responds to this threat by releasing insulin.This effector peptide diffuses through the body, interacting with specificreceptors on muscle cells, adipocytes, and hepatocytes and instructingthem to remove glucose from the blood and use it for energy productionor store it for later use as glycogen. As a result of this activity, nontoxicblood-glucose concentrations are restored. In a similar manner, excesscirculatory iron is detected by a sensor system in the hepatocytes, whichis composed of proteins involved in iron uptake and/or hepcidin tran-scription (HFE, TfR2, and HJV). The liver releases hepcidin, which inter-acts with the iron-exporter ferroportin expressed on the surfaces ofmacrophages and enterocytes. The result is the degradation of ferropor-tin, decreased iron release from macrophages and intestinal cells, andultimately the restoration of safe blood levels of iron. (D,E) Disruption ofhomeostasis: diabetes and hemochromatosis. (D) Defective insulin pro-duction (caused by immune-mediated or secondary destruction of pan-creatic beta cells or genetic defects that impair glucose sensing or insulinsynthesis) or reduced insulin sensitivity can cause unchecked increasesin blood glucose levels and diabetes. (E) Similarly, defective hepcidinsynthesis (caused by a massive loss of hepatocytes or genetic andacquired factors that impair iron sensing or hepcidin synthesis) orreduced hepcidin sensitivity can lead to progressive increases in serumiron levels and hemochromatosis.

1292 PIETRANGELO HEPATOLOGY, October 2007

ening. Hormone secretory failure is a major componentof both diabetes and hemochromatosis (Fig. 1D,E). Re-cent research has highlighted the genetic heterogeneity ofhemochromatosis, but all forms identified thus far, re-gardless of the mutations that cause them, are due toinsufficient release of hepcidin.6 The result is unrestrictediron production from macrophages and intestinal cells,which produces circulatory and later tissue iron overload(Fig. 1E). Hepcidin production, like that of insulin, canbe impaired by genetic and acquired factors. Hepcidindeficiency has been associated with the loss of hepcidinitself, HJV, HFE, or TfR2 in humans3,7-9 and with theinactivation of CCAAT/enhancer binding protein � andmothers against decapentaplegic homolog 4 (Smad4) inmice.10,11 As for the contribution of nongenetic factors,ethanol abuse (long associated with iron overload) is nowbelieved to inhibit hepcidin transcription.12,13 Similar ef-fects can be produced by toxic and viral insults (for exam-ple, the hepatitis C virus may inhibit hepcidin expression14).The unexplained hepatic iron overload associated with acuteliver failure and chronic end-stage liver disease, which closelyresembles that of hemochromatosis,15 may be a manifesta-tion of diminished hepcidin output due to a markedly re-duced functional hepatic mass. Finally, the rapidly fatal iron-loading disease known as neonatal hemochromatosis is nowfelt to be caused by the immune-mediated destruction ofanother major hepatic iron protein,16 which is currently un-identified. It might be linked to hepcidin. In short, not onlygenetic but also acquired factors seem to be able to impairliver hepcidin output and therefore cause plasma and tissueiron overload. Therefore, all these acquired factors may act aspotential modifiers of the (genetically determined) hemo-chromatosis phenotype.

Insulin resistance is another well-known component ofdiabetes, and by analogy, one would expect to see a hemo-chromatosis phenotype in the presence of factors ren-dering ferroportin insensitive to hepcidin-induced degra-dation (Fig. 1E). Indeed, discrete mutations in ferropor-tin that reportedly cause hepcidin resistance in vitro arebelieved to be the cause of certain rare forms of ferropor-

tin disease that resemble HFE hemochromatosis.17 It canbe easily predicted that other genetic and environmentalmodifiers of hepcidin sensitivity able to interfere with thehepcidin-ferroportin interaction and cause circulatoryiron overload will be soon identified.

Defining and Classifying HemochromatosisThe term hemochromatosis has been inconsistently used

in the literature (and in clinical practice). Sometimes, it isused to vaguely refer to tissue iron overload, to tissue ironoverload with organ damage, or to genetically determinediron overload or, more recently, to indicate HFE-relatediron overload. I suggest that the term hemochromatosisshould be used to refer to a unique clinicopathologic sub-set of iron-overload syndromes that currently includes thedisorder related to HFE C282Y homozygosity (the pro-totype and by far the most common form of hemochro-matosis) and the rare disorders more recently attributed tothe loss of TfR2, HAMP, or HJV or to certain ferroportinmutations. The defining characteristic of this subset isfailure to prevent unneeded iron from entering the circu-latory pool as a result of genetic changes compromisingthe synthesis or activity of hepcidin. All forms of hemo-chromatosis share the following basic features (Table 1):

● Hereditary disease. HC can be associated with mu-tations of various genes. The genetic forms recognizedthus far (Table 1), except those associated with ferropor-tin mutations, are transmitted as autosomal recessivetraits. However, the list of hemochromatosis genes is des-tined to grow as ongoing research uncovers other patho-genic mutations of proteins involved in hepcidintranscription, processing, secretion, stability, hepcidin-ferroportin interaction, or ferroportin degradation.

● Increased transferrin saturation. The first biochemi-cal manifestation of hemochromatosis is increased satura-tion of the iron transporter, transferrin. This isaccompanied by increased non–transferrin-bound iron,particularly in the portal blood. All this reflects the un-controlled release of iron into the bloodstream by entero-

Table 1. Hemochromatosis in a Nutshell

Definition Iron-overload disease caused by a genetically determined failure to prevent unneeded iron from entering the circulatory pool

Distinguishing features 1. Hereditary (usually autosomal recessive) trait2. Early and progressive expansion of the plasma iron compartment3. Progressive parenchymal iron deposition that can cause severe damage and disease involving the liver, endocrine glands, heart,

and joints4. Nonimpaired erythropoiesis and optimal response to therapeutic phlebotomy5. Defective hepcidin synthesis or activity

Postulated pathogenicbasis

Gene mutations leading to inappropriately low hepatic synthesis or impaired peripheral activity of hepcidin

Recognized geneticcauses

Pathogenic mutations of HFE, TfR2, HJV, or HAMP and certain ferroportin mutations

HEPATOLOGY, Vol. 46, No. 4, 2007 PIETRANGELO 1293

cytes and macrophages, a process normally down-regulatedby hepcidin (Fig. 2). Hepatic hepcidin expression is signifi-cantly impaired in HFE, TfR2, and HJV knockoutmice,18-20 and the iron-overload syndromes associated withHFE, TfR2, HAMP, and HJV mutations are all character-ized by inadequate hepcidin synthesis.3,7-9

● Iron overload subsequently involving parenchymalcells. Apart from menstruation, the body has no effectivemeans of significantly reducing plasma iron levels. There-fore, without therapeutic intervention, overloads in thiscompartment will lead to the progressive accumulation ofiron in the parenchymal cells of key organs, creating adistinct risk for tissue iron overload. The deposits areparticularly evident in hepatocytes (Fig. 3) but may alsobe found in parenchymal cells of the endocrine glands andheart. This stage is reflected in increasing serum ferritin(SF) levels. The time of onset and pattern of organ in-volvement vary, depending on the rate and magnitude ofthe plasma iron overloading, which depend, in turn, onthe underlying mutation. For this reason, the milderadult-onset syndromes (HFE-related and TfR2-related)are often distinguished from the more severe juvenile-onset forms (HJV-related and HAMP-related),6 but theimplied dichotomy can be misleading. These forms aremerely 2 points on a phenotypic continuum representing

the same underlying syndrome.● Unimpaired erythropoiesis. Iron is abundant (even

excessive) in the plasma, and its transport to the bonemarrow by transferrin and incorporation into hemoglo-bin are unaffected by the genetic defects that cause hemo-chromatosis. Consequently, anemia is not a feature of thisiron-overload syndrome, and therapeutic phlebotomy istolerated quite well.

● Defective hepcidin synthesis or activity. As previ-ously discussed, any genetic defect that negatively affectsthe synthesis or secretion of hepcidin or its ability todown-regulate ferroportin activity can lead to hemochro-matosis (Fig. 1E). It is thus the central pathogenic factorfor all forms of hemochromatosis6 (Fig. 2). There is highlycompelling evidence that HJV, via BMP-SMAD4 signal-ing, is required for hepcidin transcription,4 but the rolesplayed by HFE and TfR2 are still unclear21-23 (Fig. 4).If hemochromatosis is defined by the presence of all thepreviously discussed features (Table 1), other iron-over-load syndromes can be excluded from this subset if theylack at least one of its defining characteristics. The clearlyhereditary disorders listed in Table 2 include several thatdo not qualify as hemochromatosis because they fail (firstof all) to satisfy the inclusion criterion of unimpairederythropoiesis. In aceruloplasminemia, for example, re-

Fig. 2. The main pathogenic pathways of human hereditary iron overload disorders. The circulatory iron pool is essential for supplying iron to theerythropoietic organs and other functional sites. Entry into the bloodstream of iron from the intestine and storage sites depends largely on the presenceof ferroportin and the auxiliary circulatory or cell-associated ferroxidases (such as ceruloplasmin or hephestin, respectively), which help to load irononto the transporter transferrin. The half-life and membrane activity of ferroportin are mainly dependent on the circulating levels of hepcidin. Thereare 2 hereditary disorders in which iron accumulates in tissues because of impaired iron export activity: ferroportin disease, in which the underlyingdefect is the functional loss of the specialized iron carrier ferroportin, and aceruloplasminemia, which is caused by the loss of a fundamentalferroxidase. Compared with the tissue iron compartment, the circulatory iron pool may be disproportionately low, and this may pose a risk foriron-restricted erythropoiesis and anemia. In atransferrinemia, iron absorbed from the intestine or released from macrophages cannot be transportedto the bone marrow because of the absence of transferrin. Anemia is constant and severe. Tissue overload generally occurs as the unphysiologicallyhigh levels of non–transferrin-bound forms of iron pass into the cells. In the case of hemochromatosis, ferroportin-mediated iron export goesunchecked because of the loss of hepcidin or resistance to its effects. The result is circulatory iron overload followed by tissue overload as the excessiron passes from the bloodstream into parenchymal cells. Here, the ratio of circulatory iron to tissue iron is high.


duced iron export from cells decreases the iron loading ofserum transferrin (Fig. 2), creating a distinct risk for ane-mia (Table 3). The same is true of the disease listed in theOnline Mendelian Inheritance in Man database as type 4hemochromatosis.24 Despite its undeniable imperfec-tions, I prefer the term ferroportin disease25 as a simplerand less misleading name for this disorder, which is clas-sically caused by ferroportin mutations that reduce mac-rophage iron export. One of its intrinsic features is animpaired response to increased bone marrow require-ments for iron (for example, those provoked by heavymenstruation or aggressive phlebotomy), which obvi-ously constitutes a risk for anemia.25 This classic form offerroportin disease also differs from hemochromatosis in

other fundamental respects, including the absence of theearly expansion of the circulatory iron pool. Indeed, trans-ferrin saturation (TS) rises only in the later stages of thisdisease. It is also associated with massive iron overloadingof the reticuloendothelial macrophages, which typicallypresent an iron-deprivation phenotype in hemochroma-tosis (Figs. 3 and 5). Abdominal magnetic resonance im-aging (MRI) is a very useful, noninvasive tool foridentifying this macrophage-iron signature of classic fer-

Fig. 4. Molecular basis for hereditary hemochromatosis. The transcrip-tion of the hepcidin gene, HAMP, requires the interaction of membrane-bound HJV, a coreceptor for BMP, with bone morphogenic proteinreceptor (BMP-R) I and BMP-R II,4 and it is probably down-regulated byendogenous BMP ligands and agonists (currently unidentified) and bysoluble hemojuvelin (sHJV) produced in muscle and other peripheraltissues.5 The influx of iron from the bloodstream to the hepatocyte mightbe sensed directly by the HJV/BMP/BMP-R signaling complex, but itseems more likely that TfR1 and TfR2 contribute to this process bymediating the uptake of transferrin-bound (Tf) and non–transferrin-boundiron (Fe). Normal HFE is clearly associated with TfR1 (as depicted in thefigure), and some investigators maintain that it also interacts with TfR2.21

Animal and human studies indicate that HFE and TfR2 are both importantfor hepcidin expression in hepatocytes but less so than HJV. Their preciseroles are still unclear. One group has provided in vitro evidence that TfR2,HFE, and TfR1 constitute a functional sensing unit responsible forconveying the iron signal to hepcidin.21 They now maintain that HFE andTFR2 serve to amplify BMP signaling through an HJV/BMP receptorpathway22 (pathway A). Another possibility is that HFE(-TfR1) and TfR2are both components of a signaling pathway that is independent ofHJV-BMP (pathway B). This view is consistent with the recent finding ofpreserved BMP signaling in hepatocytes from HFE and TfR2 knockoutmice.23 Finally, HFE(-TfR1) and TfR2 could be components of distinct butcomplementary pathways that coregulate hepcidin expression (pathwayC). This hypothesis is supported by the fact that combined pathogenicmutations of HFE and TfR2 are associated with a more severe iron-overload phenotype than those caused by the mutation of HFE or TfR2alone.9

Fig. 3. Iron accumulation patterns in hemochromatosis and ferropor-tin disease (Perls’ Prussian blue stain). (A) HFE hemochromatosis, male,age 36, LIC of 270 �mol/g of dry weight: parenchymal cell iron depositspresent a typical portocentral gradient. (B) TfR2 hemochromatosis, male,age 24, LIC of 62 �mol/g of dry weight: iron deposits are localized inparenchymal cells, mainly in the periportal areas, as they are in HFEhemochromatosis. (C) HJV-associated hemochromatosis, female, age40, LIC of 514 �mol/g of dry weight: massive iron overload of hepato-cytes with a panlobular distribution. The arrow shows an iron-free focus.(D) Patient with ferroportin disease at age 59, LIC of 646 �mol/g of dryweight: severe hepatic iron overload, largely in Kupffer cell aggregatesand, to a lesser extent, hepatocytes. (E) Liver specimen from the samepatient at age 79, after 20 years of phlebotomy, LIC of 55 �mol/g of dryweight: iron deposits are reduced but still evident in isolated or coales-cent Kupffer cells (arrows). (F) Early-stage ferroportin disease in afemale, age 21, LIC of 110 �mol/g of dry weight. Note the earlyaccumulation of iron in the Kupffer cells (arrows).


roportin disease and differentiating this disorder fromhemochromatosis26 (Fig. 5).

In listing iron-overload states in Table 2, I have inten-tionally avoided the terms primary and secondary, whichare also used inconsistently in the literature. Is a primarydisorder one due to a primary defect of iron metabolism,that is, a defect that is not the result of some other disor-der? Or is it a disorder caused by the mutation of a proteinthat plays a primary role in iron homeostasis, that is, a roleof first-rank importance? If so, what does first-rank mean?For clinicians, it may be more helpful to distinguish be-tween inherited disorders that may require pedigree stud-ies and genetic counseling and those that are acquired, inwhich case an external cause may need to be identifiedand, if possible, eliminated.

Defining and Classifying Disorders due toTissue Iron Accumulation

Although defining and classifying iron overloadstates by their hereditary or acquired nature is simpleand effective, subcategorizing these disorders accord-ing to mechanistic aspects may even offer interestingclues for diagnosis and treatment (Fig. 6 and Table 4).

From a mechanistic point of view, iron accumulationin cells essentially results from either increased cell ironinflux or decreased efflux or, as we are just now begin-ning to recognize, altered subcellular iron traffic (Fig.6). In humans, many pathologic states result from sys-temic iron overload (for example, hemochromatosis,posttransfusion siderosis, and ferroportin disease).Others are rather caused by iron misdistribution andare associated with the regional accumulation of iron insubcellular compartments (for example, mitochondriain Friedreich’s ataxia) or certain cell types and organs(for example, macrophages in anemia of chronic dis-ease and basal ganglia in neurodegenerative disorders).In strict terms, the latter disorders may not all qualifyas true iron-overload states, as the total body iron con-tent may not be increased. If we now consider themechanisms depicted in Fig. 6, we realize that mostiron-loading states in humans belong to type 1, inwhich hepcidin deficiency is the key pathogenic factorleading to increased plasma iron and, consequentially,higher cell iron influx (Table 4).

Type 2 hereditary iron-overload states share importantclinical features: an inappropriately low plasma iron pool(that is, low-normal TS), which poses a risk for anemia,and reduced tolerance to phlebotomy (Table 4). Proto-typic examples of this category are ferroportin disease andaceruloplasminemia (see also Figs. 2 and 6). Another classof syndromes (so far underrepresented) that are associatedwith pathologic iron accumulation is due to disturbedsubcellular iron traffic; this leads to regional iron overloadand toxicity in restricted body compartments and organs(type 3 in Table 4 and Fig. 6). A classic example is Fried-reich’s ataxia, the most common hereditary ataxia, whichis caused by a large expansion of an intronic GAA repeat,resulting in decreased expression of the target frataxingene. The signs and symptoms of the disorder (mainlydue to neurological impairment) derive from decreasedexpression of the protein frataxin, which chaperones ironfor iron-sulfur cluster biogenesis and detoxifies iron in themitochondrial matrix. Because of the local accumulationof iron, iron chelators seem effective in removing andrelocating iron, as suggested by a recent study27 (Table 4).

Clinical Aspects

Clinical Expressivity. Like diabetes, hemochromato-sis is a genetically heterogeneous disease that results fromcomplex, nonlinear interactions between genetic and ac-quired factors. If the altered gene plays a dominant role inhepcidin synthesis (for example, HAMP itself or HJV),circulatory iron overload occurs rapidly and reaches highlevels. In these cases, the modifying effects of acquired

Table 2. Proposed Classification of Disorders Associatedwith Iron Accumulation

HereditaryHemochromatosisFerroportin diseaseAceruloplasminemiaA(hypo)transferrinemiaFriedreich’s ataxiaHereditary iron-loading anemias (thalassemia, hereditary sideroblastic anemia,and chronic hemolytic anemia)*

AcquiredDietaryParenteral and transfusionalAnemia of inflammationAcquired iron-loading (hemolytic and sideroblastic) anemiasLong-term hemodialysisChronic liver disease (alcoholic, viral, and dysmetabolic)Porphyria cutanea tardaAlloimmune neonatal hemochromatosis†Iron overload in sub-Saharan Africa‡

*Although severe transfusional iron overload develops during the treatment ofthese anemias, iron deposits in the hepatic parenchyma are already presentbefore transfusions are started; this may be caused by increased iron absorptionand recycling in response to inefficient erythropoiesis caused by secondaryhepcidin down-regulation.

†Massive hepatic iron loading and generally fatal perinatal liver failure. Thehereditary nature of this disorder is uncertain. It has been recently attributed to analloimmune phenomenon.

‡Particularly frequent among Africans who drink a traditional beer brewed innongalvanized steel drums, this disorder was once attributed exclusively to dietaryexcess. Segregation analysis has led to the conclusion that an unidentifiediron-loading gene may confer susceptibility to the disease. Ferroportin has beenimplicated in this disorder as a possible modifier gene.


environmental and lifestyle factors will be negligible, andthe clinical presentation will invariably be dramatic, withearly onset (first-second decade) of full-blown organ dis-ease, particularly heart and endocrine diseases. The heartand endocrine glands, which are more susceptible to irontoxicity, succumb to its effects earlier, and their failurewill dominate the clinical picture.

In contrast, mutations involving HFE result in a ge-netic predisposition that requires the concurrence of host-related or environmental factors to produce disease. Theclinical presentation, which usually occurs in mid life,varies from simple biochemical abnormalities to severeorgan damage and disease.6 The altered HFE proteinplays an essential role in this process, but its presencealone is insufficient to explain the broad spectrum of met-abolic and pathologic consequences ascribed to the dis-ease. Two main HFE mutations exist, C282Y and H63D,but only C282Y homozygosity is capable of producing

clinical manifestations.6 The development of organ dis-ease in HFE hemochromatosis obviously requires theconcurrence of genetic and nongenetic factors. Coinher-ited mutations in other hemochromatosis genes, such asHAMP and HJV, may have a role, but they are rare.28,29 Ingeneral, the modifier effect of iron genes has been docu-mented in mice,30-32 and these findings have not beenfully confirmed in humans.33-37 Debate continues overthe roles of a fatty liver, a high body mass index,38,39 andpolymorphic changes in oxidative stress-related genes,40

but there is evidence for a strong association betweenalcohol and the development of hemochromatosis-relatedcirrhosis.41 The existence of nongenetic hepcidin inhibi-tors (alcohol may be one of many) raises the possibility ofpurely acquired forms of hemochromatosis (according tothe scheme proposed in Fig. 1). It is impossible to excludethis possibility without much more complete knowledgeof the nongenetic factors that can actually suppress hep-

Table 3. Main Features of Hemochromatosis and Other Hereditary Iron Overload Disorders in Humans

DisorderAffected Gene

(symbol/location)

Known orPostulated Gene

Product Function* Epidemiology Genetics

Mechanismfor Cellular

IronAccumulation

ClinicalOnset

(Decade)Main ClinicalManifestation

ClinicalCourse

I. Hemochromatosis Hemochromatosisgene(HFE / 6p21.3)

● Interaction withtransferrin receptor1

● Uptake oftransferrin-iron

● Hepcidin regulator

● Affects Caucasians ofnorthern Europeandescent

● Associated geneticdefect (C282Yhomozygosity) highlyprevalent: 1/200-300

Autosomalrecessive

Increased ironinflux

3°-5° Liver Disease Mild-Severe

Transferrin-receptor2 (TfR2 / 7q22)

● Uptake oftransferrin andnon transferrin-bound iron

● Hepcidin regulator

● 12 publishedmutations in32 patients from 13pedigrees

Hepcidinantimicrobialpeptide(HAMP/19q13.1)

Down-regulation ofiron efflux frommacrophages,enterocytes,placenta, throughdegradation offerroportin

● 5 published mutationsin 10 patients from 7pedigrees

2°-3° Hypogonadismand cardiacdisease

Severe

Hemojuvelin(HJV/ 1p21)

● Co-receptor forbonemorphogenicproteins

● Hepcidintranscriptionalregulator

● 33 publishedmutations in 70patients from 59pedigrees

● Most prevalentmutation: G230V

Solute carrierfamily 40 (iron-regulatedtransporter),member 1(SLC40A1 /2q32)

Iron export fromcells includingmacrophages,enterocytes,placental cells

● 3 published mutationsin 20 patients from 3pedigrees

Autosomaldominant

3°-5° Liver disease Unclear

II. Ferroportin Disease Solute carrierfamily 40 (iron-regulatedtransporter),member(1SLC40A1 /2q32)

Iron export fromcells includingmacrophages,enterocytes,placental cells

● 21 publishedmutations in 112patients from 31pedigrees

● Most prevalentmutations: Val162deland A77D

Autosomaldominant

Decreased ironefflux

4°-5° ● Liverabnormalities

● Marginalanemia

Mild

III. Aceruloplasminemia Ceruloplasmin(CP / 3q23-q25)

Iron efflux fromcells

● 37 publishedmutations in45 pedigrees*

Autosomalrecessive

Decreased ironefflux

2°-3° ● Neurologicmanifestations

● Anemia

Severe

IV. A(hypo)transferrinemia Transferrin(Tf / 3q21)

● Iron transport inthe bloodstream

● 4 mutations in 10patients from 8pedigrees†

Autosomalrecessive

Increased ironinflux

1°-2° ● Anemia Severe

*As reported in www.genetest.org.†In several clinically reported cases, molecular characterization has not been performed.


cidin synthesis. However, as far as alcohol abuse is con-cerned, the loss of hepcidin activity that it causes wouldusually be episodic and transient. (The same can probablybe said of other nongenetic inhibitors.) The risk for severetissue iron overload is likely to be much greater whenthere is a persistent and life-long inability to up-regulatehepcidin that is genetically based. In fact, the iron over-load associated with alcoholic liver disease is never as rapidor extensive as that found in fully penetrant hemochro-matosis.42 In the absence of a genetically determined hep-cidin deficit, alcohol and other acquired forms ofhepcidin suppression are unlikely to produce per se clin-ically evident iron-dependent organ disease, althoughthey may be important modifiers of an HFE hemochro-matosis phenotype.

It is important to recall that, variations notwithstand-ing, all of these genetic mutations cause the same syn-drome, the targets of iron toxicity are identical (that is, theliver, heart, endocrine glands, and joints), and the patho-genic basis of all forms is a hepcidin deficiency. Unchar-acteristically, severe or anticipated-onset disease inpatients with mutations of an adult-onset gene (for exam-ple, HFE) might be the result of undetected mutations inother hemochromatosis genes, such as heterozygous mu-tations of HAMP or HJV28,29 or even pathogenic muta-tions of TfR2.9 Although the rarity of these additionalgenotypic abnormalities must be emphasized, the varietyof genotypes that can produce a hemochromatosis pheno-type highlights the importance of defining and classifyingthis disease as a unique clinicopathologic entity.

Diagnosing Hemochromatosis. Similar to hypergly-cemia in diabetes, the first abnormality in hemochroma-tosis is hyperferremia (which translates into increasedTS). Ideally, measuring circulating hepcidin would helpin diagnosing the disorder. However, a reliable test toassess bioactive serum hepcidin is not yet available; hep-cidin measurement in the urine, widely used for researchpurposes in specialized centers, needs to be validated incontrolled studies, and its reproducibility needs to betested across different centers.

Today, in patients with signs and symptoms and/ororgan disease suggestive of hemochromatosis, the diagno-sis is based on the presence of blood and tissue iron over-load and a pathogenic mutation in a hemochromatosisgene, usually C282Y HFE homozygosity. In fact, un-treated C282Y homozygotes with cirrhosis, diabetes, orcardiomyopathy invariably have abnormal TS rates and

Fig. 6. Mechanisms of cell iron accumulation. Iron accumulation incells may result from (1) increased iron influx, (2) decreased efflux, or,more rarely, (3) altered intracellular trafficking. Examples of humandiseases are reported for each category.

Fig. 5. MRI scans from patients with hemochromatosis and otheriron-loading disorders. (A,B) A 50-year-old male with HFE hemochroma-tosis before and after phlebotomy, respectively. Before the treatment (SF,1120 ng/mL; LIC, 350 �mol/g of dry weight), MRI reveals a massive ironoverload in the liver with an iron-poor spleen. The hepatic signal intensityis reduced after iron removal (SF, 65 ng/mL; LIC, 35 �mol/g of dryweight). (C) A 49-year-old female with ferroportin disease (SF, 1789ng/mL; LIC, 240 �mol/g of dry weight). Massive iron deposits areevident in the liver and in the spleen and spine. (D) A 53-year-old malewith ferroportin disease after phlebotomy (SF, 90 ng/mL; LIC, 30 �mol/gof dry weight). SF has normalized, but iron accumulation is still detect-able in the spleen and spine (arrow). (E) A female (age 32) withHJV-related hemochromatosis (LIC, 260 �mol/g of dry weight). The MRIpattern resembles that of HFE hemochromatosis. (F) A 35-year-oldwoman with B-thalassemia (LIC, 150 �mol/g of dry weight). The MRI ironsignals are increased in both the liver and spleen-spine, but those of thelatter region are much higher than those of the liver, reflecting aposttransfusion iron overload predominantly involving the macrophagecompartment.


SF levels. Prior to the identification of HFE, an evaluationof the hepatic iron content and distribution by liver bi-opsy was the method of choice for diagnosing hemochro-matosis (Fig. 3). Today, the demonstration of C282Yhomozygosity in a subject with a high TS rate and anelevated SF level is sufficient for diagnosis,6 although liverbiopsy can still play an important role in establishing theprognosis in patients with an SF level above 1000 ng/L,increased aminotransferases, and hepatomegaly.43-45 Theliver iron concentration (LIC) can be assessed noninva-sively by MRI over a wide range of iron concentra-tions46,47 (Fig. 5).

Symptomatic subjects with clear signs of circulatoryand tissue iron overload but negative results in tests forHFE mutation may have pathogenic mutations in otherHC genes. Genetic testing for non-HFE HC is complex,however, and it is not widely available. An alternativeapproach in these cases is based on the biopsy demonstra-tion of a hemochromatotic pattern of hepatic iron distri-bution (Fig. 3), together with a hepatic iron index (LIC,in micromoles, divided by age) greater than 1.9.6 Thelatter finding was considered diagnostic for human leuko-cyte antigen–linked HC in the pre-HFE era.

Therapy. Like diabetes, hemochromatosis should ide-ally be treated with hormone replacement. This is not yetpossible, but noxious blood iron levels can be reduced by theancient, but nonetheless effective, practice of bloodletting.Phlebotomy is indeed the current standard of care in HC.One unit (400-500 mL) of blood contains approximately

200-250 mg of iron. Weekly phlebotomy can restore safeblood levels of iron (reflected by SF levels of less than 20-50�g/L and TS below 30%) within 1-2 years. Maintenancetherapy, which typically involves removal of 2-4 units a year,must then be continued for life to keep TS and SF normal.Phlebotomy is generally regarded as a safe and effectivemeans for removing iron from tissues and preventing com-plications, although this idea has never been validated incontrolled studies, for obvious ethical reasons. The goal ofbloodletting during the iron-depletion stage is generally theinduction of a mildly iron-deficient state. During mainte-nance, therapy is usually target to keep ferritin levels below50 ng/mL, but less aggressive regimens might actually bemore beneficial. Excessive iron depletion could conceivablyhave negative rebound effects because anemia/hypoxiaand/or iron deficiency are major suppressors of hepcidin syn-thesis.

Conclusions and PerspectivesThe liver and the pancreas originate from the same

bipotential cell population in the primitive gut,48 bothhave important, well-known exocrine functions (the pro-duction of bile and digestive enzymes that facilitate foodabsorption), and the similarities do not end there. Few ofus think of the liver as an endocrine gland, and yet it is thesource of secreted peptides that are every bit as importantas the more familiar hormones produced by the pancreas:above all, the iron-regulatory hormone hepcidin.

Table 4. Pathophysiologic Classification of Iron-Accumulation States in Humans

Type 1. Increased cellular iron influx (hepcidin is not adequately produced or nonfunctional)Subtype A

Mechanisms: The circulatory iron pool is expanded because of the uncontrolled release of iron from enterocytes and macrophages even after erythropoieticneeds have been met.

Anemia: AbsentPhlebotomy: Indicated and well toleratedExamples: Hemochromatosis (HFE-related, TfR2-related, HJV-related, HAMP-related, or, in rare cases, ferroportin-related) and oral or parental iron overload(alcohol or hepatitis viruses?)

Subtype BMechanisms: The circulatory iron pool is expanded because of the up-regulated release of iron from enterocytes and macrophages, which is stimulated by iron-restricted or inefficient erythropoiesis and/or hemolysis.

Anemia: PresentPhlebotomy: Usually contraindicated; iron chelators usually indicatedExamples: A(hypo)transferrinemia and hereditary anemias associated with inefficient erythropoiesis

Type 2. Decreased cellular iron efflux (hepcidin is normally produced and functional)Mechanisms: The circulatory iron pool is paradoxically restricted in comparison with the amount of iron trapped in the macrophage and other cellularcompartments.

Anemia: Marginal to overtPhlebotomy: May or may not be effective; use with caution to avoid provoking anemia.Examples: Classic ferroportin disease, aceruloplasminemia, and anemia of chronic disease

Type 3. Altered intracellular or regional iron traffic (systemic iron traffic is not primarily affected)Mechanisms: The iron overload is due to altered iron traffic within subcellular organelles and/or in certain cell types.Anemia: Usually absent or marginalPhlebotomy: May not be effective or indicated (if anemia); iron chelators may prove effective.Examples: Friedreich’s ataxia, hereditary sideroblastic anemias, and neurodegenerative disorders


In healthy subjects, blood iron levels fluctuate withfood intake, exercise, menses, and other physiologic fac-tors, but they are kept within an acceptable range by hep-cidin. This hormone helps the body keep excess iron outof the bloodstream. In subjects with hemochromatosis,blood iron levels are not adequately controlled by hepci-din. The analogies with glucose homeostasis, insulin, anddiabetes are striking.

Hemochromatosis was originally considered an un-usual autopsy finding that was probably alcohol-related.Over a century later, it was finally recognized as a hered-itary disorder caused by a mutation of a human leukocyteantigen–linked protein thought to be involved in intesti-nal iron transport. Soon after the identification of HFE asthe cause of the disease, other apparently unrelated hemo-chromatosis proteins emerged. In addition, it graduallybecame clear that HFE played no direct role in intestinaliron transport. The definition of hemochromatosis and itspathogenesis has thus become increasingly confusing,particularly for clinicians.

Recognizing the analogies between this disease and aclassic endocrine disease such as diabetes simplifies thematter and places hereditary hemochromatosis within itsnatural pathogenic context. Adopting diabetes as ourmodel, we can also foresee new and more effective ap-proaches to the diagnosis of hemochromatosis (for exam-ple, perhaps the measurement of serum hepcidin andferroportin-sensitivity assays based on a hepcidin clamptechnique) and its treatment (for example, hormonal-peptide replacement, hepcidin synthesizers, and ago-nists). Like diabetes, hemochromatosis seems to be theresult of mutations that were once beneficial to our ances-tors. Prototypical HFE-related hemochromatosis proba-bly arose when hunter-gatherer societies were adapting toan agriculture-based lifestyle in the iron-poor environ-ment of northern Europe. However, the physical stress ofthose archaic societies has now been replaced by inactivityand an overabundance of food, and we are now witnessingthe emergence of disorders, such as diabetes and hemo-chromatosis, related to the overefficient absorption andstorage of micronutrients, such as glucose and iron.

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hemochromatosis: an endocrine liver disease

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