Classification and diagnosis of iron overload.

Iron overload can be classified on the basis of different criteria: route of access of iron within the organism, predominant tissue site of iron accumulation and cause of the overload. Excess iron can gain access by the enteral route, the parenteral route, and placental route during fetal life. The different distribution of iron within parenchymal or reticuloendothelial storage areas indicates different pathogenetic mechanisms of iron accumulation and has relevant implications in terms of organ damage and prognosis of the patients. Iron overload may be either primary, resulting from a deregulation of intestinal iron absorption as in hemochromatosis or secondary to other congenital or acquired conditions. Diagnosis of iron overload can be suspected on the basis of clinical data, high transferrin saturation and/or serum ferritin values. However, several hyperferritinemic conditions are not related to iron overload, but may imply severe disorders (inflammations, neoplasia) or a deregulation of ferritin synthesis (hereditary hyperferritinemia-cataract syndrome), and iron overload secondary to aceruloplasminemia, and the recently described dysmetabolic-associated liver iron overload syndrome, are characterized by low or normal transferrin saturation levels. Liver biopsy is still very useful in the diagnostic approach to iron overload disorders, by defining the amount and the distribution of iron within the liver. The analysis of HFE gene mutations (C282Y and H63D) is a simple and strong tool in the diagnostic work out of iron overload conditions.