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Print version ISSN 1516-8484
Rev. Bras. Hematol. Hemoter. vol.34 no.4 São Paulo 2012
Paulo Caleb Júnior de Lima SantosI; Carla Luana DinardoI; Rodolfo Delfini CançadoII; Isolmar Tadeu SchettertI; José Eduardo KriegerI; Alexandre Costa PereiraI
IFaculdade de Medicina da Universidade de São Paulo - USP, São Paulo, SP, Brazil
IIFaculdade de Ciências Médicas da Santa Casa de São Paulo - FCMSCSP, São Paulo, SP, Brazil
Hereditary hemochromatosis (HH) is an autosomal recessive disorder classically related to HFE mutations. However, since 1996, it is known that HFE mutations explain about 80% of HH cases, with the remaining around 20% denominated non-HFE hemochromatosis. Nowadays, four main genes are implicated in the pathophysiology of clinical syndromes classified as non-HFE hemochromatosis: hemojuvelin (HJV, type 2Ajuvenile HH), hepcidin (HAMP, type 2B juvenile HH), transferrin receptor 2 (TFR2, type 3 HH) and ferroportin (SLC40A1, type 4 HH). The aim of this review is to explore molecular, clinical and management aspects of non-HFE hemochromatosis.
Keywords: Hemochromatosis; Iron overload; Iron metabolism disorders
Hereditary hemochromatosis (HH) is a disorder characterized by enhanced intestinalabsorption of dietary iron. Without therapeutic intervention, iron overload leads to multipleorgan damage such as liver cirrhosis, cardiomyopathy, diabetes, arthritis, hypogonadism andskin pigmentation. The most common intervention is therapeutic phlebotomy, which consists ofregular blood withdrawal (usually 400-500 mL per session) until serum ferritin is controlled(1-5).
HFE mutations are, by far, the most common genetic abnormality involved in HH, especially the genotypes: homozygosity for p.Cys282Tyr or the p.Cys282Tyr/p.His63Asp compound heterozygosity. However, since the causal association between HFE mutations and HH was discovered in 1996, it became evident that there are cases of HH that cannot be explained by HFE gene mutations. As a consequence, cases of HH that are not associated with HFE mutations are collectively referred to as non-HFE hemochromatosis; these comprisemutations in the genes that encode hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor2 (TFR2) and ferroportin (SLC40A1)(6-8). Cases of HH due to HJV or HAMP mutations are denominated type 2 HH; those related to TFR2 mutations are named type 3 HH; and cases associated with SLC40A1 mutations, which can be significantly different from classic cases of HH, receive the denomination of type 4 HH or "ferroportin disease".
Considering that the group of non-HFE hemochromatosis has many peculiarities, the aim of this review is to explore molecular, clinical and management aspects of non-HFE hemochromatosis.
Juvenile Hemochromatosis or Type 2 hereditary hemochromatosis
Juvenile hemochromatosis (JH), also classified as type 2, is a rare autosomal recessive disorder of iron overload that leads to organ damage before the age of 30. JH is characterized by severe iron overload usually associated with liver damage, cardiomyopathy and/or hypogonadotrophic hypogonadism. Hypogonadism is the main symptom at disease presentation, and the course of symptoms is more rapid and severe than classic HFE hemochromatosis (type 1)(9). Men and women are equally affected. Typically, patients with JH die prematurely of cardiovascular causes before reaching their fourth decade of life. JH is subdivided in types 2A (OMIM 602390) and 2B (OMIM 613313), which are caused by mutations in the HJV and HAMP genes, respectively(10-12).
Both types 2A and 2B HH are associated, in their final pathophysiology, with hepcidin regulation. Hepcidin is a hormone produced by hepatocytes, which plays an important role in iron homeostasis by regulating its absorption and release in the enterocytes and macrophages(13).
The HJV (OMIM 608374) gene is constituted by 4 exons located in chromosome 1. It wasidentified in 2004 and encodes a protein called hemojuvelin(10). This protein is critical for ironhomeostasis regulation and for hepcidin expression in response to iron. In this scope, patientswith type 2A JH and HJV knockout mice models demonstrate low hepcidin levels suggestingthat hemojuvelin is involved in hepcidin synthesis(14). Several HJV mutations associated with JH have been described in the literature (Table 1). However, HJVp.Gly320Val is the most important mutation and has been reported inJH patients in several different populations around the world(10,15-19).
The HAMP (OMIM 606464) gene directly encodes hepcidin which is produced by hepatocytes and plays a role in iron absorption related to ferroportin degradation of the enterocytes(12,20). Mutations in the HAMP gene, which is constituted by 3 exons and located in chromosome 19, are a very rare cause of JH. Since its description, some mutations havealready been described (Table 1)(12,19,21,22).
Type 3 hereditary hemochromatosis
Type 3 HH (OMIM 604250) is an autosomal recessive disease caused by mutations in the TFR2 gene. The first description of this disease, in two Sicilian families, dates back to 2000 and is the first diagnosis of hemochromatosis attributed to a gene mutation other than HFE(23).
Type 3 HH leads to an iron overload similar to HFE hemochromatosis, and, consequently, may present with abnormal liver function, diabetes, hypogonadism, cardiomyopathy and arthritis(24). The typical onset is during adulthood, but inheritance of both TFR2 and HFE mutations are known to lead to an earlier onset of the disease(25).
TFR2 gene (OMIM 604720) is constituted by 18 exons and encodes the transferrin receptor 2 protein (TFR2). Different to TFR1, TFR2 expression is restricted almost entirely to the liver(26). Rather than only being involved with the uptake of transferrinbound iron by hepatocytes, TFR2 is a sensor of iron levels and is also involved in hepcidin synthesis(23,27-29).
Type 3 HH is a rare condition and usually presents with decreased hepcidin levels. Known TFR2 mutations are shown in Table 1(19,23,30-34).
Type 4 hereditary hemochromatosis or ferroportin disease
Type 4 HH (OMIM 606069), or ferroportin disease, is an autosomal dominant disease that has been associated with mutations in the SLC40A1 gene since 2001 (Table 1)(19,30,35-40). The SLC40A1 (OMIM 604353) gene, constituted by 8 exons, encodes a protein named ferroportin, which is a transmembrane iron transporter expressed in macrophages, enterocytes, hepatocytes and syncytiotrophoblasts(35,41). Ferroportin is responsible for irontransportation across the enterocyte surface and for iron recycling in the reticuloendothelial system(26). It is known that hepcidinbinds to ferroportin, promoting its internalization and degradation leading to a decrease in iron absorption and, consequently, to a reduction in serum iron. Even ferroportin expression on the cell surface can be regulated by hepcidin(20).
Patients with ferroportin disease, differently from HFE HH, typically present with low to normal transferrin saturation (TS) and iron overload within macrophages, mainly from the liver, spleen and bone marrow. In these cases, a mild irondeficient anemia may be present at the initial stage leading to a reduced tolerance to therapeutic phlebotomy(40-42). However, it is also known that some cases of ferroportin disease may present phenotypically very similar to HFE HH with high TS and an iron overload predominantly in hepatocytes(43,44). Regarding these twopossible phenotypes of the disease, it has recently been shown that this difference may be due to the patterns of SLC40A1 mutations. While the most common phenotype is related to a loss of iron exporting activity of ferroportin, the latter (more similar to HFE HH), may be associated with mutations that lead to a hepcidin-resistant ferroportin(41).
Diagnosis of non-HFE hemochromatosis
Similarly to HFE HH, initial suspicions of non-HFE HH are related to abnormalities in iron biochemical assays. Typically, patients present with increased levels of TS (> 45%), which is the earliest phenotypic biochemical indication of HH, and raised serum ferritin. It is important to point out that ferritin is an acute phase reactant and, as a consequence, can be elevated in many situations other than HH; other possible causes must be discardedbefore proceeding with the HH investigation process(45-47). However, hyperferritinemia remains one of the most common signs and is identified from either a systematic biochemical workout or the diagnostic procedure with a large number of opening symptoms such as fatigue, joint pain, jaundice, skin pigmentation, neurological signs, impotence, diabetes, heart disease and even anemia.
A four-step strategy can be proposed to progressively narrow the field of putative causes of hyperferritinemia(48,49).
Step 1) Rule out an acquired cause of hyperferritinemia unrelated to significant iron overload (IOL). Non-hereditary causes of hyperferritinemia are numerous and much more prevalent than hereditary abnormalities of iron metabolism. Thus, neglecting this step usually results in unnecessary genetic testing. The main causes of non-IOL related hyperferritinemia are: inflammatory syndrome, cell necrosis, chronic alcohol consumption and metabolic syndrome. Personal and family history, clinical examination including biometric evaluation (body mass index, waist circumference and blood pressure), iron parameters (serum ferritin and TS) and some simple biochemical tests (C-reactive protein, hemoglobin, alanine aminotransferase and aspartate aminotransferase) in most cases, allow the diagnosis of acquired hyperferritinemia.
Step 2) Confirm IOL and rule out acquired causes. The determination of TS is necessary at an early stage in the diagnostic algorithm. However, due to the test variability throughout a day and depending on technical procedures, any increase in TS must be verified. Repeatedly high TS levels usually denote IOL. It should be noted that a high TS is a particularly valuable indicator for the presence of a HFE mutation. The main causes of acquired IOL are: chronic anemia (thalassemia major, myelodysplastic syndrome, sideroblastic anemia, chronic hemolysis), excessive iron supplementation (oral or parenteral iron, transfusions), porphyria cutanea tarda, chronic liver disease (alcoholic, viral or metabolic), end stage chronic liver disease.
Step 3) As serum ferritin may be increased due to a variety of causes unrelated to IOL, the third step is to assess hepatic iron stores directly. Magnetic resonance imaging is then necessary to authenticate high hepatic iron content. Liver biopsy is indicated if it can supply information that imaging or blood tests cannot and that will help patient management.
Step 4) Confirm the hereditary character of IOL and the precise gene(s) involved. The term of hereditary IOL is restricted to IOL conditions related to primary (genetic) abnormalities of iron metabolism. However in clinical practice, once hepatic IOLhas been proven, phlebotomy must be initiated rapidly without waiting for sequencing results. Quantification of the total iron removed by phlebotomies may serve as an additional argument for retrospective evaluation of the extent of iron accumulation.
Molecular assaying of HFE mutations should be performed only in cases with increased biochemical values and in those with familial history of HFE HH(50). Initially, the two main HFE mutations (p.Cys282Tyr and p.His63Asp) should be tested and, in their absence, non-HFE HH should be suspected. Hence, when there is iron overload in an under 30-year-old patient with cardiac or endocrine manifestations, a diagnosis of type 2 HH needs to be considered. Thus, the evaluation of the p.Gly320Val mutation in the HJV gene must be the molecular test of choice(5,51). If the result is negative, sequencing should be considered to evaluate the HJV and HAMP genes (Figures 1 & 2).
In addition, mutations in the TFR2 and SLC40A1 genesare rare, but they have been reported in child, adolescent, andadult cases. Considering the current advances in sequencing, itis recommended that, ideally, these genes should be evaluated toinvestigate non-HFE HH in patients with negative results for theHFE mutation but with clinical manifestations of primary ironoverload (Figures 1 & 2). Considering that direct sequencing isyet not widely available, usually this last approach is reserved forscientific studies and in the investigation of refractory cases(5,7,52-54).
Therapeutic management of non-HFE hemochromatosis,except for ferroportin disease, is similar to that of HFE HH. Venesection (phlebotomy) is the cornerstone of therapy; its goal is to reduce ferritin to low normal range, usually 50-100 µg/L(52). This therapeutic strategy is associated with significant improvement in liver and skin manifestations of the disease and it is also related to higher survival(55). On the other hand, extrahepatic manifestations such as hypogonadism, arthropathy and diabetes are irreversible irrespective of treatment(52). The benefits of phlebotomy for HH have been demonstrated in cohort studies, but not in clinical randomized trials. However, it is known that survival of HH patients subjected to phlebotomies without diabetes and cirrhosis is similar to that of the general population(56,57).
There are no studies addressing precisely when to initiate phlebotomy sessions, but it is known that an earlier beginning is associated with a better survival(55,58). Currently, the threshold of serum ferritin used to start phlebotomies is taken as above normal range(50). After achieving a ferritin level of less than 50 side effects with phlebotomy, such as in patients with anemia or heart failure, the use of oral iron chelators such as deferasirox may be a safe therapeutic option(1-5).
Erythrocytapheresis has also been mentioned as a possible therapeutic option for patients with HH, but its use is rarely seen in clinical practice(50).
Advances in the understanding of non-HFE HH have been obtained over the years including: association of HJV and HAMP mutations with the juvenile form, several pathogenic mutations associated with non-HFE HH, hepcidin as an iron hormone and its relationship with HFE protein, comprehension of the molecules involved in iron homeostasis, new techniques for the laboratorial evaluation, and increased knowledge about HH therapeutic management. Nonetheless, there are still unclear points to be explored in the non-HFE HH context, such as the better approach to the molecular investigation and therapeutic management.
In this scope, considering the rapid development of molecular techniques, which are becoming faster, more precise and economically viable, it is possible to consider that the diagnosis of non-HFE HH, or even the identification of combinations of mutations in the HJV, HAMP, TFR2, SLC40A1 and HFE genes,may become more common in the clinical practice.
Excluding HFE mutations and secondary iron overload are crucial steps before considering the diagnosis of non-HFE HH. Thus, genetic testing can lead to more adequate and faster therapeutic management.
Paulo Caleb Júnior de Lima Santos is recipient of a fellowship from FAPESP, Proc. 2010-17465-8, Brazil. This work was financed by FAPESP, Proc. 2011-18702-6.
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Paulo Caleb Júnior de Lima Santos
Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), Faculdade de Medicina da Universidade de São Paulo - USP
Av. Dr. Enéas de Carvalho Aguiar, 44 Cerqueira César
05403-000 São Paulo, SP, Brazil
Phone: 55 11 2661-5329
Conflict-of-interest disclosure: The authors declare no competing financial interest