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Disorders of Iron Metabolism. Part II: Iron Deficiency and Iron Overload

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Disorders of Iron Metabolism. Part II: Iron Deficiency and Iron Overload Best practice J Clin Pathol: first published as 10.1136/jcp.2010.086991 on 20 December 2010. Downloaded from Disorders of iron metabolism. Part II: iron deficiency and iron overload Manuel Mun˜oz,1 Jose´ Antonio Garcı´a-Erce,2 A´ngel Francisco Remacha3 1Transfusion Medicine, School ABSTRACT system (RES) macrophages, haem is metabolised by of Medicine, University of Main disorders of iron metabolism Increased iron heme-oxygenase, and iron is stored as ferritin. Malaga, Malaga, Spain requirements, limited external supply, and increased Iron is later released from macrophages and bound 2Hematology and Hemotherapy, University Hospital Miguel blood loss may lead to iron deficiency (ID) and iron by transferrin, which transports iron to the bone Servet, Zaragoza, Spain deficiency anaemia. In chronic inflammation, the excess marrow. This internal turnover of iron is essential 3Hematology and Hemotherapy, of hepcidin decreases iron absorption and prevents iron to meet the requirements for erythropoiesis Complejo Hospitalario de recycling, resulting in hypoferraemia and iron restricted (20e30 mg/day).1 After reviewing the main path- Toledo, Toledo, Spain erythropoiesis, despite normal iron stores (functional iron ways of iron metabolism (namely, iron absorption, Correspondence to deficiency), and finally anaemia of chronic disease (ACD), distribution, usage, storage and recycling) and Professor Manuel Mun˜oz, which can evolve to ACD plus true ID (ACD+ID). In their regulation,1 in this paper we will review iron Medicina Transfusional, contrast, low hepcidin expression may lead to hereditary deficiency (ID) and iron overload statuses. Facultad de Medicina, Campus haemochromatosis (HH type I, mutations of the HFE de Teatinos, s/n, 29071-Ma´laga, Spain; [email protected] gene) and type II (mutations of the hemojuvelin and IRON DEFICIENCY hepcidin genes). Mutations of transferrin receptor 2 lead Under physiological conditions, there is a balance All authors have equally to HH type III, whereas those of the ferroportin gene lead between iron absorption, iron transport and iron contributed to this paper. to HH type IV. All these syndromes are characterised by storage in the human body. However, ID and iron iron overload. As transferrin becomes saturated in iron Accepted 15 November 2010 deficiency anaemia (IDA) may result from the overload states, non-transferrin bound iron appears. Part Published Online First interplay of three distinct risk factors: increased of this iron is highly reactive (labile plasma iron), inducing 20 December 2010 iron requirements, limited external supply and free radical formation. Free radicals are responsible for 2 increased blood loss (box 1). ID can be either the parenchymal cell injury associated with iron overload absolute or functional. In absolute ID, iron stores syndromes. are depleted; in functional iron deficiency (FID), Role of laboratory testing in diagnosis In iron iron stores, although replete, cannot be mobilised as deficiency status, laboratory tests may provide evidence fast as necessary from the macrophages of the RES of iron depletion in the body or reflect iron deficient red to the bone marrow. cell production. Increased transferrin saturation and/or ferritin levels are the main cues for further investigation Laboratory assessment of ID of iron overload. The appropriate combination of different Laboratory tests for investigating ID fall into two http://jcp.bmj.com/ laboratory tests with an integrated algorithm will help to categories: measurements providing evidence of establish a correct diagnosis of iron overload, iron iron depletion in the body, and measurements deficiency and anaemia. 3 reflecting iron-deficient red cell production (table 1). Review of treatment options Indications, advantages The appropriate combination of these laboratory and side effects of the different options for treating iron tests will help to establish a correct diagnosis of overload (phlebotomy and iron chelators) and iron 4 anaemia and ID status (figure 1). deficiency (oral or intravenous iron formulations) will be on September 23, 2021 by guest. Protected copyright. discussed. ID without anaemia A normal haemoglobin (Hb) level does not exclude ID, because an individual with normal body iron INTRODUCTION stores must lose a large portion of body iron before Iron is an essential micronutrient, as it is required the Hb falls below the laboratory definition of for an adequate erythropoietic function, oxidative anaemia (generally, Hb <12 g/dl for women and Hb metabolism and cellular immune response. Absorp- <13 g/dl for men), although higher levels have been tion of dietary iron (1e2 mg/day) is tightly regu- recently proposed, according to gender, age and lated, and just balanced with losses, because there is racial origin.5 In non-anaemic patients, the most no active iron excretion. Dietary iron is found in important clinical clue of ID is the symptom of haem (10%) and non-haem (ionic, 90%) forms and chronic fatigue (iron is required for the enzymes their absorption occurs at the apical surface of involved in oxidative metabolism). However, it is of duodenal enterocytes via different mechanisms. Iron little screening value because clinicians rarely is exported across the basolateral membrane of the consider the presence of ID in patients who are not enterocyte into the circulation (absorbed iron), anaemic, and therefore ID is invariably diagnosed in where it binds to transferrin and is transported to the laboratory.3 A normal Hb level with a mean sites of use and storage. Transferrin-bound iron corpuscular Hb (MCH) in the lower limit of enters target cellsdmainly erythroid cells, but also normality (normal range 28e35 pg) or an increased immune and hepatic cellsdthrough a process of red cell distribution width (RDW, normal range receptor-mediated endocytosis. Senescent erythro- 11e15) indicate mild ID without anaemia. cytes undergo phagocytosis by reticuloendothelial However, although RDW may be the earliest J Clin Pathol 2011;64:287e296. doi:10.1136/jcp.2010.086991 287 Best practice J Clin Pathol: first published as 10.1136/jcp.2010.086991 on 20 December 2010. Downloaded from inflammation, true ID could be defined by a ferritin concentra- Box 1 Main causes of iron deficiency tion <100 ng/ml and a TSAT <20%, whereas FID is defined by a ferritin concentration >100 ng/ml and a TSAT <20%. FID Increased demands may also occur in response to the therapeutic use of erythro- fi < Growth during infancy and childhood poiesis-stimulating agents, which place a signi cant demand on < Treatment with erythropoiesis-stimulating agents iron stores that may surpass the iron-release capacity of the 6 Limited external supply RES. < Poor intake < Inappropriate diet with deficit in bioavailable iron and/or Iron deficiency anaemia ascorbic acid Patients should be considered to suffer from IDA when they < Malabsorption present with low Hb (men <13 g/dl, and women <12 g/dl), – Gastric resection TSAT (<20%) and ferritin concentrations (<30 ng/ml) but no – Helicobacter pylori infection (even without significant signs of inflammation.3 The MCH rather than mean corpuscular bleeding) volume (MCV) has become the most important red cell marker – Malabsorption syndromes (Crohn disease and coeliac for detecting ID in circulating red blood cells (figure 1). MCV is disease) a reliable and widely available measurement, but it is a relatively < Drug interference (gastric anti-acid agents and antisecretory late indicator in patients who are not actively bleeding. In the drugs) presence of low MCV, differential diagnosis must be made with Increased losses thalassaemia (normal RDW). In addition, patients may present < Phlebotomy with IDA and without microcytosis when there is coexisting fi – Blood donation vitamin B12 or folate de ciency, post-bleeding reticulocytosis, – Dialysis (particularly haemodialysis) initial response to oral iron treatment, alcohol intake or mild < Haemorrhage myelodysplasia. – Surgery A truncated, soluble form of the transferrin receptor (sTfR) – Trauma can be detected in human serum, and its concentration is – Gastrointestinal bleeding proportional to the total amount of cell surface transferrin – Genitourinary bleeding receptors. Normal median concentrations are 1.2e3.0 mg/l, – Respiratory tract bleeding although the level is not standardised and depends on which reagent kit is used. Increased sTfR concentrations indicate ID even during the anaemia of chronic disease. However, increased indicator of ID, the main laboratory finding is a low ferritin level sTfR levels can also be found in increased erythropoietic activity (1 ng/ml of serum ferritin corresponds to approximately 8 mg of without ID, during reticulocytic crisis, and in congenital dyser- stored iron). Thus, measurement of ferritin provides the most ythropoietic anaemias. In contrast, lower sTfR concentrations fl 7 8 useful indirect estimate of body iron stores. In the absence of may re ect decreased number of erythroid progenitors. inflammation (eg, serum concentrations of C reactive protein Nevertheless, although sTfR levels are usually high or very high (CRP) <0.5 mg/dl), true ID can be defined by a ferritin level in uncomplicated IDA, they are not usually required for the http://jcp.bmj.com/ <15e30 ng/ml. In the presence of inflammation, a normal diagnosis. ferritin level does not exclude ID, and transferrin saturation (TSAT) should also be measured. As transferrin is the only iron- Anaemia of chronic disease binding protein involved in iron transport, TSAT reflects iron Patients should be considered
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