Iron Disorders, An Issue of Hematology/Oncology Clinics (eBook)

Matthew M. Heeney (Autor)

eBook Download: PDF | EPUB

2014 | 1. Auflage
348 Seiten
Elsevier Health Sciences (Verlag)
978-0-323-29940-4 (ISBN)

Infos

This issue of Hematology/Oncology Clinics, guest edited by Drs. Matthew Heeney and Alan Cohen, is devoted to Iron Disorders.  Articles in this issue include: Hereditary Hemochromatosis (HFE and Non-HFE); Iron Refractory Iron Deficiency Anemia (IRIDA); Sideroblastic Anemia; Anemia of Chronic Disease/Inflammation; Pathophysiology of Transfusional Iron Overload; Transfusional Iron Overload and Iron Chelation Therapy; Iron Overload and its Management in Non-Transfusion-Dependent Thalassemia; Treatment of Iron Deficiency Anemia; and Iron Overload Assessment.

Textauszug

Diagnostic Evaluation of Hereditary Hemochromatosis (HFE and Non-HFE)

Edouard Bardou-Jacquet, MD, PhDabc∗[e-mail] and Pierre Brissot, MD, PhDabc,     aCHU Rennes, French Reference Center for Rare Iron Overload Diseases of Genetic Origin, 2 rue Henri le guilloux, F-35033 Rennes, France; bINSERM, UMR 991, 2 rue Henri le guilloux, F-35000 Rennes, France; cCHU Rennes, Liver disease department, 2 rue Henri le guilloux, F-35033 Rennes, France

∗Corresponding author. CHU Rennes, French Reference Center for Rare Iron Overload Diseases of Genetic Origin, 2 rue Henri le guilloux, F-35033 Rennes, France.

The management and understanding of hereditary hemochromatosis have evolved with recent advances in iron biology and the associated discovery of numerous genes involved in iron metabolism. HFE-related (type 1) hemochromatosis remains the most frequent form, characterized by C282Y mutation homozygosity. Rare forms of hereditary hemochromatosis include type 2 (A and B, juvenile hemochromatosis caused by HJV and HAMP mutation), type 3 (related to TFR2 mutation), and type 4 (A and B, ferroportin disease). The diagnostic evaluation relies on comprehension of the involved pathophysiologic defect, and careful characterization of the phenotype, which gives clues to guide appropriate genetic testing.

Keywords

Hemochromatosis

Hepcidin

HFE

TFR2

Hemojuvelin

Ferroportin

Phlebotomy

Key points

• Hereditary hemochromatosis can damage liver, heart, pancreas, endocrine glands, bones, and joints. However clinical expression spans from a few biologic anomalies to full-blown multiorgan involvement.

• Hereditary hemochromatosis is mainly related to inappropriately deficient hepcidin secretion related to mutations in genes involved in hepcidin regulation.

• Ferroportin disease is associated with normal hepcidin secretion, but mutations in ferroportin induce loss of iron export function or resistance to hepcidin regulation.

• HFE-related hemochromatosis is the most frequent form in the white population. Genetic testing for rare forms of hereditary hemochromatosis must be guided by the clinical phenotype.

Introduction

To efficiently assess patients with suspected hereditary hemochromatosis, clinicians must understand the normal physiology of iron metabolism and the pathophysiologic mechanisms leading to iron overload.

Iron Metabolism

Iron absorption and export

Iron absorption occurs in the proximal duodenum. Nonheme iron is transported across the luminal membrane of the duodenal enterocyte into the cytoplasm by divalent metal transporter 1.1 Transport of heme iron into the enterocyte membrane is performed by a pathway that remains controversial.

Ferroportin (SLCA40A1)2 is located at the basolateral membrane of the enterocyte and at the membrane of macrophages. It is the only known cellular iron exporter, allowing iron egress from the cytoplasm into the bloodstream.

Hepcidin

Hepcidin (HAMP)3 is synthesized primarily by hepatocytes, but is also produced at lower levels by adipocytes and macrophages. This small peptide, initially identified as an antimicrobial peptide, was later shown to be the key hormone regulator of iron metabolism.4,5

Hepcidin regulates iron availability through the modulation of iron export by ferroportin: hepcidin binds to ferroportin at the membrane of enterocytes or macrophages, and causes subsequent ferroportin endocytosis and degradation, thus impairing iron export.6

Hepcidin regulation

Because of its central role in iron metabolism, hepcidin is tightly regulated by several pathways including inflammation, erythropoiesis, and body iron stores. The regulation of hepcidin according to body iron stores involves distinct pathways for long- and short-term regulation. Basal expression is regulated through a bone morphogenetic protein/Son of Mother Against Decapentaplegic (SMAD) pathway. Bone morphogenetic protein 6 plays a major role in association with its coreceptor hemojuvelin (HJV),7 and is also involved in the response of hepcidin expression to iron stores over the long term.

Regarding the short-term regulation, it is proposed to be mediated through serum transferrin saturation.8 Although the molecular mechanisms remain debated, it is proposed that HFE, TFR1, TFR2, and HJV form an iron-sensing complex at the hepatocyte membrane, with subsequent regulation of hepcidin expression.

Iron Overload

Iron overload in hereditary hemochromatosis occurs through two main distinct mechanisms.

Hepcidin deficiency

Hepcidin deficiency is the key mechanism of iron overload in HFE, HJV, HAMP, and TFR2 related hemochromatosis.9 Mutations in these genes lead to defective or inappropriately low hepatic synthesis of hepcidin for the degree of iron burden. In HFE hemochromatosis it has been demonstrated that correction of liver hepcidin secretion normalized iron metabolism, confirming the predominant role of liver.10

Relative hepcidin deficiency leads to a sustained and unregulated activity of ferroportin with two consequences: increased duodenal iron absorption, and enhanced release of iron from reticuloendothelial macrophages into the bloodstream originating from erythrophagocytosis.

The overall result is increased plasma iron concentration and increased saturation of transferrin. If the capacity of transferrin is exceeded, an abnormal physiologic form of iron appears, called nontransferrin bound iron. Nontransferrin bound iron is rapidly taken up by the liver, pancreas, and heart, and leads to pathologic parenchymal iron deposition and organ dysfunction. Moreover, if transferrin saturation exceeds 75%, labile plasma iron appears, which has a high propensity for generating reactive oxygen species that can directly damage tissues.11

Ferroportin disease

There are two types of ferroportin disease that are distinguished by the molecular mechanism involved. Type A is characterized by a loss of ferroportin activity caused by mutations in the SLC40A1 gene.12 As a consequence of the functional deficiency, macrophage iron overload results from decreased iron export. The pathologic consequence is reticuloendothelial macrophage iron loading. Type B is characterized by mutations in ferroportin, which confer “resistance” to hepcidin.13 Thus, despite an increased serum hepcidin level, ferroportin regulation is defective, resulting in constitutive ferroportin activity and a “functional” hepcidin deficiency, as in HFE hemochromatosis. The pathologic consequence is reticuloendothelial macrophage iron sparing and parenchymal iron loading in target organs.

Penetrance

Clinical expression in hereditary hemochromatosis is variable, especially regarding HFE hemochromatosis.14 This variable phenotype makes it difficult to define hereditary hemochromatosis: does it correspond only to the identification of genetic mutations, to the association of biologic iron overload with genetic mutations, or only to iron-related clinical expression? Moreover, for the latter two conditions, the clinically significant level of iron overload remains to be determined.

HFE hemochromatosis is primarily associated with homozygosity for the C282Y HFE mutation. However, depending on the diagnostic criteria used, clinically significant iron overload is observed in only 5% to 75% of homozygotes patients.14,15 A recent meta-analysis showed an overall penetrance of 13.5%,16 and longitudinal studies showed iron overload in up to 50% of patients.

This variable penetrance is caused by numerous other acquired and genetic factors affecting iron metabolism regulation. Male sex17 and alcohol consumption18 increase the severity of iron overload, whereas obesity, through higher hepcidin expression, has been proposed to exert a protective effect.19 Furthermore, the occurrence of mutations in other genes involved in iron metabolism has been showed to modify the iron burden; however, the search for other genetic factors has shown variable results.20,21

Because of the relatively few cases of type 2 and 3 hemochromatosis described, data regarding their penetrance and expression are scarce. If the penetrance is nearly complete, the severity of iron burden and age of presentation seems to be more variable than initially thought. This may be caused by the same reasons as seen in HFE hemochromatosis, but likely...

Produkt-Details

• Erscheint lt. Verlag: 28.8.2014
• Sprache: englisch
• Themenwelt: Medizinische Fachgebiete ► Innere Medizin ► Hämatologie
• ISBN-10: 0-323-29940-7 / 0323299407
• ISBN-13: 978-0-323-29940-4 / 9780323299404