Serum ferritin and erythrocyte indices in iron overload.

Abstract

Raised levels of serum transferrin saturation (TS) and ferritin (SF) are frequently associated with increased values of haemoglobin and erythrocyte indices. In hereditary haemochromatosis this phenomenon has been considered to be a beneficial effect of the C282Y mutation, protecting women from iron deficiency. The elevated values of mean corpuscular volume (MCV) in hereditary haemochromatosis may reflect increased iron uptake and haemoglobin synthesis by immature erythroid cells1–3. In a large screening study of a European population, a higher haemoglobin concentration was found in C282Y homozygous women with either normal or increased TS or SF4. However, when the effect of the C282Y mutation was analysed separately in subjects from different parts of Europe, the mean haemoglobin concentration and MCV were higher in C282Y carriers from northern Europe than in those from southern Europe. This could be due to the higher prevalence of thalassaemia trait in southern Europe5. The variability in TS and SF may depend not only on mutations in HFE or other genes involved in haemochromatosis, but also on other genetic and environmental factors. A recent large screening study (the HEIRS study) conducted in the USA and in Canada found higher mean TS and SF levels among Asians and Pacific Islanders, who do not have an HFE mutation or H63D allele, than in white subjects. There is no consistent evidence supporting the hypothesis that the increased SF in Asians is attributable to liver disease or diabetes. A reduced MCV in Asian men with increased SF could be explained by a high prevalence of thalassaemia trait in this population, although further studies are required to clarify this issue6. In anaemia of chronic diseases (ACD), normal or increased SF and reduced TS levels are usually associated with low haemoglobin levels and normocytic or microcytic erythrocytes. An increased uptake of iron and retention in active macrophages, which is the pathophysiological mechanism of ACD, is linked to increased pro-inflammatory and anti-inflammatory cytokines and is responsible for reduced availability of iron for erythroid progenitors. Recently, it was speculated that a small peptide hormone, hepcidin, might be involved in the pathogenesis of ACD. Hepcidin has antimicrobial activity and its expression increases in response to inflammatory stimuli. In mice, hepcidin mRNA expression is increased in response to lipopolysaccharides and infection. It has been suggested that hepcidin may be one cytokine-regulated gene that impairs erythrocyte iron acquisition by modifying the release of iron from macrophages7. In alcoholic steatosis, the serum TS and SF levels are unrelated to iron deposits. In alcoholic cirrhosis, low haemoglobin concentrations and increased MCV are often detected in association with increased levels of ferritin. These haematological findings are dependent on several factors, including direct and indirect effects of alcohol on the bone marrow, an impaired nutritional state, and the different stages of the liver disease. Hyperferritinaemia is also frequently observed in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome. The increased SF values are associated with insulin resistance and mild hepatic iron accumulation. So far, no significant modifications of haematological indices have been reported in NAFLD8.