Disorders of iron metabolism can be inherited and acquired, and include iron deficiency, iron overload and conditions in which iron is increased in the body but the distribution is altered, with excess iron in the stores and low iron in erythroid cells (Table I). Most acquired disorders, such as iron deficiency anemia and anemia of inflammation or anemia of chronic disorders (ACD), are secondary to other diseases. In this chapter, only the iron-related aspects of these disorders will be discussed.

Inherited conditions leading to iron overload and iron deficiency have been better clarified in the last years, following advances in our understanding of iron metabolism and of its regulation (Andrews 2008) PubMed.

 

Camaschella_DISORDERS_OF_IRON _METABOLISM _Table

Table I. Classification of iron metabolism disorders

 

Acquired forms of anemia related to iron metabolism

These are the most frequent anemias worldwide and include both the forms associated with iron deficiency and those resulting from chronic inflammatory disorders characterized by immune dysfunction, commonly defined ACD.

 

Iron deficiency and iron deficiency anemia

Iron deficiency is a condition characterized by a considerable reduction of total body iron. If this condition persists, iron supply is compromised to all body organs, but especially to erythropoiesis leading to the development of iron deficiency anemia.

Iron deficiency anemia is the most common form of anemia worldwide. The WHO estimates around 2 billion people affected by iron deficiency, prevalently in developing countries due to inappropriate diet or to intestinal worm colonization (Beutler 2006).

Iron deficiency is a typical acquired condition, although recently a great interest has been focused on the identification of genetic variants that confer susceptibility to its development (Benjamin et al, 2009;PubMed Tanaka et al, 2010PubMed). Causes of acquired iron deficiency are well established. An increased need of iron is physiological during infancy, growth spurt of adolescence, in women with heavy menstrual losses, in the third trimester of pregnancy and during breast-feeding. Other causes in developed countries are due to strictly vegetarian diets, reduced intestinal iron absorption and chronic blood losses. The latter may be of variable severity. In both gender and especially in old individuals, chronic -often occult – blood losses from the gastrointestinal tract are extremely common. This could be related to benign disorders, side effects of drugs but also malignancies. In women blood losses due to hypermenorrhea or repeated pregnancies with insufficient iron supplementation are often underestimated. Repeated blood donations without iron supplementation are another cause of iron deficiency in blood donors. Atrophic gastritis, colonization by Helicobacter pylori (Hershko and Ronson, 2009) PubMed, inflammatory bowel diseases (IBD), celiac disease, especially the late-onset form, and reduction of the ability to acidify the gastric content reduce iron absorption. Less commonly iron deficiency can develop as a complication of intravascular hemolysis as in paroxysmal nocturnal hemoglobinuria (PNH) or for a mechanical damage of red cells on abnormal cardiac valves, because iron is lost in the urine. Other uncommon causes are due to the presence of a congenital hemorrhagic defect, as in some forms of von Willebrand disease that favor mild but chronic bleeding. The iron-restricted erythropoiesis is a condition of iron deficiency without anemia that follows erythropoietin treatment. In this case, the expansion of erythropoiesis caused by the hormone overcomes both the duodenal capacity to absorb and the stores ability to mobilize iron (Goodnough et al 2010)PubMed. Iron deficiency that develops in patients with chronic renal failure following erythropoietin treatment is a typical example. Another example is the iron deficiency that develops in longstanding or particularly severe chronic inflammatory diseases, since iron is present in the body, but sequestered in macrophages (see below).

Since iron deficiency anemia develops slowly, it does not cause symptoms until the Hb level is below 7-9 g/dL. Several compensatory mechanisms maintain tissue oxygenation in chronic anemia. Increased cardiac output augments blood flow and increased erythrocyte 2,3-DPG reduces hemoglobin oxygen affinity. Pallor, asthenia and, in severe forms, cardiovascular signs such as tachycardia, exertional dyspnea and angina, may be a signal of the presence of anemia. The Plummer-Vinson syndrome, a triad of dysphagia, esophageal webs and glossitis, and koilonychia (spoon nails) described in severe iron deficient anemia, has become uncommon nowadays. Some patients complain of dry mouth and alopecia. Irritability and inability to concentrate can be signs of iron deficiency in neurons and the restless leg syndrome responds to iron supplementation in some patients. “Pica”, the compulsion to eat substances like earth, chalk and clay, may be rarely observed in pregnant women and in children, especially in tribal populations.

The first sign of iron deficiency is the reduction of iron stores that translates into decreased serum ferritin (<30-40 ng/ml). In the second phase, there is a reduction of transferrin saturation (<16%), because of impaired iron release and enhanced transferrin synthesis. At this stage, erythropoiesis becomes iron deficient and Perl’s staining of bone marrow smears reveals the reduction/absence of macrophage iron. Ultimately, anemia of variable degree develops. If iron deficiency persists, anemia becomes microcytic-hypochromic (low MCV and MCH). Transferrin saturation is low (<16%) and ferritin <10ng/ml (Beutler and Waalen, 2006)PubMed. Reduction of serum ferritin is highly specific (99%) of iron deficiency. Other parameters signaling iron deficient erythropoiesis are the increase of serum soluble transferrin receptor (sTfR) (Beguin, 2003)PubMed (Table II) and of erythrocyte protoporphyrins. It is essential to recognize the cause of iron deficiency anemia for two reasons. First, if the cause is not corrected, after iron supplementation anemia may subsequently relapse. Second, the cause of iron deficiency anemia may be clinically more relevant than anemia itself (i.e. colon cancer, IBD or other causes of occult bleeding). Since anemia is often due to chronic gastrointestinal bleeding, search for occult blood is routinely recommended in individuals with persistent anemia not due to elevated iron requirements.

 

Camaschella_DISORDERS_OF_IRON _METABOLISM _Table2

Table 2. Differential diagnosis of iron related anemias

 

An iron absorption test based on the oral administration of 65 mg elementary iron followed by dosage of serum iron may in theory recognize all the cases of iron malabsorption, although its use in clinics is uncommon.

Other types of microcytic anemia such as the beta- and alpha-thalassemia trait are easily recognized by specific Hb tests (Table II).

An early marker of iron restricted erythropoiesis is the reduction of reticulocyte hemoglobin content (CHr), and a late one the percent of hypochromic reticulocytes (% HYPO) (Piva et al, 2010)PubMed, while the dosage of soluble transferrin receptor (sTfR) and the sTfR/log ferritin ratio are less specific.

Most patients are treated with oral iron (100-200 mg elementary iron) administered under fasting conditions in separate doses. Iron salts, namely iron sulfate, based treatment is simple, effective, inexpensive and has no relevant side effects. In established iron deficiency anemia, since the liver production of hepcidin is suppressed (Ganz et al, 2008)PubMed, pharmacological iron is easily absorbed from the gut. Patients with malabsorption due to intestinal disorders or under treatment with proton pomp inhibitors may be refractory to oral iron. The Helicobacter Pylori infection can also decrease the absorption of oral iron.

A few patients cannot tolerate oral iron therapy because of intestinal side effects (nausea, vomiting, constipation) or because of reduced compliance and must be treated with parenteral iron. Indications to i.v. iron are blood losses that cannot be adequately compensated by iron absorption, active IBD, iron deficient erythropoiesis due to erythropoietin treatment in chronic renal failure or neoplastic disorders. The risk of severe allergy to i.v. iron has made these indications strict in the past. It is possible that with new well-tolerated iron formulations the use of i.v. iron may become more common. To make the correct iron dose calculation for parenteral treatment it should be considered that 1 g of Hb contains 3.3 mg elementary iron.

Blood transfusions should not be used to correct iron deficiency, unless clinical conditions of the patients are unstable or bleeding is important.

 

Anemia of chronic disorders (ACD)

Anemia of chronic disorders (ACD) or anemia of inflammation is observed in chronic infections, autoimmune and inflammatory disorders, cancer, Hodgkin’s disease and in the last stages of chronic renal failure. It is a common form of anemia prevalent in hospitalized and elderly patients.

The pathophysiology is multifactorial, including low erythropoietin production, partial erythropoiesis inhibition by inflammatory cytokines (particularly IL-1 beta and TNF-alpha), mild hemolysis and abnormalities of iron metabolism. Iron absorption is decreased and iron is sequestered in macrophages by the elevated hepcidin levels (Weiss and Goodnough, 2005)PubMed, whose production is stimulated by IL-6. For these reasons, ACD leads to iron maldistribution. Total body iron is normal; however, macrophage iron is increased, while circulating and bone marrow iron levels are low. It has been proposed that high hepcidin levels are responsible for the production of normochromic, instead of hypochromic, red cells as expected from the iron restriction. Indeed, high levels of hepcidin cause degradation of the iron exporter ferroportin and iron retention in all cells (Nemeth et al, 2004)PubMed, including erythroid precursors. In contrast, in iron deficient erythroid cells the limited iron available is actively released by the erythroid precursors by an intact ferroportin, since hepcidin levels are low.

Anemia is moderate (Hb 8-10 g/dL), normocytic-normochromic and accompanied by low serum iron and normal/high ferritin levels (Weiss and Goodnough, 2005)PubMed. Anemia is an adaptation mechanism and usually well tolerated. In severe and persistent inflammation, true iron deficiency may develop and anemia may become hypochromic-microcytic. The recognition of iron deficiency in the course of ACD is especially challenging. Several tests have been proposed as the determination of sTfR levels or of the sTfR/log ferritin ratio (Table II) (Weiss and Goodnough, 2005)PubMed. At present, none of the proposed tests is capable of recognizing all forms; it is possible that the introduction of serum hepcidin dosage in the clinics might prove useful in the future.

No specific treatment is available for ACD. Anemia reverts when the underlying disorder is over. Erythropoietin administration is useful only in chronic renal insufficiency and in some cancer patients undergoing chemotherapy. Several attempts to ameliorate anemia through the use of anti-hepcidin antibodies (Sasu et al, 2010) are ongoing in animal models of anemia of inflammation and phase I/II clinical trials are underway in patients with anti-hepcidin molecules.

 

Ectopic hepcidin production

This is an extremely rare form of microcytic anemia, identified in pediatric patients with glicogenosis due to glucose-6-phosphatase deficiency. These patients may develop hepatic adenomas (Andrews, 2008)PubMed. In case the adenomas secrete hepcidin, a moderate anemia may be observed with features of ACD that revert after the adenoma removal.

 

 

INHERITED ANEMIAS RELATED TO IRON METABOLISM

 

Inherited anemias related to defects of iron absorption, transport, utilization and recycling are rare, but represent distinct entities that differ from iron deficiency anemia because of atypical laboratory tests.

 

Iron-refractory iron deficiency anemia (IRIDA)

Iron-refractory iron deficiency anemia is a recently characterized autosomal recessive condition similar to iron deficiency anemia, but refractory to oral iron, because of the high levels of the circulating hormone hepcidin, which inhibit iron absorption. IRIDA is refractory to oral and partially refractory to parenteral iron that, in the presence of high hepcidin levels, remains sequestered in macrophages.

IRIDA is likely the most frequent microcytic anemia due to genetic abnormalities of iron metabolism. It has been recently recognized (Finberg et al, 2008)PubMed, hence only a limited number (approximately 50) of cases are reported in the literature (De Falco et al, 2013)PubMed.

IRIDA is caused by different mutations inactivating the TMPRSS6 gene on chromosome 22. TMPRSS6 encodes matriptase-2, a serine protease that inhibits hepcidin. Hepcidin excess, inducing ferroportin degradation (Nemeth et al, 2004)PubMed, blocks iron release to plasma and causes hypochromic-microcytic anemia with extremely low transferrin saturation and normal/high serum ferritin (Finberg, 2009)PubMed. Serum and urine hepcidin levels are normal or increased but in any case inappropriately high, considering the condition of iron deficiency, usually associated with a reduced hepcidin expression (Ganz et al, 2008)PubMed. Reported cases are of different ethnic origin and usually of pediatric age. Anemia and microcytosis are not present at birth, but become manifest in the first months/years of life. Children show a healthy physical and psychological development notwithstanding iron deficiency.

A correct diagnosis requires the exclusion of inflammatory conditions because IRIDA has features similar to ACD. The detection of increased levels of serum hepcidin may help the diagnosis, which requires nucleotide sequencing of the TMPRSS6 gene to identify homozygous or compound heterozygous causal mutations.

During childhood and adolescence, parenteral iron infusions are needed (Finberg, 2009)PubMed. In adulthood, with lower iron requests, the degree of anemia improves; however MCV, MCH, serum iron and transferrin saturation remain low.

 

Hypotransferrinemia

Hypotransferrinemia is a recessive condition characterized by a strong reduction of the iron carrier protein transferrin. It is often indicated as “atransferrinemia”, an incorrect definition as the true “atransferrinemia” is likely incompatible with life.

Hypotransferrinemia is an extremely rare condition and few and sporadic cases have been reported since the first description in 1961. Reduction of iron transport leads to an iron deficient bone marrow and consequently to microcytic anemia. On the other hand, the increased non-transferrin-bound-iron (NTBI) is easily taken up from the circulation by liver, pancreas and heart. For these reasons, anemia is associated with iron overload and damage of these organs. Hepcidin levels are strongly decreased in response to the iron-deficient erythropoiesis and implement a vicious circle of increased iron acquisition.

Anemia is severe and associated with a strong reduction of circulating transferrin (<20 mg/dL) and with an increase of fully saturated (>100 %) transferrin. Survival is possible only with replacement therapy, i.e. regular plasma (or transferrin) infusions. This ameliorates Hb levels and increases hepcidin secretion, thus reducing iron overload (Trombini et al, 2007)PubMed.

 

Anemia due to DMT1 mutations

Deficiency of divalent metal transporter 1 (DMT1) is an autosomal recessive condition caused by inactivating mutations of the metal transporter, which is essential in the endosomal cycle of transferrin receptor (Andrews, 2008PubMed; De Domenico et al, 2008PubMed). The disease is extremely rare with less than 10 families reported. DMT1 deficiency affects prevalently the erythroid compartment, whereas at the duodenal level the defect is likely to be compensated by an increased heme absorption. The affected subjects have a low weight at birth and microcytic-hypochromic anemia of variable severity, in some cases requiring blood transfusions in the first days/months of life (Iolascon and De Falco, 2009)PubMed.

At variance with iron deficiency anemia, iron levels and transferrin saturation are increased, but sTfR is high (Table II) as in iron deficiency anemia, since erythropoiesis is iron restricted. Iron overload of the liver develops with time in almost all reported patients. Hepcidin levels are inappropriate to the levels of iron stores. Sequencing of DMT1 is needed to demonstrate the causal mutations.

There is no causal therapy. Recombinant erythropoietin is used to increase Hb levels and may allow transfusion-independence. However, the erythrocyte indices remain unchanged, suggesting that erythropoietin does not ameliorate iron utilization but decreases apoptosis of erythroblasts, increasing total erythropoiesis.

 

Camaschella_DISORDERS_OF_IRON _METABOLISM _Table3

Table 3. Parameters employed to assess iron overload

 

Congenital sideroblastic anemia

Sideroblastic anemia is characterized by iron accumulation in mitochondria that gives origin to ringed sideroblasts at Perl’s staining of bone marrow smears. Hereditary sideroblastic anemia is rare and due to a deficient utilization of mitochondrial iron for heme or iron sulfur cluster biogenesis. Acquired forms are clonal disorders classified under refractory anemias with ringed sideroblasts (RARS) in the chapter of myelodysplasia (MDS).

Hereditary sideroblastic anemia is genetically heterogeneous (Camaschella, 2009)PubMed. The commonest form is X linked, due to a deficiency of the erythroid-specific enzyme delta-amino-levulinic-acid-synthase-2 (ALAS2). It prevalently affects males; females may show features of the disease in case of a marked inactivation of the X chromosome carrying the normal allele. A similar but recessive form recently characterized, is due to mutations of SLC25A38, an erythroid-specific mitochondrial transporter, hypothesized to import glycine, an amino acid essential for mitochondrial ALA synthesis. A recessive form reported in a single patient is due to mutations of GLRX5 that encodes a mitochondrial protein involved in iron sulfur cluster biogenesis (Camaschella, 2009)PubMed. X-linked sideroblastic anemia associated with spinocerebellar ataxia results from mutations of the “ATP binding cassette B7” (ABCB7), a protein involved in the metabolism of mitochondrial iron sulfur clusters.

Anemia is microcytic-hypochromic, serum iron and ferritin are elevated (Table II). Perl’s staining of bone marrow smears allows the diagnosis: ring sideroblasts are >30% of total erythroblasts. When sideroblastic anemia is identified in adult patients, a myelodysplastic RARS disorder should be considered in the differential diagnosis. A better definition of molecular basis of RARS, generally associated to SF3B1 gene mutations, coding for an essential splicing component (Papaemmanuil, 2011)PubMed, will likely help in the diagnosis of these forms.

Some types of sideroblastic anemia due to ALAS2 deficiency may improve when treated with pyridoxine (vitamin B6). Recessive forms due to SLC25A38 mutations are more severe, do not respond to pyridoxine and require blood transfusions. Iron overload, both transfusion-dependent and also transfusion-independent, requires iron chelation therapy or, if anemia is really mild, phlebotomy treatment. In rare cases, Hb levels improve after iron depletion.

 

Aceruloplasminemia

Aceruloplasminemia is a rare recessive disorder due to mutations of ceruloplasmin (Cp), a copper-dependent oxidase, with an essential role in iron mobilization from macrophages, hepatocytes and central nervous system cells. In this condition, anemia is a minor component. Affected patients present mild anemia, develop iron overload, diabetes and show retinal degeneration and progressive neurological (ataxia) and psychiatric symptoms up to dementia (Ponka et al, 2004)PubMed.

Anemia is normochromic-normocytic with decreased transferrin saturation and high serum ferritin (Table II). Anemia may precede the onset of other symptoms, thus its recognition may help the early diagnosis of the disease. Serum ceruloplasmin is usually undetectable. Iron accumulates in the liver, pancreas and basal nuclei where it may be quantified by magnetic resonance imaging (MRI).

There is no causal treatment. Iron oral chelators able to cross the blood brain barrier may be used as an experimental treatment.

 

IRON OVERLOAD

In iron overload, total body iron is above the levels considered normal according to age and sex. Mild iron overload does not cause any clinical symptoms. Clinical iron disorders appear when iron stores are >5 g (normal iron stores 300-1800 mg). Since liver is the main iron store site, LIC (liver iron concentration) is a good surrogate for total body iron (Angelucci et al, 2008)PubMed. Studies in iron loaded thalassemia patients have defined the LIC values considered safe and the levels that may be associated with organ damage. A LIC value <1.2 mg Fe/g tissue dry weight is assumed as normal. Allowing for individual variability, values between 3-7 mg/g tissue corresponds to a mild overload, LIC values >7 and <15 mg/g correspond to a moderate overload and values >15 mg to a severe iron overload. Liver iron overload is usually well reflected by the circulating ferritin levels, but this correlation does not hold true for cardiac iron overload. In addition, high ferritin levels are characteristic also of inflammation; thus, ferritin should always be measured together with C reactive protein. The clinical parameters used to define iron overload are reported in Table III. It is accepted that a ferritin trend variation over time is more useful than a single ferritin determination to assess iron overload.

 

GENETIC IRON OVERLOAD: HEMOCHROMATOSIS

Hereditary hemochromatosis is a disease known since the nineteenth century, characterized by parenchymal iron accumulation, especially in the liver. Iron favors oxygen radical formation, with a consequent cell damage, necrosis and fibrosis.

Hemochromatosis is listed among rare disorders, whereas the susceptible genotype and the “biochemical penetrance”, i.e. the iron alterations (increased transferrin saturation and increased serum ferritin), are rather frequent. Hemochromatosis is genetically heterogeneous and may be caused by mutations in several genes. The classic and most frequent type (type 1) is due to mutations of HFE, juvenile hemochromatosis (type 2) is in most cases related to hemojuvelin and, in rare cases, to hepcidin mutations, the rare type 3 is due to mutations of the transferrin receptor 2 (TFR2) and type 4 to mutations of ferroportin (Table I) (Pietrangelo, 2010)PubMed. Types 1-3 are inherited as autosomal recessive traits, while type 4 is autosomal dominant. The molecular pathogenesis of types 1-3 is related to a variable deficiency of hepcidin, since the proteins inactivated in the different forms are involved in the hepcidin upregulation induced by iron through BMPs. Hemojuvelin is the BMP coreceptor, essential in the signaling through the SMAD proteins (Babitt et al, 2006)PubMed; HFE and TFR2 are likely modulators of the main pathway of hepcidin activation (Hentze et al, 2010)PubMed (Figure 1).

 

Camaschella_DISORDERS_OF_IRON _METABOLISM _Figure

Figure 1.  Control of iron homeostasis by hepcidin and his iron-dependant regulation. The synthesis of hepcidin in the liver is regulated by the iron through BMP6, that on the hepatocyte surface forms a complex with type 1 and type 2 BMP receptors (BMPR) and the co-receptor hemojuvelin (HJV) to activate SMAD. Phosphorylated (P) SMAD 1/5/8 translocates to the nucleus to activate the target HAMP gene promoter. Active hepcidin hormone is secreted and acts on the iron exporter ferroportin (FPN) on the basolateral membrane of duodenal enterocytes and macrophages. The interaction of hepcidin with FPN blocks the intestinal iron absorption and iron export from macrophages. Iron itself regulates BMP6, although the mechanism has not yet been characterized. Following increase of iron-loaded transferrin, HFE, normally linked to TFR1, bind to TFR2, promoting the activation of hepcidin, through a mechanism not yet well defined (?).

 

In hemochromatosis type 1, C282Y homozygosity occurs in 60-90% of the cases; the C282Y/H63D genotype is uncommon and more benign. Biochemical alterations of iron parameters are present in 70% of adult males and in less than 30% of adult females. In juvenile hemochromatosis (type 2), iron overload is severe and symptoms of cardiac involvement and hypogonadism occur in the second-third decade of life in both genders. If left untreated, the disease may be fatal because of heart failure or major arrhythmias. In the rare patients with type 3 hemochromatosis, the onset may be as early as in juvenile hemochromatosis, but the disease is less severe and less progressive (Camaschella and Poggiali, 2009a)PubMed.

Hemocromatosis type 4 or “ferroportin disease” is clinically heterogeneous. In the most frequent subtype (type 4A), iron accumulates in macrophages since the mutated ferroportin releases less iron. Erythropoiesis may be iron-restricted because of normal/low transferrin saturation and may lead to low tolerance to phlebotomy. Serum ferritin is high reflecting stored iron. Other ferroportin mutations (type 4B) reduce hepcidin linking, causing “hepcidin resistance” with a phenotype indistinguishable from hemochromatosis; indeed, iron release to plasma is increased in these cases, transferrin saturation is as high as in hemochromatosis and iron accumulates in the liver and in other organs (De Domenico et al, 2007)PubMed.

Early symptoms of hemochromatosis are asthenia, apathy, abdominal pain, liver enlargement and alteration of liver function tests. In men, reduced libido and erectile dysfunction may be present. Later on, patients may develop liver cirrhosis, diabetes, hypogonadism and, more rarely, other endocrine complications, cardiomyopathy, arthropathy and skin pigmentation. Hepatocellular carcinoma is the main cause of death in cirrhotic patients. Heart failure refractory to treatment and arrhythmias are observed especially in the juvenile forms. In the skin, iron deposition favors an increased melanin synthesis. Arthropathy affects the metacarpo-phalangeal joints of the second and third finger, but also hip and knee with synovial deposition of calcium pyrophosphate, or chondrocalcinosis.

Transferrin saturation is increased (>45%) in all recessive types and may reach 100% in the most severe cases. Serum ferritin levels increase according to iron stores. Liver biopsy may document the degree of fibrosis and allows the assessment of LIC. Nowadays, liver biopsy is performed only for prognostic evaluation in C282Y homozygous patients with ferritin levels >1000 ng/ml. In these cases, the stage of the disease should be assessed to exclude clinical complications, especially cardiac disease, and reduced glucose tolerance/diabetes (Pietrangelo, 2010PubMedAdams and Barton, 2010 PubMed). MRI allows a non-invasive LIC assessment (St Pierre et al, 2005)PubMed. MRI T2* techniques have been developed to quantify iron in the heart and recently also in the pancreas and in the pituitary gland (Wood and Noetzli, 2010)PubMed. Genetic tests are essential for diagnosis and family screening. Referral to specialized centers may be necessary for the diagnosis of mutations unrelated to the HFE gene.

Treatment relies on weekly phlebotomy (of about 350-400 ml) (Adams and Barton, 2010)PubMed. Iron chelation with deferioxamine (20-40 mg/kg subcutaneously with the use of a pump 8-10 hours) may be used in patients with anemia, cardiac disease or cirrhosis who cannot tolerate phlebotomy. Oral iron chelators as deferiprone and deferasirox are not used to treat hemochromatosis. A phase I/II trial of deferasirox treatment in non-cirrhotic hemochromatosis patients has demonstrated a dose-dependent efficacy but also side effects, prevalently gastrointestinal complaints as nausea and diarrhea. More extensive studies are needed to explore the potential utility of the drug. Cardiac or liver transplantation must be considered in young subjects diagnosed late in the course of a severe disease. However, organ transplantation should be planned only after iron depletion, to avoid iron-induced post-transplant complications.

 

Acquired iron overload

The commonest type of secondary hemochromatosis results from chronic blood transfusions for congenital anemia (as beta-thalassemia) or for acquired conditions as low risk MDS. Since every ml of packed red cells contains about 1 mg of iron, 20 blood units may double total body iron. Excess iron accumulates firstly in the macrophages, which release more iron to plasma, increasing transferrin saturation and iron uptake by parenchymal organs. There is a concurrent effect of NTBI that, easily taken up by liver, heart and pancreas, is toxic to cells through the generation of reactive oxygen species. The rate of iron loading favors cardiac deposition and the onset of severe complications as in transfusion-dependent homozygous thalassemia patients.

Secondary iron overload irrespective of transfusions occurs in the “iron loading anemias”, characterized by high degrees of ineffective erythropoiesis. In these cases, the erythroid marrow suppresses hepcidin production. It has been suggested that this occurs through the release of cytokines, produced by the erythroblasts as growth differentiation factor 15 (GDF15) (Tanno et al, 2007)PubMed. Clinical complications are the same as in hemochromatosis and include cardiomyopathy, cirrhosis, hypogonadism, diabetes, endocrine disorders and skin pigmentation. The fast rate of iron accumulation in transfused patients causes a preferential iron deposition in the heart that is especially dangerous. Indeed, cardiac complications (heart failure and major arrhythmias) are the main cause of death in thalassemia patients.

In chronically transfused patients, it is useful to calculate the amount of iron introduced with transfused blood and, when possible, the amount excreted by chelation treatment (iron balance), as well as serial evaluation of serum ferritin ((Angelucci et al, 2008)PubMed. However, the correct diagnosis of iron overload requires the demonstration of increased tissue iron levels, which is possible by LIC determination through a liver biopsy, or non invasively by MRI. The latter is also useful for the follow-up of patients. Methods to quantify cardiac iron are available and important, since serum ferritin correlates poorly with iron accumulation in the myocardium. T2*, available in referral centers, has become the golden standard. Based on T2* values, cardiac iron overload may be classified as mild for T2* of 14-20 milliseconds, moderate for 8-14 and severe if T2* is <8 ms (normal T2* levels >20 ms) (Hoffbrand et al, 2012)PubMed.

Treatment of iron overload implies administration of iron chelators, which should be started after the infusion of approximately 20 packed red cell units or when serum ferritin is >1000 ng/ml. In the past, deferoxamine was the only available chelator, usually administered subcutaneously through a pump for 10-12 hours daily. Twenty-four hours high dose deferoxamine i.v. infusions have been successfully used for short periods in patients with iron -induced heart failure, especially in combination with deferiprone. Deferiprone may rarely cause severe side effects (agranulocitosis) on an idiosyncrasic basis, and requires monitoring of the blood cell count. Since a few years, deferasirox, an efficacious oral iron chelator more convenient for chronic use in transfusion-dependent thalassemia, is also on the market (Hoffbrand et al, 2012)PubMed.

A moderate iron overload may be secondary to the interaction between genetic susceptibility and environmental factors, as observed in middle age males with metabolic syndrome. Here, a mild inflammatory condition coexists with metabolic abnormalities, in some cases associated with heterozygous mutations of HFE. Serum ferritin is increased, but the transferrin saturation is usually normal and hepatic iron accumulation is habitually mild. A moderate iron overload characterizes chronic liver diseases due to hepatitis C viral infection. At variance with hemochromatosis, in the latter conditions iron overload is restricted to the liver and never affects other organs.

 

ISOLATED HYPERFERRITINEMIA

Familial cases of isolated hyperferritinemia have been reported: probands are symptomless, have normal transferrin saturation and normal iron stores. The condition is benign. These individuals must be recognized and reassured also to avoid expensive and time-consuming exams and useless follow-up.

 

Hyperferritinemia-cataract syndrome (HHCS)

The hyperferritinemia-cataract syndrome is a rare autosomal dominant disorder caused by heterozygous mutations of the IRE element in the 5’ untranslated region (UTR) of L-ferritin mRNA (Camaschella and Poggiali, 2009b)PubMed. The reported mutations (>30) reduce IRE-IRP binding in the presence of iron deficiency and ferritin translation thus becomes constitutive and iron-independent. Patients have high levels of ferritin with normal serum iron and transferrin saturation, and normal iron stores. Excess ferritin accumulates in the lens, causing congenital or early onset bilateral cataract. Patients are otherwise symptomless. Surgery is the only therapeutic approach.

Rare familial cases of isolated hyperferritinemia have been reported, negative for IRE mutations of L-ferritin mRNA, and who did not have cataract. In some cases, a threonineàisoleucine mutation has been detected at position 30 (p.Thr30Ile) in the coding sequence of L-ferritin. The individuals analyzed had highly glycosylated circulating ferritin, suggesting that the mutant ferritin is secreted into the plasma. In other cases, no mutations have been detected.

 

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