Haematologica 1998; 83:447-455 decision making and problem solving Classification and diagnosis of iron overload ALBERTO PIPERNO Istituto di Scienze Biomediche, Azienda Ospedaliera S. Gerardo, Divisione di Medicina 1, Monza, Italy Abstract Background and Objective. Iron overload is the result ron overload is the result of many disorders and of many disorders and could lead to the development could lead to the development of organ damage of organ damage and increased mortality. The recent Iand increased mortality. The recent description description of new conditions associated with iron of new conditions associated with iron overload and overload and the identification of the genetic defect the identification of the genetic defect of hereditary of hereditary hemochromatosis prompted us to review hemochromatosis prompted us to review this subject this subject and to redefine the diagnostic criteria of and to redefine the diagnostic criteria of iron over- iron overload disorders. load disorders. Evidence and Information sources. The material exam- ined in the present review includes articles published Classification of iron overload in the journals covered by the Science Citation Index® Iron overload is the result of many disorders and ® and Medline . The author has been working in the field could lead per se to the development of organ dam- of iron overload diseases for several years and has contributed ten of the papers cited in the references. age and increased mortality. In humans total body iron stores is maintained normally within the range State of the art and Perpectives. Iron overload can be of 200-1500 mg (in men, the normal concentration classified on the basis of different criteria: route of of iron in the storage pool is 13 mg/Kg and in access of iron within the organism, predominant tis- sue site of iron accumulation and cause of the over- women 5 mg/kg) by adequate adjustment of intesti- load. Excess iron can gain access by the enteral nal iron absorption, since no excretory mechanisms route, the parenteral route, and placental route dur- exist.1-4 In normal individuals, feedback mechanisms ing fetal life. The different distribution of iron within inhibit iron absorption as storage iron increases.1 parenchymal or reticuloendothelial storage areas indi- Each condition that induces an increased net entry cates different pathogenetic mechanisms of iron of iron within the body inevitably leads to iron over- accumulation and has relevant implications in terms load.2 Iron overload could be defined as an increase of organ damage and prognosis of the patients. Iron of storage iron, regardless of the presence or absence overload may be either primary, resulting from a deregulation of intestinal iron absorption as in hemo- of tissue damage. It can be classified on the basis of chromatosis or secondary to other congenital or different criteria: route of access of iron within the acquired conditions. Diagnosis of iron overload can organism, predominant tissue site of iron accumu- be suspected on the basis of clinical data, high trans- lation and cause of the overload. ferrin saturation and/or serum ferritin values. How- ever, several hyperferritinemic conditions are not Route of access of iron related to iron overload, but may imply severe disor- Excess iron can gain access to the organism in ders (inflammations, neoplasia) or a deregulation of three ways: the enteral route, through absorption of ferritin synthesis (hereditary hyperferritinemia- cataract syndrome), and iron overload secondary to dietary heme and non-heme iron, the parenteral aceruloplasminemia, and the recently described dys- route, through transfusions or injections of iron-con- metabolic-associated liver iron overload syndrome, taining compounds, and placental route during fetal are characterized by low or normal transferrin satura- life (Table 1). tion levels. Liver biopsy is still very useful in the diag- nostic approach to iron overload disorders, by defin- Enteral route ing the amount and the distribution of iron within the Hereditary hemochromatosis (HHC) leads to liver. The analysis of HFE gene mutations (C282Y and absorption of excess dietary iron. Besides the recent H63D) is a simple and strong tool in the diagnostic discovery of the genetic defect in HHC, the patho- work out of iron overload conditions. ©1998, Ferrata Storti Foundation genic mechanism leading to inappropriately high iron absorption in this disorder is still undefined.4,5 The Key words: iron overload excess of daily iron uptake is not large, but over time, due to the absence of iron excretory pathways in 4 Correspondence: Dr. Alberto Piperno, Istituto di Scienze Biomediche humans, substantial body overload develops. In S. Gerardo, Divisione di Medicina 1, via Donizetti 106, 20052 Monza, juvenile hemochromatosis, iron absorption is also Italy. Phone: international +39-39-2333361 • Fax: international +39-39- increased, but the genetic as well as the biochemical 322274 • E-mail: [email protected] defect of this kind of hemochromatosis is still 448 A. Piperno unknown.6 Ineffective erythropoiesis is associated with this point excess iron is delivered to the hepatocytes increased uptake of dietary iron, presumably in and other parenchymas leading to the development response to the increased demand from an expanded of organ damage.1,2 pool of erythrocyte precursors.1-3,7 However, in most of Iron overload from parenteral administration of such disorders transfusion therapy is needed; in that iron compounds is rare and is the result of inaccurate case the contribution of increased enteral absorption determination of body iron stores.26 to iron overload is relatively small. Iron absorption is increased in the hemolytic state, although a signifi- Placental route cant iron overload (in the absence of over-transfu- Throughout pregnancy, iron is taken up from sions) is commonly evident only when heterozygosity maternal plasma by trophoblasts and transferred for HHC or ineffective erythropoiesis coexists.7-11 A into the fetoplacental circulation.27 This process is puzzling finding is the apparent relationship between thought to accelerate during the last trimester. In the splenectomy and increased absorption and accumu- fetus, the hepatocyte is the main site of storage iron. lation of iron in hemolytic patients.11-13 Increased Thus, based on the tests used in adults, the term dietary iron from traditional beer brewed in steel infant is markedly iron overloaded and iron stores drums has been regarded as the sole cause of iron may even increase within the first post-natal weeks.27 overload in African populations, but recent data sug- It is then difficult to dissect whether systemic or liver gest that a genetically determined defect in the regu- diseases that develop during fetal or neonatal life are lation of iron absorption exists in these patients and merely superimposed on an otherwise physiological that this defect is necessary for the development of iron overload status or they are the result of excess iron overload.14-16 According to the model presented transplacental delivery of iron. Perinatal or neonatal in that study, heterozygotes for the iron-loading locus hemochromatosis is a syndrome of severe idiopath- develop iron overload only in the face of high dietary ic liver disease of fetal onset associated with marked iron, but homozygotes may become iron-loaded with- hepatic and extra hepatic siderosis that is not a vari- out increased dietary iron.16 ant of HHC.28 It has been argued that this disease is Similarly, increased iron absorption has been due to abnormal iron handling in the throphoblast regarded as a cause of liver iron overload in chronic and fetal liver, but no specific defect has yet been hepatic disorders17-20 (see below). However, it is pos- identified.27,28 sible that the coexistence with heterozygous HHC may further increase iron absorption in these patients.17,20 Sites of iron accumulation Iron absorption is increased in the hypotransfer- Parenchymal vs. RE iron overload rinemic mouse,21 probably as the result of the iron The different distribution of iron within parenchy- deficient erythropoiesis. Although not proved, this mal or RE storage areas indicates different patho- probably occurs also in congenital hypotransferrine- genetic mechanisms of iron accumulation and has mia in humans. In systemic hemosiderosis associated relevant implications for organ damage and progno- with aceruloplasminemia,22,23 the cause of iron over- sis of the patients (Table 1). In fact, organ damage is load does not primarily depend on defective regula- related to the amount of iron present in the parenchy- tion of iron absorption, but it is likely that the mech- mal cells, whereas iron within RE cells appears to be anisms that normally inhibit iron absorption as iron relatively innocuous.1,7 Liver parenchymal iron over- storage increases do not operate in this rare disease, load is usually the result of excessive iron absorption due to the low serum iron levels secondary to the by the enteral route, such as in HHC and anemias impaired iron release from cells to plasma. However, with ineffective erythropoiesis (iron loading anemias), functional studies on iron metabolism in this human but may also reflect enhanced internal redistribution hereditary disorder have not yet been reported. of transfused erythrocyte iron recycled from the RE Cases of iron overload induced by prolonged oral cells, as observed in the more advanced stage of administration of iron-containing compounds are transfusional iron