Non- HFE hemochromatosis

The term ‘hemochromatosis’ refers to an autosomal recessive disorder of iron metabolism associated with two mutant alleles of the HFE gene (usually leading to a Cys282Tyr mutation in the gene product) and characterized by a slow and progressive increase in plasma iron content, which, in adults, may lead to systemic iron loading of parenchymal cells (particularly hepatocytes) and, eventually, to organ disease. In rare cases, mutations in other iron-loading genes may result in a similar syndrome. The term was coined by von Recklinghausen in 1889 to describe the association at autopsy of widespread tissue injury, usually cirrhosis, with increased tissue staining for iron.1 Sheldon, in his review of all published cases, linked this term to an inherited disorder of iron metabolism that is overwhelmingly more common in males and sometimes has a familial incidence.2 A breakthrough in the history of the disease came with the recognition of its autosomal recessive nature and the location of the pathogenic gene on the short arm of chromosome 6.3, 4 These observations preceded the identification of an iron-regulating gene, now named HFE,5 that is mutated in hemochromatosis. Once the HFE gene was identified, it immediately appeared to be clear that not all patients with an inherited hemochromatosis-like phenotype carried pathogenic mutations in the HFE gene. This was particularly evident in southern European countries.6, 7 Therefore, the term ‘non-HFE hemochromatosis’ was coined to define hereditary iron overload in patients without pathogenic mutations in the HFE gene.8 Like ‘non A-non B hepatitis’, ‘non-HFE hemochromatosis’ was mainly a negative term, based on the ignorance of the genetic basis of the underlying disorders. Since then, unprecedented progress in animal and human iron genetics has led to the identification of new forms of primary iron overload caused by mutations in other genes involved in iron metabolism. For one of these disorders (i.e., ferroportin-associated iron overload, or ferroportin disease), epidemiology, natural history, and molecular pathogenesis are different from the corresponding characteristics in HFE hemochromatosis. These differences also may suggest a different approach to diagnosis and screening. Other disorders share pathogenic mechanisms, clinical presentation characteristics, and an autosomal recessive genetic nature (e.g., TFR2 and juvenile-associated iron overload) with classic hemochromatosis. In this context, these disorders might be considered different forms of the same clinicopathologic syndrome. Therefore, the term ‘non-HFE hemochromatosis’ probably should be restricted to TFR2 and juvenile-associated iron overload. In addition to classic hemochromatosis and ferrorportin disease, they define the group of ‘primary iron-overload disorders’, i.e., disorders due to a defect in a gene primarily involved in iron homeostasis. Other primary iron-overload diseases are the rare forms of aceruloplasminemia9, 10 and atransferrinemia.11 In the former, the lack of ferroxidase activity of plasma ceruloplasmin leads to defective iron release from tissues; the clinical picture is dominated by a neurological syndrome. In the latter, the lack of transferrin leads to increased iron absorption and excessive iron influx in parenchymal cells; severe iron-deficiency anemia is the main clinical manifestation. A unique pedigree in which iron overload is associated with a mutation in the iron-regulatory element of the H-ferritin gene also has been described.12 A distinction should be made between primary iron-overload disorders and secondary iron-overload disorders, in which iron overload is secondary to specific diseases (e.g., thalassemia or other iron-loading anemias, porphyria, etc.) or acquired factors (e.g., alcohol exposure, liver diseases, etc.). RE, reticuloendothelial; mRNA, messenger RNA; IRE, iron-responsive element. Ferroportin disease (also known as ferroportin-associated iron overload) is an autosomal dominant inherited disorder of iron metabolism that results from pathogenic mutation of the SLC40A1 gene, previously called SLC11A3. The first description of the disease was published in 1999, when an autosomal dominant form of hereditary iron overload similar to classic hemochromatosis but not linked to chromosome 6p was reported.13 Distinctive features included tissue iron accumulation predominantly in reticuloendothelial (RE) cells, steadily increasing serum ferritin levels, which were disproportionately high compared with transferrin saturation, marginal anemia, and mild organ disease.13 In 2001, a genomewide screen in the original pedigree provided evidence of linkage with respect to markers on 2q32.14 A candidate gene, SLC40A1, was identified in that region, and all affected patients were heterozygous for a 230C→A substitution; which resulted in replacement of alanine 77, a small, hydrophobic amino acid, with aspartate, a large, negatively charged amino acid; within a predicted myristylation site of the ferroportin protein. In the same year, another group reported that a form of non-HFE hereditary iron overload was associated with heterozygosity for another ferroportin mutation (N144H) in a Dutch pedigree.15 Ferroportin disease now has been reported in many countries, and, at variance with the distribution of the C282Y mutation in the HFE protein, it is distributed worldwide regardless of ethnicity. A common mutation involves three sequential bases in exon 5 and predicts the loss of one of three valine residues at positions 160–162. It probably is due to a slipped-strand mispairing and has been found in pedigrees from the United Kingdom, Australia, Italy, and Greece.16-19 Other ferroportin mutations have been reported in French, French Canadian, and Asian families with hyperferritinemia.20-22 In 2000, ferroportin 1/IREG1/MTP1 protein was identified independently by three different laboratories and was shown to play a role in the export of iron in frog oocytes and in cell lines.23-25 It is expressed in cells that play a critical role in mammalian iron metabolism, including placental syncytiotrophoblasts, duodenal enterocytes, hepatocytes, and RE macrophages. In the human intestine, this protein is expressed strongly under conditions of enhanced iron absorption, such as anemia or hemochromatosis.26, 27 It is involved in the pathogenesis of the hypoferremia associated with anemia of chronic disease, characterized by iron trapping in reticuloendoethelial (RE) cells and reduced intestinal iron transfer.28 Ferroportin expression is responsive to iron and inflammatory stimuli.25, 26, 29-31 Its messenger RNA (mRNA) possesses an iron-responsive element (IRE) in the 5′ untranslated region that binds iron-regulatory proteins and may confer iron-dependent regulation. In agreement with this model, the ferroportin promoter is responsive to iron in HepG2 and CaCo2 cells: deletion of various promoter fragments does not eliminate iron-dependent regulation, whereas removal of the IRE leads to loss of iron control.32In vivo, additional mechanisms may be important in controlling ferroportin expression, particularly in the duodenum, in response to stimuli such as hypoxia or erythron demands.33 According to consensus structural predictions, ferroportin has 9 or 10 transmembrane helices.16, 23, 24 Although the reported mutations span the entire protein, the majority involve the region between the first and fourth transmembrane domains (Fig. 1). This region may be involved in iron binding and/or transport activity or may define a functional binding site for a circulating protein (possibly serum ceruloplasmin or hepcidin) that is important for export of iron from the cell. Positions along the protein backbone of known ferroportin mutations associated with hereditary iron overload. The software prediction of ferroportin membrane organization is adapted from Devalia et al.16 Copyright American Society of Hematology, used with permission. The proposed function of the gene product of SLC40A1 in iron export is consistent with the phenotype of the disease and with the original hypothesis of a selective disturbance of iron recycling in RE cells.13 The finding that different mutations in the same protein lead to the same disorder, characterized by iron accumulation in macrophages, is more consistent with a loss of protein function14 than with a gain of protein function.15 Nonetheless, no experimental proof of the functional effects of various ferroportin mutations has been provided yet. A loss-of-function mutation might cause impairment of iron export from cells, and mainly RE cells, which normally must process and release a large quantity of iron derived from the lysis of senescent erythrocytes (Fig. 2). This leads to tissue iron accumulation (which is responsible for high serum ferritin levels) but also to the decreased availability of iron for circulating transferrin (reflected in low transferrin saturation), which may be responsible for marginal anemia. Progressive tissue iron loading may result from both impaired release of iron from macrophages and hepatocytes and from increased iron influx following the compensatory activation of iron absorption due to marginal anemia. Lack-of-function mutations may be more relevant pathophysiologically in the context of macrophage iron metabolism but less important in iron export from the intestine and from hepatocytes, for which other systems may overcome the functional deficiency. Nonetheless, it is possible that different mutations throughout the protein may affect iron transfer capability differently or involve protein domains that are important in interactions with cell-specific molecular partners. These mutations also may have different effects on protein function depending on the specific cellular context. At the molecular level, it is likely, but not proven, that a mutated allele exerts a dominant negative effect over the wild-type allele. Pathogenesis of primary iron-overload diseases. Inactivation of genes primarily involved in iron metabolism, such as HFE, TFR2, and hepcidin, leads to uncontrolled release of iron from intestinal and macrophage cells and expansion of the circulating iron pool (transferrin-bound and non-transferrin-bound iron). Subsequently, increased iron influx into parenchymal cells is responsible for cell damage and organ toxicity. If the rapidity and extent of expansion of the circulating iron pool are high, as in the case of hepcidin-associated iron overload, endocrine and cardiac damage will dominate clinical presentation. The opposite occurs in the case of inactivation of HFE or TFR2. In ferroportin disease, defective release of iron from storage sites (particularly, reticuloendothelial macrophages) is primarily responsible for tissue iron overload. In ferroportin disease, reduced transferrin saturation may lead to inadequate iron supply to bone marrow and marginal anemia. Late in the disorder, progressive saturation of transferrin with iron also occurs, while the continuing iron retention in organs progresses. The earliest biochemical abnormality, appearing in the first decade of life, is high serum ferritin levels with normal or low transferrin saturation.13 Serum ferritin levels, as well as tissue iron loading, increase with age. In young females, hypochromic anemia may be reported and may require oral iron supplementation. In the fourth and fifth decades, the level of transferrin saturation also may increase, but it rarely reaches 100%, as it does in classic HFE hemochromatosis (Table 1). The biochemical penetrance of the genetic defect is complete, as all documented patients to date have exhibited hyperferritinemia. Clinically, according to available reports, the picture appears more heterogeneous, ranging from simple biochemical abnormality to the full spectrum of symptoms and signs that are typical of hemochromatosis.15 In general, the phenotype appears to be mild, and in spite of severe iron burden, liver disease is limited to signs of fibrosis, primarily sinusoidal. This is consistent with the typical pattern of hepatic iron distribution (Fig. 3) and with the notion that non-parenchymal cell (Kupffer cell) iron overload is better tolerated and less fibrogenic than parenchymal cell iron overload.34 In fact, histologically, early Kupffer cell iron overload is a characteristic feature of the disease; however, other studies have confirmed the original finding that some degree of parenchymal iron overload also is present (Fig. 3B).16, 17, 35 Hepatocellular iron overload has a homogeneous lobular distribution without the periportal-central iron gradient that is typical of hemochromatosis. Due to the mixed pattern of iron accumulation in parenchymal and nonparenchymal cells, a decrease in both liver and spleen signal intensity (due to a decrease in T2 relaxation time) can be observed on magnetic resonance imaging study (Pietrangelo A, unpublished observation, 2002). This differs from classic hemochromatosis, in which decreased signal intensity is evident only in the liver. It is likely that additional environmental factors (e.g., alcohol abuse, hepatitis infection, etc.) and genetic factors (e.g., HFE and non-HFE gene status) may influence the final clinical manifestation of the disease, as in classic hemochromatosis. Hepatic histologic pattern of iron accumulation in primary iron-overload disorders (Perls' Prussian blue stain). (A) Hemocromatosis. Cirrhotic-stage disease in a patient (age, 58 years) who is homozygous for C282Y. Inset: granular iron deposits in hepatocytes. (B) Ferroportin disease. Advanced-stage disease with massive iron overload characterized by coalescent iron deposits in Kupffer cells and macrophages (patient age, 65 years). Inset 1: early-stage disease with typical iron accumulation predominantly in Kupffer cells (patient age, 25 years). Inset 2: late-stage disease, viewed at high magnification; both Kupffer cells and hepatocytes accumulate iron. (C) TFR2-associated hemochromatosis (patient age, 32 years). Iron is observed in Zone 1 and in parenchymal cells (inset), as in early HFE hemochromatosis. (D) Hepcidin-associated hemochromatosis (patient age, 20 years). Massive iron overload of hepatocytes, with panlobular iron distribution, can be seen. Although phlebotomy is an effective therapeutic tool, in some individuals, a weekly phlebotomy program is not tolerated and slight anemia and low transferrin saturation rapidly occur despite still-elevated serum ferritin levels. With a less aggressive phlebotomy regimen, these patients also can become iron depleted, although a therapeutic target of serum ferritin concentration < 30 ng/mL, adopted for classic hemochromatosis, should be avoided, due to the risk of anemia. Adjuvant therapy with erythropoietin may be beneficial. Discontinuation of phlebotomy treatment is followed by a rapid rise in serum ferritin levels. Ferroportin disease should be suspected in all cases of familial hyperferritinemia and in sporadic cases in the absence of known secondary causes (e.g., infection, dysmetabolism, inflammation, or malignancy). Differential diagnosis also should consider the rare form of familial hyperferritinemia—congenital cataract syndrome—which is not associated with tissue iron overload,36, 37 aceruloplasminemia,9, 10 or dysmetabolic which are present in with with autosomal recessive iron loading disorders similar to hemochromatosis may mutations in the TFR2 only one of transferrin transferrin 1 been in 1999, et a human transferrin gene, TFR2, which chromosome with and the cellular of iron. The of TFR2 mutations is and to they have been in one and one of the TFR2 gene have been found in an form which is and a form which is probably is a form of The tissue distribution and expression level of TFR2 are different from the corresponding characteristics in the is expressed in liver and normal cells and the is expressed at low levels in the liver and in all of cells for The of expression of these two genes also is by cellular iron level the protein as well as by the and of does not an and its expression is not by cellular iron levels, but it is cell expression and expression also and The in the TFR2 promoter of consensus for factors and for the may be important in the of expression of in the liver and in the of similar to but the of for transferrin is less than that of may be of in hepatocytes, which low levels of In fact, an of iron of transferrin has been to be when expression is It is to the which defective tissue iron following with the finding that pathogenic mutations of TFR2 in and gene deletion in lead to a In forms of both and HFE to a between these two In one was not found in intestinal interactions may be important for hemochromatosis In and and HFE in specific of and both are in the hepatocytes, expression or iron by a process may the expression of and affect the of tissue iron retention (Fig. 2). of hereditary iron overload associated with TFR2 are the available the clinical phenotype appears to be similar to that of hemochromatosis. In all human diseases characterized by iron loading, iron in hepatocytes (Fig. In one disease with early was observed in a patient while another patient severe of hemochromatosis’ was in two of hepatic iron was observed over with no signs of In another affected with hepatic iron mild hypochromic anemia (which is not a typical feature of classic and, in one young in a massive hepatic iron overload and were observed in a is an important protein in iron however, the of hereditary iron overload associated with mutations is The TFR2 gene is large, and including of new TFR2 mutations in patients of TFR2 mutations should for with non-HFE hepatic iron overload who from families with high levels of In a term, has been used to to a form of hereditary iron overload that and and in a pattern that of hemochromatosis, but at a The disorder first was in of the of iron loading and the increased of tissue to the effects of affected are more likely to present with and including reduced than with severe liver disease (Fig. 2). was to be it now is clear that hemochromatosis is It is likely that pathogenic mutations in proteins that are of primary in the of iron may rise to a similar clinical In fact, homozygous mutations in have been reported in with a clinical that the of gene responsible for a similar is on chromosome a candidate gene named was in this The also that a gene is linked to metabolism or both and HFE influence the and/or function of hepcidin, mutations in TFR2 and HFE should rise to a similar iron loading syndrome. the product of the gene, is a circulating in the hepatocytes in response to inflammatory stimuli and to with in the or in both of which are for have a that due to severe iron-deficiency anemia in the context of RE cell iron In appears to be the main of hypoferremia associated with chronic diseases, characterized by iron in macrophages and decreased intestinal iron Therefore, is the primary negative of iron release from and placental cells, and from other cells as In HFE hemochromatosis, of this appears to be and it may be responsible for the chronic release of iron from macrophages and intestinal cells (Fig. 2). It is that in HFE hemochromatosis is not associated with hepatic iron This finding that may the iron-loading effect of mutated HFE, but it does not that of a role in the pathogenesis of hemochromatosis. Nonetheless, a dominant role in cellular iron Its absence may rise to a release of iron from storage sites and from the intestine into the This release leads to expansion of the plasma iron pool and to the of iron in parenchymal cells or mechanisms (Fig. 2). The common at presentation is which, at the of the may be present in all cases (Fig. In sporadic cases, and cardiac disease also are common and a in the of the with hemochromatosis of the fourth decade of The of or that endocrine organs and the have a to iron toxicity. iron accumulation in these organs may be less tolerated than in the which is more iron toxicity. The liver a in the of iron metabolism, as the site in which the main and storage proteins (i.e., transferrin and and the iron are and in which the iron HFE and the iron and ferroportin are expressed (Fig. the liver also has a role both in the pathogenesis of and as a organ in hemochromatosis and other primary iron-overload disorders (Fig. that are responsible for the inactivation of these proteins may cause enhanced influx and hepcidin) or reduced export of iron in the liver. This will lead to hepatic iron accumulation and, organ disease. In the case of hemochromatosis, the protein, HFE, is not an iron is it involved in intestinal iron it the function of other such as the for transferrin and Therefore, it is not that in hemochromatosis, are for the genetic defect to into a evident In in other primary iron-overload disorders in which a iron or a of iron is the appears at and hepcidin-associated iron overload) and, in the case of hepcidin-associated iron overload, is more severe than in classic hemochromatosis 1). The liver in iron homeostasis. proteins in iron metabolism are and in hepatocytes) or expressed and HFE in Kupffer in the liver. HFE is in Kupffer cells, but expression in hepatocytes also has been The important iron in also is In this iron reticuloendothelial macrophages, it is by the of senescent cells, to the circulating iron transferrin and to bone it is into the of A limited of iron is to for and to a iron The liver as the organ in the pathogenesis of primary iron-overload disorders. The main pathogenic involved in various primary iron-overload disorders, with on the role of or expressed iron are on the and are important proteins in metabolism, and recognition has been in the of iron however, with the possible of ferroportin-associated disease, the of hereditary iron overload associated with mutations in the genes that these proteins is Nonetheless, it is that or of these genes may have a on the penetrance of other diseases, such as classic hemochromatosis. with mutations in HFE may have an severe These additional in genes that share common pathogenic with HFE such as and TFR2. the other the main protein responsible for iron to circulating transferrin from RE cells and the intestine, may in the levels of circulating iron and In this it is that a in ferroportin was found to be associated with a low and high serum ferritin levels in and American the have progress in the of iron that has led to the recognition of new and diseases. The which is the main storage organ for the main of iron and the main site for function in iron metabolism, at the of the that iron metabolism and in and in disease.

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