Swiss Functional Iron Deficiency Study

In dialysis patients the degree of anemia is highly correlated to both morbidity and mortality. A drop in Hb by 10 g/L translates into an increase in the rate of hospitalizations of 5 to 6 % and a rise in mortality by 4 to 5 %. The past two decades have seen great progress in the treatment of renal anemia with the advent of erythropoietin, and, more recently, darbepoetin. Quite soon, however, it became clear, that anemia in patients with chronic renal failure is complicated by a lack of bioavailable iron, which confers these patients partly resistant to treatment with erythropoietin/darbepoetin.

There are several parameters in use to estimate total body iron stores in the diagnosis of iron deficiency and iron deficiency anemia. Serum iron represents only a minor fraction of total body iron and is subject to major fluctuations due to influx or efflux from tissue iron stores. In addition, it shows a great diurnal variability, and is therefore a very poor parameter of iron deficiency. Iron saturation of its transporter protein in blood, transferrin, is similarly difficult to interpret, as it depends also in part on the determination of serum iron levels. Ferritin, the tissue iron storage protein, is released into the circulation during active liver cell damage, and, quite unlike serum transferrin levels, ferritin levels rise during the acute phase response of the inflammatory reaction. In most cases, however, the serum ferritin level, if substantiated by the concurrent determination of the C-reactive protein and the alanine-leucine-aminotransferase (ALT) to exclude both, occult liver cell damage and inflammation, correlates well with total body iron stores and total body iron deficiency, respectively.

The serum ferritin level, however, is a poor marker of functional iron deficiency when erythropoiesis is inhibited by the relative lack bioavailable iron in high turnover states of the bone marrow such as in hemolysis and in the thalassemias. Correspondingly, in patients with hemochromatosis and an increased functional iron availability, erythropoiesis will be augmented following acute blood losses.

To date no golden standard exists to measure functional iron deficiency in a routine clinical setting. As a matter of fact, in some clinical studies functional iron deficiency is still diagnosed indirectly and retrospectively by the effect of an iron substitution therapy (increase in Hb by 10 g/L following 4 weeks of iron supplementation)

The percentage of hemoglobin-deficient, hypochromic erythrocytes, as measured by some hemocytometers, reflects the availability of iron for erythropoiesis and has become a surrogate marker of functional iron deficiency. As the lifespan of erythrocytes varies according to the degree of the patient's uremia between approximately 60 and 120 days, hypochromic erythrocytes, measured as a percentage of total erythrocytes (%-Hypo), become detectable only late in the course of erythropoietin therapy, and are therefore thought by some to be of only limited sensitivity in the diagnosis of functional iron deficiency.