Gastroenterology
Volume 139, Issue 2 , Pages 393-408.e2, August 2010

Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment

  • Antonello Pietrangelo

      Affiliations

    • Corresponding Author InformationReprint requests Address requests for reprints to: Antonello Pietrangelo, MD, PhD, 2nd Division of Medicine and Center for Hemochromatosis, University Hospital of Modena, Via del Pozzo 71, 41100 Modena, Italy

2nd Division of Internal Medicine and Centre for Hemochromatosis, University Hospital of Modena, Modena, Italy

Received 1 April 2010; accepted 3 June 2010. published online 14 June 2010.

John P. Lynch and David C. Metz, Section Editors

Article Outline

In the late 1800s, hemochromatosis was considered an odd autoptic finding. More than a century later, it was finally recognized as a hereditary, multi-organ disorder associated with a polymorphism that is common among white people: a 845G→A change in HFE that results in C282Y in the gene product. Hemochromatosis is now a well-defined syndrome characterized by normal iron-driven erythropoiesis and the toxic accumulation of iron in parenchymal cells of liver, heart, and endocrine glands. It can be caused by mutations that affect any of the proteins that limit the entry of iron into the blood. In mice, deletion of the iron hormone hepcidin and any of 8 genes that regulate its biology, including Hfe, transferrin receptor 2 (Tfr2), and hemojuvelin (Hjv) (which all sense the accumulation of iron that hepcidin corrects) or ferroportin (Fpn) (the cellular iron exporter down-regulated by hepcidin), cause iron overload but not organ disease. In humans, loss of TfR2, HJV, and hepcidin itself or FPN mutations result in full-blown hemochromatosis. Unlike these rare instances, in white people, homozygotes for C282Y polymorphism in HFE are numerous, but they are only predisposed to hemochromatosis; complete organ disease develops in a minority, when these individuals abuse alcohol or from other unidentified modifying factors. HFE gene testing can be used to diagnose hemochromatosis, but analyses of liver histology and clinical features are still required to identify patients with rare, non-HFE forms of the disease. The role of hepcidin in the pathogenesis of hemochromatosis reveals its similarities to endocrine diseases such as diabetes and indicates new approaches to diagnosis and management of this common disorder in iron metabolism.

Keywords: Iron Metabolism, Hereditary Disorders, Micronutrients, Hepcidin, HFE

Abbreviations used in this paper: BMP, bone morphogenic protein, FPN, ferroportin, HAMP, hepcidin gene, HJV, hemojuvelin, RGM, repulsive guidance molecule, TfR, transferrin receptor, TS, transferrin saturation

 

Hemochromatosis is a well-defined syndrome characterized by normal iron-driven erythropoiesis and toxic accumulation of iron in parenchymal cells of vital organs that can be caused by mutations in any gene that limits iron entry into the blood. A milestone in hemochromatosis research occurred in 1996 when Feder et al discovered that mutation in HFE caused hereditary hemochromatosis.1 Research in the fields of hemochromatosis and iron metabolism have progressed, side by side, for 150 years (Table 1). The presence of iron in the blood was first shown in 1713,2 but more than 2 centuries passed before the first iron protein, ferritin, was characterized3 and the basic principles of iron homeostasis were discovered.4 In the mid-1800s, hemochromatosis was described from an autopsy of a patient with diabetes by the French physician Armand Trousseau,5 who was struck by the “bronze-like appearance of [the patient's] countenance.” The liver, he noted, was “granular, of a uniform grayish-yellow color, and very dense.” At the time, the only known iron disease was the condition known today as iron-deficient hypochromic anemia, referred to as chlorosis or, given its frequency in adolescent girls and young women, morbus virgineous.6 Trousseau advocated treating chlorosis with iron but classified it as a ”nervous disease.” Soon other French physicians described a syndrome known as “bronze diabetes and pigmented cirrhosis,”7, 8 and until the mid-20th century this condition was attributed to diabetes, hemolysis, toxins, or metabolic disturbances. In 1935, Joseph Sheldon described the multi-visceral nature of the syndrome and the probable role of iron among its causes.9 He was also the first to suggest that the disease resulted from an inherited metabolic defect. Over the next few decades, studies of ferrokinetics provided more information about iron regulation,10 and by the 1950s bloodletting was introduced to treat hemochromatosis.11

Table 1. Timeline of Iron Metabolism and Hemochromatosis Research

NOTE. Green lines show the milestones in hereditary hemochromatosis.

Eventually, research on hemochromatosis was no longer limited to postmortem observations. Researchers like MacDonald questioned the hereditary nature of hemochromatosis and advocated the pathogenic role of alcohol and dietary iron12 until 1975, when Simon et al linked the syndrome to the major histocompatibility complex on chromosome 6.13 Twenty years later, Feder et al cloned HFE, leading to genetic studies in humans and mice that provided important new information about iron metabolism and hemochromatosis. As genetic tests were developed for HFE polymorphisms and larger genetic studies were performed, it became clear that the disorder was more complicated than previously believed. Sporadic and familial cases of hemochromatosis were identified that were not associated with HFE, particularly in southern Europe. In 1999, a large pedigree of patients with hereditary iron overload was described, but the trait was autosomal dominant and iron accumulated in the reticuloendothelial, rather than parenchymal, cells.14 Two years later this phenotype was associated with a loss-of-function mutation15 in the gene that encodes the transmembrane iron transporter ferroportin (FPN).16, 17, 18 In 1999 a second receptor for serum transferrin, transferrin receptor 2 (TfR2), was cloned,19 and the following year mutations in TfR2 were reported in individuals with non–HFE-related hemochromatosis.20 Subsequent studies led to insights into the pathogenesis of juvenile hemochromatosis,21 considered to be a distinct entity because of its early age of onset and rapid progression, which results in severe cardiomyopathy and endocrine disorders by adolescence or early adulthood. As hepcidin, a circulating hormone that normally checks the release of iron into the bloodstream, was identified,22, 23, 24 mutations in the hepcidin gene (HAMP) were discovered in 2 pedigrees with juvenile-onset hemochromatosis.25 However, in most families with juvenile hemochromatosis, the disease segregated not with HAMP but with hemojuvelin (HJV), a gene on chromosome 1.26 Discoveries of multiple genes that regulate iron homeostasis and the diverse, hereditary iron overload syndromes associated with mutations in these genes indicate that we should better define the characteristics of hemochromatosis.

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What Is Hemochromatosis? 

The term “hemochromatosis” was coined by the German pathologist Friedrich Daniel Von Recklinghausen in a short report published in 188927 describing the bronze stain of organs that was attributed to blood-borne pigments. The term, he maintained, could be applied to different conditions, including “cases of pigmentary cirrhosis, whose association with diabetes,” he noted, “has led the French authors to ask whether the bronze pigment is ([as suggested by] Hanot and Schuchmann) over-produced in the diseased liver, absorbed there, and then transferred to the pancreas and the skin (melanodermia) or ([as proposed by] Letulle) formed primarily in the blood vessels upon the destruction of red cells.”

Von Recklinghausen was clearly thinking of more than one disease, and the term hemochromatosis was later used for different disorders, including hereditary iron overload, iron overload associated with organ damage, tissue iron overload, and the iron-loading disease characterized by pigmentary cirrhosis and diabetes reported in the mid-19th century. Although iron-loading syndromes are heterogeneous and can be hereditary or acquired, (Supplementary Table 1), several hereditary forms arise from a common pathogenic mechanism that involves entry of iron into the bloodstream in excess of that required for erythropoiesis. In the absence of other metabolic disorders, this unregulated iron traffic first causes increased saturation of transferrin (which transports iron to cells such as erythroid precursors in the bone marrow) and then iron accumulates in the parenchymal cells of various organs, resulting in cirrhosis, hypogonadism, diabetes, cardiomyopathy, arthropathy, and skin pigmentation, although erythropoietic activity is unimpaired.

These characteristics are usually related to the deficient synthesis or reduced activity of hepcidin, which down-regulates the entry of iron into the bloodstream. Hepcidin insufficiency can arise from loss-of-function mutations in HAMP25 or from mutations that hamper the interaction of hepcidin with the transmembrane iron export protein FPN.28, 29 Most cases of hemochromatosis arise from alterations in genes that regulate hepcidin synthesis, including HFE (mutated in more than 80% of cases of hemochromatosis),1 TfR2,20 and HJV.26 In mice, severe, hemochromatosis-like iron loading has been associated with the loss of additional proteins that activate HAMP transcription: C/EBPβ, SMAD4, BMP6, and neogenin.30, 31, 32, 33, 34 Although no pathogenic mutations in the relevant genes have been reported so far in humans, defects in any gene that activates hepcidin or, in general, limits iron transfer into the blood might be found to cause a hemochromatosis-like syndrome in humans.

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What Causes Hemochromatosis? 

Research in the 1930s showed that iron enters the human body exclusively through the small intestine (Table 1);4 once it enters, it has to be used or stored because there are no active physiological means for its removal apart from menstrual blood loss. In the 1950s and 1960s, metabolic studies of patients with hemochromatosis (most, if not all, of whom probably had HFE disease) revealed rates of dietary iron absorption by small intestinal enterocytes that exceeded iron loss by approximately 3 mg/day.35

A high flux of dietary iron across duodenal enterocytes increases the total body iron content in patients with hemochromatosis, but most of the iron found in the plasma compartment comes from reticuloendothelial macrophages.36 These cells remove senescent or damaged red blood cells from the circulation and recycle their hemoglobin iron back into the plasma, where it can be used to produce new red cells in the bone marrow and for other purposes. Macrophages of patients with hemochromatosis release more iron than those of healthy individuals,37 and increased iron entry from the gastrointestinal tract depends mainly on increased release from enterocytes into the plasma (rather than increased uptake from the intestinal lumen).38 Macrophage and enterocyte abnormalities have been now associated with unrestricted, FPN-mediated, iron export activities that arise from hepcidin deficiencies.

Without treatment, iron overload in the blood eventually affects the organs, particularly the parenchymal cells, leading to the production of highly reactive oxygen species that can damage intracellular structures. In organs such as liver, pancreas, heart, and gonads, the iron content of parenchymal cells increases progressively and finally exceeds the storage capacity of the intracellular iron storage protein ferritin. As shown in Figure 1, the hemochromatosis phenotype is determined primarily by the rate and magnitude of the circulatory iron overload, which depends on the specific protein that is altered and its interaction with hepcidin. Rapid massive influx of iron into the plasma causes severe, early-onset organ disorders (juvenile forms of hemochromatosis) that include heart failure and endocrine insufficiency. The cardiac and endocrine systems are particularly susceptible to rapid iron loading, probably because their cells have more mitochondria and less antioxidants than liver cells.39 The rapid buildup of iron in these cells causes severe oxidative stress by producing a constant leak of high-energy electrons from the mitochondrial respiratory chain. In contrast, gradual iron loading leads to a milder phenotype with later onset of symptoms (referred to as classic HFE-related hemochromatosis), but intermediate phenotypes have also been described. It is important to remember that, variations notwithstanding, all of these genetic mutations cause the same syndrome because the targets of iron toxicity are identical (ie, liver, heart, and endocrine glands) and the pathogenic basis of all forms is hepcidin deficiency (Figure 1).

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  • Figure 1. 

    The common genetic basis and phenotypic continuum of hemochromatosis. The basic features of hereditary hemochromatosis can be produced by pathogenic mutations of a number of iron metabolism genes (HJV, HAMP, TfR2, FPN, and HFE). Depending on the gene involved and its role in hepcidin biology, the hemochromatosis phenotype varies. If the altered gene plays a dominant role in hepcidin synthesis (eg, HAMP itself or HJV), circulatory iron overload occurs rapidly and reaches high levels. In these cases, the clinical presentation will invariably be dramatic, with early onset (first to second decade) of full-blown organ disease (particularly affecting the heart and endocrine glands). If the hemochromatosis gene is less critical to this process (eg, HFE), a milder late-onset phenotype will arise. This continuum also includes ”intermediate phenotypes” (eg, those caused by pathogenic mutations of TfR2 or by rare combinations of mutations).

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Defects in Iron Metabolism 

Iron is an important dietary nutrient that is continuously recycled by the body; its uptake, storage, and utilization must be carefully coordinated at the cellular and systemic levels. Intracellular iron levels are controlled by iron regulatory proteins 1 and 2 (reviewed by Muckenthaler et al40), which are not significantly disrupted in patients with hemochromatosis. Less is known about the highly complex regulation of systemic iron traffic. Signals from storage compartments (mainly hepatocytes and macrophages) and utilization sites (primarily the bone marrow), historically referred to as “store” and “erythroid” regulatory signals,41 are transmitted to a central control site in the liver, where they regulate expression of hepcidin. Hepcidin was first isolated in 2000 from human blood ultrafiltrate and named LEAP-1 for liver expressed antimicrobial protein (Table 1).22 Its C-terminus has antibacterial and antifungal effects and the protein itself is classified, along with the thionins and the defensins, as a member of the cysteine-rich, cationic, antimicrobial peptide family. In 2001, the same peptide was independently isolated from human urine24 and mouse liver23 and renamed hepcidin. Pigeon et al23 were the first to associate hepcidin with iron, and shortly thereafter, transgenic mouse studies revealed that hepcidin down-regulated iron traffic toward the bloodstream from the environment (ie, the intestinal lumen or, for the fetus, maternal blood) and of iron release from the macrophage storage compartment.30, 42, 43

Hepcidin is believed to regulate iron homeostasis by binding to FPN, the main cellular iron exporter in mammals. Independently identified in 2000 by 3 different laboratories,16, 17, 18 FPN (previously referred to as IREG1 or MTP1) is a multi-domain transmembrane protein encoded by the SLC40A1 gene. It is expressed by cells that regulate mammalian iron metabolism, including placental syncytiotrophoblasts, duodenal enterocytes, hepatocytes, and reticuloendothelial macrophages. The molecular mechanisms by which hepcidin suppresses FPN activity have been delineated in in vitro and in in vivo studies.44, 45, 46 As shown in Figure 2A, as a result of its interaction with circulating hepcidin, FPN is internalized and degraded, thereby diminishing the ability of the cells to transfer iron to the plasma compartment. Later, if iron is needed in the bone marrow for hemoglobin synthesis, hepcidin production is reduced, FPN is re-expressed at the cell surface, and iron export to the bloodstream resumes. This negative feedback mechanism keeps circulating iron at the proper level for erythropoiesis without causing oxidative damage to cells.

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  • Figure 2. 

    Hepcidin-FPN axis regulation of iron metabolism. (A) Hepcidin is secreted by the liver in response to excess iron or inflammation; it binds to the extracellular region of FPN, between transmembrane domains 7 and 8, likely at or nearby C326. (The N-terminus of the hormone seems to be critical for this interaction.) Binding causes Jak2-mediated tyrosine phosphorylation at residues 302 and 303 in the cytosolic loop of FPN. Fpn is then internalized, dephosphorylated, ubiquitinated, and ultimately degraded in the late endosome/lysosome compartment. (B) The hepcidin iron-sensing machinery. The iron content of the blood, reflected by transferrin-bound and not transferrin-bound iron (the latter appearing during iron overload), is monitored by the hepatocytes. Within normal levels, the sensing process probably involves the local iron-induced production of BMPs such as BMP6 and the subsequent assembly of a membrane-associated hetero-tetrameric signaling complex, composed of 2 type I and 2 type II serine threonine kinase receptors. BMP ligands interact with a limited number of receptors, all of which activate a common signal transduction cascade at the intracellular level. The process involves the phosphorylation of intracellular receptor-activated Smad1, Smad5, and Smad8, which interact with Smad4 in the cytoplasm. The resulting complex then translocates to the nucleus, where it activates transcription of the hepcidin gene (see text for details). Neogenin, a membrane receptor for RGM, has been proposed to stabilize HJV and participate in HJV shedding, but its role is still controversial. The soluble form of HJV (sHJV), whose release (HJV shedding) is inhibited by increasing extracellular concentrations of iron, is believed to compete for BMP binding with its membrane-anchored counterpart (either by sequestering free ligands or by displacing HJV from its BMP-R binding site), thereby providing iron-sensitive modulation of hepcidin expression. Iron may also stimulate the expression of other mediators and modulators, such as SMAD7, which seems to attenuate the signal for hepcidin activation. Normal HFE definitely interacts with TfR1 and probably also with TfR2. Together, these 3 proteins might constitute a functional sensing unit responsible for conveying the iron signal to hepcidin. It is currently unclear whether this sensing unit responds directly to serum iron (diferric transferrin) or works in tandem with the BMP/HJV/SMAD system, or if it cooperates with the latter and forms a unique multi-protein sensing complex (see text for details). Recent studies indicate that the presence of HFE is necessary for efficient BMP/SMAD signaling responses to iron, suggesting that it may help sensitize the hepatocytes to low levels of BMPs. A similar activity is likely played also by TfR2.

Signals from the bone marrow are most likely to reduce synthesis of hepcidin. The body maintains a constant source of iron (approximately 20 mg/day) for hemoglobin synthesis, and when increased erythropoiesis occurs, hepatic hepcidin production decreases. Hypoxia, anemia, and iron deficiency all inhibit hepcidin synthesis.47 The details of this regulatory process are being investigated, but putative mediators include hypoxia-inducible factor,48 erythropoietin,49 and circulating factors derived from maturing erythroblasts in the bone marrow.50, 51 The serine protease TMPRSS6/matriptase 2 appears to be an essential component of an iron-sensing pathway in mice that blocks Hamp transcription when iron deficiencies occur, thereby increasing the absorption of dietary iron.52 In humans, loss of matriptase 2 produces iron-refractory iron deficiency anemia,53 characterized by inappropriately high levels of hepcidin and unresponsiveness to oral iron supplementation. Recent studies have suggested that this enzyme down-regulates hepcidin expression by cleaving HJV, a membrane-bound protein that promotes hepcidin signaling in hepatocytes.54

Apart from its role in oxidative stress, excess iron in the bloodstream and/or tissues can facilitate proliferation of invading pathogens. Hepcidin secretion is part of the innate immune response, so it is induced by infections and inflammation;23, 47 it is also involved in pathogenesis of anemia and hypoferremia of chronic disease (also known as anemia of inflammation). These antimicrobial responses have been well characterized and involve inflammatory cytokines, particularly interleukin-6.55 Like other acute phase proteins, hepcidin synthesis appears to be stimulated by intracellular events such as endoplasmic reticulum stress through CREBH;56 it might save iron for specific cell functions under conditions of cell stress.

Less is known about how hepcidin senses plasma levels of iron (Figure 2B), which has been shown to involve HFE, TfR2, and HJV, as well as bone morphogenic proteins (BMPs). BMPs are members of the transforming growth factor β superfamily57 that signal through transmembrane receptors to Smad proteins (Figure 2B), which translocate to the nucleus and activate the expression of genes that include HAMP. The timing, location, and specific downstream effects of BMP signaling are controlled by a network of regulatory proteins, which includes a family of BMP coreceptors known as the repulsive guidance molecules (RGMs). The RGM that provides specificity to the iron signal in the liver, RGMc, is HJV.26 HJV encodes a protein of 426 amino acids and includes a C-terminal glycosylphosphatidylinositol anchor, so it can function in a soluble and a transmembrane form. BMP signaling up-regulates expression of hepcidin, but a soluble form of HJV competes with BMP for binding to BMP transmembrane receptors. Increased extracellular concentrations of iron inhibit release of a soluble form of HJV, which might be a mechanism of iron down-regulation of hepcidin expression.58

Neogenin, a member of the deleted in colorectal cancer (DCC) family of tumor suppressor molecules, has been identified as a receptor for RGMs that appears to interact with HJV.59, 60 It has been reported that neogenin modulates hepcidin expression and iron traffic in vitro,59 but these activities have not been confirmed.61 Neogenin has been proposed to promote62 and also to inhibit34 HJV shedding; inhibition would increase BMP signaling and hepcidin expression. However, livers of neogenin-mutant mice have been reported to have reduced BMP signaling, low levels of hepcidin, and iron overload.34

The hepcidin regulatory signaling pathways might also be regulated by HFE, which does not bind iron but can interact with receptor 1 for serum transferrin (TfR1).63 The C282Y mutation in HFE disrupts a disulfide bond that is required for it to bind β2-microglobulin; this interaction normally allows HFE to be transported to the cell surface and endosomal membranes, where it interacts with TfR1. Expression of TfR1 in the liver is normally low and is down-regulated by iron overload,64 so it seems unlikely that this receptor has a physiological role in hepatocyte iron uptake (although it does in maturing red cells). It was once believed that HFE might somehow regulate TfR1-mediated iron uptake and that the disruption of HFE-TfR1 interaction that occurs in hemochromatosis would cause abnormal entry of iron into regulatory cells in the intestine, but this theory was abandoned.65 It now seems that the HFE-TfR1 complex might regulate hepcidin expression. Disruption of HFE in mice66 and humans67, 68 reduces hepcidin synthesis, but this reduction does not occur when HFE is disrupted only in enterocytes.69 Instead, hepcidin expression is down-regulated by hepatocyte-specific deletion of Hfe.70

TfR2 is also involved in hepcidin and HFE signaling. Unlike TfR1, TfR2 is highly expressed in the liver and its expression is not affected by intracellular levels of iron. TfR2 mediates the uptake of transferrin-bound iron by hepatocytes in vitro,19 possibly via receptor-mediated endocytosis, like TfR1, but its in vitro affinity for transferrin is 25- to 30-fold lower than that of TfR1. Loss of TfR2 function in mice71 and in humans20 is associated with severe hepatocyte iron overload. Like TfR1, TfR2 interacts with HFE, so HFE and TfR2 might form an iron-sensing complex that modulates hepcidin expression in response to blood levels of diferric transferrin.72, 73 In this model, the iron-loaded transferrin protein and HFE compete for binding to TfR1. In the presence of increased saturation of serum transferrin, HFE dissociates from TFR1 and is free to bind TfR2. The interaction of transferrin-HFE with TfR2 might signal the high iron content of the blood to an iron sensor and signal transduction effector complex, possibly the BMP/HJV complex or a distinct system.

How does this iron-monitoring machinery work in vivo? In mice, iron administration has been shown to increase hepatic BMP signaling, and the administration of BMP increases hepcidin expression and reduces serum iron levels.31, 74, 75 In addition, the expression of Smad7 (one of the so-called inhibitory Smad proteins) in primary hepatocytes from mice is coregulated with hepcidin by BMPs, and SMAD7 overexpression has been found to abrogate BMP-mediated activation of hepcidin.76 This suggests that the expression of the iron hormone is regulated by intracellular negative feedback pathways (Figure 2B). Various BMPs have proved to be capable of stimulating hepcidin synthesis in vitro, but a particularly important role is emerging for BMP6.32, 33 In wild-type mice, Bmp6 and HAMP messenger RNA levels are concordantly modulated by iron.77 Notably, Bmp6-null mice exhibit a hemochromatosis-like phenotype characterized by reduced hepcidin expression and tissue iron overload.32, 33 Finally, physical interaction between BMP6 and soluble HJV increases hepcidin expression and reduces serum levels of iron in mice.32 These data indicate that BMP6 is an endogenous regulator of hepcidin expression and iron metabolism in vivo. HFE is not required for transcriptional regulation of BMP6 in response to dietary iron, but loss of HFE reduces BMP6 signaling in vitro and in vivo.78, 79 Thus, HFE promotes hepcidin expression via some interaction with the BMP6-SMAD signaling pathway. The effects of HFE might be necessary for an optimal response to low endogenous basal levels of BMP6, which is believed to act in an autocrine or paracrine manner in the liver.79

In summary, serum levels of iron (indicated by the extent to which transferrin is saturated with iron) can influence hepcidin synthesis indirectly (through BMP-activated signaling)32, 74 and via signaling through a (TfR1-)HFE/TfR2 complex.72, 73 It is also possible that all of these proteins are components of a single signaling complex whose activation leads to the synthesis of hepcidin.

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The Common Pathogenic Basis for All Forms of Hemochromatosis 

If one or more components of the blood iron-sensing machinery fail, adequate levels of hepcidin will not be produced in response to the increased levels of iron, intestinal and macrophage iron release will not be checked, and iron overload and hemochromatosis will result. In mice, loss of Hjv,80, 81 Bmp6,32, 33 Hfe,66 TfR2,82 Smad4,31 neogenin,34 C/EBP alpha,30 and Hamp itself83 all lead to reduced hepcidin synthesis and systemic iron overload that resembles hemochromatosis. In humans, hepcidin deficiency has been associated with HFE-associated,67, 68 TfR2-associated,84 HJV-asssociated,25 and HAMP-associated24 hemochromatosis. In a pathogenic model for all forms of hemochromatosis, HFE, TfR2, and HJV are all independent but complementary regulators of hepcidin synthesis in the liver (Figure 3). When functional forms of HAMP are expressed at normal levels and each of the 3 regulators is also functional, the amount of iron transferred into the blood will be appropriate for the body's needs; excessive levels of iron will not be deposited in tissues (Figure 3A). Loss of function of HFE or TfR2 increases with the amount of iron that enters the bloodstream, but HJV is sufficient for expression of hepcidin. Therefore, plasma iron loading will proceed at a slower rate and the buildup of iron in parenchymal tissues will be more gradual, as it is in hemochromatosis associated with loss of HFE function (Figure 3B). The phenotype of iron overload associated with loss of HJV, which is required for hepcidin, is more severe and similar to that associated with loss of hepcidin itself. A similar phenotype might be expected when HFE and TfR2 are lost together, particularly if these 2 proteins function through distinct but complementary pathways (Figure 2B). Severe forms of juvenile hemochromatosis have been described in individuals with mutations in HFE and TfR285; in mice, combined deletion of Hfe and TfR2 greatly decreases hepcidin levels and causes massive iron overload.86 When hepcidin expression is normal, mutations in FPN (mutations in domains that interact with hepcidin or those that allow FPN to be internalized following hepcidin binding) can result in “hepcidin resistance” and hemochromatosis (Figure 3D).

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  • Figure 3. 

    Hepcidin deficiencies are the central pathogenic factor in hemochromatosis. (A) In healthy subjects, hepcidin secreted by the liver regulates iron release from macrophages and duodenal enterocytes by interacting with the FPN expressed on their surfaces. HFE, TfR2, and HJV are all required to adjust hepcidin expression to current iron needs. Loss of any one of these hepcidin regulators leads to unrestricted flow of iron into the plasma iron pool. Some of the iron will be taken up by the bone marrow for erythropoiesis or by skeletal muscle for incorporation in myoglobin; some will be stored in the hepatocytes in the form of ferritin. The rest remains in circulation because, other than menstruation, the body has no effective way of eliminating iron. From the blood, the excess iron spills over into parenchymal tissues, where it causes oxidative damage to key cell structures. The characteristics of the circulatory iron loading depend on which hepcidin regulator is lost. The buildup can be (B) mild-moderate and gradual in the absence of HFE or (C) massive and rapid, as it is when HJV is lost, and this results in milder (HFE associated) or more severe forms of hemochromatosis (HJV or HAMP associated). Loss of TfR2 probably causes an intermediate level of hepcidin deficiency that produces an adult-onset iron-loading syndrome that appears somewhat earlier than HFE-related hemochromatosis and is somewhat more severe. (D) Classic hemochromatosis can also be associated with rare mutations in FPN that render the iron exporter unresponsive to hepcidin. Although hepcidin is appropriately synthesized and released in response to rising plasma levels of iron, the mutant FPN continues to release dietary iron into the plasma. Modified with permission from Pietrangelo A. Hereditary hemochromatosis—a new look at an old disease. N Engl J Med 2004;350:2383–2397.

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How Frequently Do Cases of Hemochromatosis Occur? 

The C282Y polymorphism in HFE is 10-fold more prevalent than the mutation that causes most cases of cystic fibrosis. HFE-related hemochromatosis would be the most frequently inherited metabolic disorder among white individuals if not for the fact that the phenotype penetrance of the polymorphism is low; C282Y increases the risk of hemochromatosis. Because of its prevalence in certain populations, C282Y is a polymorphic variant rather than a pathogenic mutation. Its mean allelic frequency based on several screening studies is approximately 6%,87 and the prevalence of C282Y homozygosity among white subjects is 1:200 to 1:30088; it is much less common in Hispanic, Asian American, Pacific Islander, and black persons.89 Approximately 80% of patients with hemochromatosis who are of northern European ancestry are homozygous for C282Y. The polymorphism probably arose from a mutation in a single Celtic or Viking ancestor who inhabited northwestern Europe centuries ago.90 Because the genetic defect does not affect reproduction (and might even have conferred advantages against iron deficiency or pathogen infection), it spread through populations. The presumably northern origins of C282Y are consistent with its distribution. Reported frequencies of the C282Y allele range from 12.5% in Ireland to 0% in southern Europe. Another polymorphism in HFE, H63D, has a higher prevalence in the general population (average allelic frequency of ∼14%,)87 and is less subject to geographic variation, but it seems to have limited or no penetrance.91 The S65C polymorphism in HFE has also been associated with excess iron in very rare cases when it is inherited along with C282Y on one allele.

Homozygosity for C282Y is frequent among patients with diabetes, chondrocalcinosis, porphyria cutanea tarda, and/or liver disease.87 Compared with the general population, a person with liver disease is approximately 5 to 10 times more likely to be homozygous for C282Y; the odds are even higher if transferrin saturation (TS) is increased or if the patient has hepatocellular carcinoma, one of the most devastating complications of hemochromatosis. Some subjects with compound heterozygosity (H63D/C282Y) or H63D homozygosity also present with abnormal iron parameters, or even increased deposits of hepatic iron, but these patients usually have disease cofactors.92, 93, 94 Other, very rare mutations have been described in HFE; homozygosity for some of these (or heterozygosity with C282Y) reportedly results in a hemochromatosis phenotype.

The non–HFE-related forms of hemochromatosis are much rarer as compared with HFE-related hemochromatosis but are spread in various parts of the world, regardless of race. The most common TfR2 mutation associated with hemochromatosis is the nonsense mutation (Y250X) that truncates TfR2 at amino acid 250.20 Juvenile hemochromatosis is also rare. The disease has been linked to mutations in HAMP in 3 pediagrees25 but frequently in HJV (59 published pedigrees). The HJV G320V mutation has been detected in 50% of families with juvenile hemochromatosis.26 Most mutations in FPN that result in an iron overload syndrome are associated with FPN disease, which is pathogenetically distinct from hemochromatosis.95 However, FPN mutations (C326S28 and C326Y29) can result in a hemochromatosis syndrome by causing hepcidin resistance; even though hepcidin is produced at normal levels in response to increasing plasma levels of iron, the mutations in FPN cause hyperabsorption of iron from the diet and hepatocellular iron overload (see Figure 3D).

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Signs of Hemochromatosis 

The clinical presentation of HFE-related hemochromatosis, which usually occurs in middle-aged patients, ranges from simple biochemical abnormalities to severe organ damage and disease.65 The variations in symptoms occur because C282Y HFE homozygosity only predisposes an individual to hemochromatosis; additional host or environmental factors are required. The classic presentation of hemochromatosis—unexplained cirrhosis, bronze-colored skin, diabetes (and other endocrine diseases), joint inflammation, and heart disease in middle-aged white men—is rarely seen in modern-day clinical practices. Screening and greater awareness of the disease among clinicians have allowed hemochromatosis to be diagnosed at early stages. The most common symptoms now include fatigue, malaise, arthralgia, and hepatomegaly (Table 2). The TS is almost always increased in patients with hemochromatosis. Later, serum ferritin levels also begin to increase, indicating the accumulation of iron in tissues. A meta-analysis of data from 1382 patients who were homozygous for HFE C282Y (reported in 16 studies) showed that 26% of female patients and 32% of male patients had increased serum levels of ferritin (>200 μg/L for female patients, >300 μg/L for male patients) at diagnosis.87 Among the 626 HFE C282Y homozygotes who underwent liver biopsy (reported in 13 different studies), excess tissue iron (>25 μmol/g liver tissue or an increased siderosis score) was detected in 52% of female patients and 75% of male patients.87 In patients with HFE-related hemochromatosis, serum ferritin levels greater than 1000 mg/L may indicate liver fibrosis, even if transaminase levels are normal;96 once cirrhosis has developed, patients are at increased risk for hepatocellular carcinoma. A meta-analysis conducted in 2006 concluded that 10% to 33% of all patients homozygous for HFE C282Y eventually develop hemochromatosis-associated morbidity.97 The risk was higher in family members with hemochromatosis (32%–35%) than in subjects identified through population-based studies (27%–29%). Increased levels of liver enzymes were present at diagnosis of 24% to 32% of C282Y homozygotes identified by screening.98, 99 In a subgroup that underwent liver biopsy analysis, fibrosis was found in 30% to 42% of male patients and 2.7% to 4.0% of female patients; cirrhosis was present in 4.4% to 11.8% of male patients and up to 2.7% of female patients.98, 99 Penetrance is usually higher among male patients homozygous for HFE C282Y than female patients, probably because of menstruation.

Table 2. Typical Presentations of Various Forms of Hemochromatosis

Three longitudinal population screening studies in which patients were followed up for more than 20 years have shown that disease progresses in only a minority of untreated patients with HFE C282Y.100, 101, 102 As many as 38% to 50% of patients homozygous for HFE C282Y develop iron overload and 10% to 33% eventually develop hemochromatosis-associated morbidity.97 Again, the risk of iron overload–related disease is substantially higher among male patients homozygous for HFE C282Y (28% vs 1% in female patients).102

Apart from male sex, and obvious causes of blood loss, what are the main factors associated with penetrance of HFE C282Y homozygosity? Combinations of mutations in genes such as in HAMP or HJV have been associated with disease, but patients with these are rare.103, 104 Polymorphisms in other genes that regulate iron105, 106, 107, 108, 109 or oxidative stress110 have been proposed to determine the penetrance of hemochromatosis. Certain BMP2 variants have been associated with increased penetrance of HFE C282Y homozygosity,111 but alcohol abuse is likely the main “modifier” associated with hemochromatosis-related cirrhosis.112

Hemochromatosis that is associated with mutations in TfR2 usually presents at an earlier age than HFE-related hemochromatosis and the phenotype is usually more severe. Most patients already have symptomatic organ disease (liver disease, diabetes, cardiomyopathy) at the time of diagnosis (Table 2). Unlike HFE-related hemochromatosis, this form strikes white and nonwhite people with equal frequencies. Patients with juvenile-onset forms of hemochromatosis usually have symptoms related to the heart and endocrine glands, which develop earlier than in adult-onset forms (Table 2).

HFE-related hemochromatosis is diagnosed based on detection of HFE C282Y homozygosity in a patient with circulatory and parenchymal cell iron overload. Serum iron levels and TS do not quantitatively reflect body iron stores and should not be used as surrogate markers of tissue iron overload. Measurement of serum ferritin levels is most widely used to determine tissue iron overload; if serum ferritin levels are normal, tissue iron overload can be excluded. However, increased levels of serum ferritin are difficult to interpret because they can be caused by a variety of inflammatory states, metabolic disorders, and neoplastic diseases, including diabetes mellitus, alcohol abuse, and liver cell necrosis. In the absence of these factors, hyperferritinemia in a patient who is homozygous for HFE C282Y indicates iron overload; untreated patients with cirrhosis, diabetes, or cardiomyopathy invariably have high rates of TS and levels of serum ferritin. Therefore, symptomatic subjects with abnormal levels of iron should be tested for HFE mutations (Figure 4).

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  • Figure 4. 

    Algorithm for the diagnosis and management of hemochromatosis. In patients with symptoms or signs suggestive of hemochromatosis, serum iron parameters should be evaluated. If any of the symptoms are related to hemochromatosis, the TS and serum ferritin level will both be increased. Findings of this type in white subjects are an indication for HFE gene testing. If the patient is a C282Y homozygote, the diagnosis of HFE-related hemochromatosis is confirmed. In the presence of any other genotype, comorbidities (eg, obesity, chronic alcohol consumption) have to be considered first. Factors of this type are almost always also responsible for altered iron parameters in nonwhite patients, who rarely have HFE-related hemochromatosis. In the absence of these comorbidities, or if the iron abnormalities persist after these conditions have been effectively treated, tissue iron overload must be confirmed, ideally by liver biopsy, before considering non–HFE-related forms of hemochromatosis. Parenchymal iron overload in the absence of hematologic disorders or advanced cirrhosis is typical of TfR2-related hemochromatosis or rarer forms of HFE-related hemochromatosis. In symptomatic patients with combined heterozygosity for C282Y/H63D or H63D homozygosity, the actual pathogenic factors are usually unrecognized comorbidities. In the absence of these, they can present with increased iron measures and modest periportal hepatic iron overload, which can be reversed by phlebotomy. In symptomatic patients with abnormal TS and normal serum ferritin level, hemochromatosis can be excluded because the symptoms of hemochromatosis organ disease are invariably accompanied by an increased serum ferritin level. In symptomatic patients with increased serum ferritin levels and a normal TS, the workup should focus on other common causes of hyperferritinemia. If they are not found, or if the hyperferritinemia persists after treatment, the next step depends on whether or not the liver iron content is increased on magnetic resonance imaging or liver biopsy. If so, hereditary non–HFE-related iron overload such as FPN disease can be considered (see text for details).

Before HFE was identified, hemochromatosis was diagnosed based on results of liver biopsy specimens and hepatic iron content and distribution (an approach introduced in the early 1950s; Table 1). Today, patients can be diagnosed based on HFE C282Y homozygosity and increased levels of TS and serum ferritin. Although analysis of liver biopsy specimens is not required for diagnosis of hemochromatosis in C282Y homozygotes65 (Figure 4), it might be used in certain cases to rule out the presence of hepatic fibrosis or cirrhosis (eg, in patients who are homozygous for HFE C282Y, older than 40 years, with serum ferritin levels >1000 mg/L, increased transaminase levels, and hepatomegaly96, 113, 114). Liver iron content can also be assessed noninvasively by magnetic resonance imaging over a wide range of concentrations.

Symptomatic subjects with clear signs of circulatory and tissue iron overload but who are not homozygous for HFE C282Y might have mutations in other hemochromatosis genes, but other common conditions that can alter iron test results should be considered first (eg, metabolic disorders, chronic hepatitis, alcoholic liver diseases). This is particularly true among nonwhite patients, because HFE-related hemochromatosis is extremely rare. If a liver biopsy specimen reveals a pattern of hepatic iron load compatible with hemochromatosis, genetic testing for non–HFE-related hemochromatosis should be offered after other causes of parenchymal iron overload (particularly iron-loading anemias) have been ruled out (Figure 4).

As shown in Supplementary Figure 1, hemochromatosis-related iron accumulation typically affects the hepatocytes; Kupffer cells are usually spared until late stages of disease progression. Fine granules accumulate mainly at the biliary pole of cells, and the lobular distribution displays a decreasing gradient from periportal to centrolobular areas. Mesenchymal iron deposits generally do not appear until the liver cell iron content is high enough to cause cell necrosis. When the iron overload is confined exclusively to the hepatocytes, the first condition that has to be excluded is compensated iron-loading anemia with inefficient erythropoiesis. End-stage cirrhosis must also be ruled out. In this case, the iron is distributed heterogeneously from one nodule to another; no deposits have been detected at the levels of fibrous tissues or the walls of bile ducts and blood vessels. Severe hepatic iron overload can also be caused by the hereditary disorders aceruloplasminemia and hypotransferrinemia or atransferrinemia (Supplementary Table 1). Both are extremely rare and can easily be distinguished from hemochromatosis by their clinical features. Aceruloplasminemia causes neurologic manifestations (progressively severe extrapyramidal signs, cerebellar ataxia, dementia), and hypotransferrinemia or atransferrinemia causes life-threatening anemia.

Patients with symptomatic hemochromatosis inevitably have tissue iron overload, reflected by increased levels of serum ferritin. Therefore, among patients (of any race) with signs and/or symptoms of hemochromatosis and increased TS, a finding of normal serum ferritin levels excludes a diagnosis of hemochromatosis (Figure 4). In symptomatic patients who present with increased levels of serum ferritin and normal TS, other common causes of hyperferritinemia must be ruled out (Figure 4). If these conditions have been excluded or if the hyperferritinemia persists after the condition has been adequately treated, hepatic iron stores should be assessed by direct means (magnetic resonance imaging or liver biopsy analyses).

If a patient has increased iron content in the liver, hereditary iron overload diseases unrelated to HFE should be considered. FPN disease, for example, is an autosomal dominant disorder of iron metabolism that is the second most common cause of hereditary hyperferritinemia (after HFE-related hemochromatosis). Its symptoms were described in 199914 and associated with FPN mutations in 2001 (Table 1),15, 115 and it has been reported in various ethnic groups. In contrast to the rare forms of hemochromatosis that are associated with mutations in FPN (Figure 3D), FPN disease is caused by loss-of-function mutations in FPN.95 These mutations are believed to impair iron export, particularly by reticuloendothelial macrophages. The result is an accumulation of iron in macrophage populations of the spleen, liver, and bone (reflected by high levels of serum ferritin) (Table 2). Parenchymal cells of these organs are largely spared (Supplementary Figure 1D), so the disorder is associated with mild visceral disease. Levels of iron in the bloodstream are low (reflected by low-normal TS), despite increased serum ferritin levels (Table 2), and under certain circumstances (eg, aggressive phlebotomy regimens), this phenomenon can also lead to iron-restricted erythropoiesis and anemia.

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How Is Hemochromatosis Managed? 

Bloodletting (phlebotomy) is the standard treatment for all forms of hemochromatosis. It was first used in 1950 to eliminate excess iron in patients with hemochromatosis11 (Table 1). There are no evidence-based guidelines on the use of therapeutic phlebotomy. Systematic studies have never been conducted to determine when it should be started, how frequently it should be performed, or therapeutic end points. Treatment is conventionally initiated when serum ferritin levels exceed the normal range. Patients who are homozygous for HFE C282Y and do not express functional protein should have their serum ferritin level checked yearly; if abnormalities are noted, patients should be examined thoroughly and phlebotomy started.

The goal of bloodletting during the iron-depletion stage is generally the induction of a mildly iron-deficient state. Weekly removal of 1 unit (400–500 mL) of blood (which contains approximately 200–250 mg of iron) can generally restore safe iron levels to blood (reflected by serum ferritin levels less than 20–50 μg/L and a TS of less than 30%) within 1 to 2 years. Maintenance therapy, which typically involves the removal of 2 to 4 units a year, is then started to keep serum ferritin levels between 50 and 100 μg/L, whereas iron deficiency with lower serum ferritin levels should be avoided because this may be associated with unnecessary symptoms or, paradoxically, lead to further hepcidin depression and increased iron absorption. Despite the nonspecificity of the test, serum ferritin levels should always be monitored during phlebotomy.

When possible, blood taken from patients with hemochromatosis should be made available for transfusion. Many patients with HFE-related hemochromatosis are rejected as donors for other reasons, such as abnormal liver function test results, diabetes, and medication use, but in the absence of these factors, their blood should be available for transfusion. If phlebotomy is contraindicated because of severe anemia, cardiac failure, or poor tolerance, other therapeutic strategies can be considered, such as administration of iron chelators. Recently, in a phase 1/2 study dose-escalation trial, the oral iron chelator deferasirox was reported to be safe (although at doses lower than those currently used in transfusion-dependent anemias) and effective in reducing serum ferritin levels in C282Y homozygotes (Phatak et al, manuscript in submission).

Patients with hemochromatosis are at risk for serious organ disease, including hepatocellular carcinoma, which is at least twice as frequent among patients with HFE-related hemochromatosis compared with those who have other types of liver disease. Phlebotomy is generally regarded as a safe and effective means for removing iron from tissues and preventing complications, although for obvious ethical reasons the efficacy of this assumption has never been validated in controlled studies. Its survival benefits have never been evaluated in patients with hemochromatosis who have confirmed C282Y/C282Y genotypes, but studies conducted before genetic testing was available, on patients diagnosed with hemochromatosis who were treated with phlebotomy, indicated that phlebotomy increased survival compared with that of patients who underwent inadequate phlebotomy or did not undergo phlebotomy at all (Figure 1).116 Cirrhosis or diabetes significantly reduces survival, but in the absence of these complications, the life expectancy of treated patients with hemochromatosis is similar to that of the general population. Bloodletting seems to improve transaminase levels, skin pigmentation, and hepatic fibrosis. Regression of biopsy-proven liver fibrosis has been reported in 13% to 50% of patients with hemochromatosis who underwent phlebotomy; the best results occur when baseline fibrosis is mild.87 Other features of the disease, such as joint pain, are unlikely to improve with iron depletion. Hemochromatosis-related hypogonadism, cirrhosis, destructive arthritis, and insulin-dependent diabetes are usually irreversible, but certain aspects of these diseases might be improved with phlebotomy (eg, daily insulin requirements, increased levels of aminotransferase, weakness, lethargy, abdominal pain). End-stage liver disease and hepatocellular carcinoma secondary to hemochromatosis are frequently treated by orthotopic liver transplantation. Posttransplantation survival rates in untreated cases of hemochromatosis are reduced compared with those of non–iron-loaded patients due to cardiac and infectious complications, whereas successful pretransplantation iron depletion by phlebotomy improves survival.117

Early diagnosis and prompt initiation of iron-depletion therapy increase survival times of patients with hemochromatosis. The low penetrance of HFE C282Y is the main argument against the use of genetic screening among the general population. However, biochemical screening (followed by genetic testing when indicated) should be considered in groups with a high prevalence of this polymorphism (patients with liver disease, porphyria cutanea tarda, and/or chondrocalcinosis; family members with hemochromatosis; northern European populations).

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Perspectives 

Hemochromatosis was originally considered to be an odd finding in autopsies that was probably alcohol related. More than a century later, hemochromatosis is recognized as a hereditary disorder associated with one of the most common polymorphisms among white people. We have made major advances in understanding this disease, but there is still much that we do not know, such as the exact role of HFE in iron metabolism. Hemochromatosis models of pathogenesis have been developed based on studies of genetically modified mice. However, it is not clear if these are true models of hemochromatosis or simply models of iron overload. In mice, organ disease is not associated with loss of any of the hemochromatosis genes described thus far, including Hamp and Hjv. Rodents are probably less vulnerable to iron toxicity than humans.

It will also be important to identify factors that affect penetrance (genetic and nongenetic) of HFE-related hemochromatosis. In humans, C282Y homozygosity confers only a predisposition to iron overload, whereas loss of genes such as HJV or HAMP causes severe, early-onset organ disease. Therefore, the development of hemochromatosis among patients homozygous for HFE C282Y requires host-related, environmental, or lifestyle factors (alcohol intake). Recent genome-wide association studies indicate that polymorphic variants of hepcidin inhibitor, matriptase-2, strongly predict low serum iron and low hemoglobin levels in humans;118, 119 similar studies might associate HFE-related hemochromatosis expressivity with polymorphisms in hepcidin inhibitors or activators such as BMP6.

The discovery of hepcidin revealed parallels between hemochromatosis and classic endocrine diseases such as diabetes;120 diabetes was an important feature of hemochromatosis and a major cause of death among patients until insulin therapy was first introduced in 1921. Both diseases are caused by reduced synthesis or insensitivity to hepcidin and insulin, which are produced by the liver and the pancreas, respectively—the homeostatic regulators of vital micronutrients, iron, and glucose. Recent discoveries into the pathogenesis of hemochromatosis will improve diagnosis and management; FPN sensitivity assays based on a hepcidin clamp technique, along with hepcidin replacement therapies, and hepcidin synthesizers and agonists, are all under development.121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137

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Supplementary material 

Supplementary Table 1. Human Diseases Associated With Iron Overload
Hereditary
Hemochromatosis (HFE, TfR2, human immunodeficiency virus, HAMP, FPN associated)
FPN disease
Aceruloplasminemia
Atransferrinemia, hypotransferrinemia
DMT1 deficiency
Hereditary iron-loading anemias (eg, thalassemia intermedia)a
H ferritin mutation
Friedreich's ataxia
Porphyria cutanea tarda
Acquired
Dietary
Parenteral
Anemia of inflammation
Transfusion-dependent iron-loading (thalassemia major, hemolytic, sideroblastic) anemias
Long-term hemodialysis
Chronic liver disease (alcoholic; viral; dysmetabolic)
Alloimmune neonatal hemochromatosisb
African hemochromatosis (Bantu siderosis)c

aParenchymal iron overload is detectable before transfusion. It is caused by inefficient erythropoiesis and hepcidin down-regulation.

bOnce considered hereditary, now believed to be caused by maternal alloimmunity to the fetal liver.

cParticularly frequent among Africans in sub-Saharan regions who drink a traditional beer brewed in nongalvanized steel drums, in this disorder an unidentified iron-loading gene may confer susceptibility to the disease. FPN has been implicated as a modifier gene.

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  • Supplementary Figure 1. 

    Liver histology in patients with hemochromatosis. Perls' Prussian blue stain for iron. (A) HFE-related hemochromatosis is characterized by purely parenchymal iron overload that is heaviest in the periportal areas and less intense in the centrolobular areas. (B) TfR2-related hemochromatosis. The histopathologic picture is identical to HFE-related hemochromatosis with iron accumulation in periportal parenchymal cells. (C) HJV-related juvenile-onset hemochromatosis: massive pan-lobular parenchymal iron overload. (D) Classic ferroportin disease. Unlike the previous 3 cases, this liver displays iron overload that predominantly affects the Kupffer cells (arrows).

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 Conflicts of interest The author discloses no conflicts.

 Funding Supported by the PRIN 2008 grant from the Italian National Research Council.

PII: S0016-5085(10)00872-3

doi:10.1053/j.gastro.2010.06.013

Gastroenterology
Volume 139, Issue 2 , Pages 393-408.e2, August 2010

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