Iron, anaemia, and inflammatory bowel diseases.

Iron deficiency anaemia is one of the most common disorders in the world. Also, one third of inflammatory bowel disease (IBD) patients suffer from recurrent anaemia. Anaemia has significant impact on the quality of life of affected patients. Chronic fatigue, a frequent IBD symptom itself, is commonly caused by anaemia and may debilitate patients as much as abdominal pain or diarrhoea. Common therapeutic targets are the mechanisms behind anaemia of chronic disease and iron deficiency. It is our experience that virtually all patients with IBD associated anaemia can be successfully treated with a combination of iron sucrose and erythropoietin, which then may positively affect the misled immune response in IBD.

Single value of serum transferrin receptor is not diagnostic for the absence of iron stores in anaemic patients with rheumatoid arthritis.

Serum transferrin receptor (sTfR) concentrations were measured in anaemic patients with rheumatoid arthritis (RA). Serum transferrin receptor concentrations were positively correlated with the percentage of hypochromic cells and negatively correlated with MCH. There was a weak correlation with serum ferritin (sFn) concentration but not with reticulocyte count. Thus, high concentrations of sTfR indicate iron-deficient erythropoiesis rather than levels of storage iron in the tissues. Patients were divided into three groups on the basis of sFn concentration: those with probable tissue iron deficiency, those with adequate iron stores and those with intermediate values of sFn which did not allow classification. The median sTfR concentration was significantly higher in the iron-deficient group than in the other two groups but because of overlap between the three groups, a single sTfR value was of limited value in determining the level of storage iron in an individual with RA.

Erythropoiesis and iron.

Iron and erythropoiesis are inextricably linked. Erythropoiesis is a dynamic process that requires 30-40 mg of iron per day. In normal circumstances this is met from red cell destruction but in anaemia this will not be the case. Reduced iron stores will limit iron supply to erythroblasts but normal or raised iron stores may not be able to supply iron fast enough. This is particularly true when the marrow is stimulated by erythropoietin therapy; the most common cause of failure to respond is "functional iron deficiency"'. This entity can only be effectively addressed by intravenous iron therapy. While haemoglobin and serum ferritin concentrations reflect the major iron pools, iron supply to erythroid cells can only be assessed by measuring effective haemoglobinization through the percentage of hypochromic red cells in the circulation.

Iron status as measured by serum ferritin: the marker and its limitations.

Assessment of iron status is important, because iron deficiency and overload have pathologic consequences. Serum ferritin, the function of which is unknown, is frequently used to assess labile iron stores for the purpose of ensuring their adequacy for erythropoiesis. However, measurable ferritin levels can be increased when tissue ferritin is released during cellular injury, and erythropoietic blockade can increase the labile iron pool, elevating serum ferritin levels despite suppressed erythropoiesis. Erythropoietin-stimulated red blood cell (RBC) production can quickly decrease the labile cellular iron pool and reduce serum ferritin, unless supplemental iron is supplied. A serum ferritin level less than 12 microg/L indicates that there is no iron in the stores (absolute iron deficiency), and levels above 15 microg/L may still not be sufficient to meet erythropoietic demand. This is particularly true in patients receiving erythropoietin, in which the stimulated erythropoiesis requires extra iron supplies. Because of the limitations of serum ferritin measurements and questions regarding the effects of free iron, clinicians need not be too alarmed by high serum ferritin levels. At the very least, safety concerns must be balanced against the real need for iron supplementation to maintain adequate erythropoiesis.

Role of iron in optimizing responses of anemic cancer patients to erythropoietin.

Approximately 50% of cancer patients develop anemia. In the past, the only available treatment option for these patients was transfusion. Since the late 1980s, recombinant human erythropoietin (rHuEPO, epoetin alfa [Epogen, Procrit]) has provided a treatment alternative. Controlled clinical trials have shown that rHuEPO increases hemoglobin and hematocrit levels and reduces the need for transfusions in patients with cancer-related anemia. These controlled trials have suggested (as larger, uncontrolled studies) that the improvements in hemoglobin are associated with increases in energy level, functional status, and overall quality of life. However, only about 50% of patients respond adequately to usual doses of rHuEPO. In the chronic renal failure population, functional iron deficiency is the most common cause of inadequate response to rHuEPO. It has been hypothesized that functional iron deficiency may also occur in cancer patients receiving rHuEPO and may account for the lack of response in up to half of those patients. Studies in renal failure patients have shown that administration of intravenous iron can correct functional iron deficiency more effectively than oral iron and may improve response to rHuEPO. Intravenous iron also reduces the total amount of rHuEPO needed to normalize hematocrit and hemoglobin levels, thereby reducing treatment costs. Ongoing clinical trials are evaluating whether IV iron can also improve rHuEPO responsiveness in patients with cancer-related anemia.

In vitro stability of the reticulocyte count.

A collaborative study was undertaken to investigate the effect of storage conditions on the measured reticulocyte count in venous blood samples. It was designed to cover variation in the three main determinants, namely time, temperature and anticoagulant. The aim was to determine the time for which samples could be stored for subsequent analysis for clinical purposes.

Assessing erythropoiesis and the effect of erythropoietin therapy in renal disease by reticulocyte counting.

Renal disease is characterized by failure of erythropoietin (Epo) production and low bone marrow sensitivity to Epo. The reticulocyte count is the best laboratory marker of erythropoiesis available, but reticulocytes have not been extensively studied in renal disease. Cluster analysis suggests that in non-haemodialysed renal patients the anaemia is associated with uraemia while the reticulocyte number and immature subclasses are correlated with the ineffective erythropoietic component of the anaemia. This emphasizes the importance of treating the renal disease in patients with the anaemia of end-stage renal failure. Human recombinant Epo therapy has been demonstrated to be effective in correcting anaemia in most cases of chronic renal insufficiency. In renal patients the reticulocyte count should only be monitored by automated methods to assure reliability at low counts.

Cytometric analysis and maturation characteristics of reticulocytes from myelodysplastic patients.

Myelodysplasia is characterized by a hypoproliferative anaemia with ineffective intramedullary erythropoiesis. We have used the novel technology of the Bayer H3 analyser to characterize reticulocytes (RNA containing red cells) from 32 MDS patients and 10 elderly normal subjects. In comparison with reticulocytes from normal subjects, those from MDS patients were larger with a lower haemoglobin concentration. Reticulocytes from sideroblastic patients had a lower haemoglobin content and concentration than for refractory anaemia patients but no other differences between FAB subtypes were found. H3 reticulocyte RNA content parameters correlated poorly with those derived by the Sysmex R-1000, particularly in the MDS group. On reticulocyte maturation to red cells MDS patients concentrated haemoglobin more than normal subjects and this was most evident in the sideroblastic group. Platelet depletion of whole blood suggested that large platelets in the sideroblastic group may have partly contributed to this observation. Prospective evaluation of changes towards normal reticulocyte cytometric parameters may assist in assessment of early erythroid response to therapy in MDS patients.

Serum erythropoietin during autologous bone marrow transplantation: relationship to measures of erythroid activity.

Marked elevation of serum erythropoietin (sEPO) occurs following high dose chemotherapy for malignant disease. It has been proposed that the subsequent fall in sEPO constitutes a relative erythropoietin (EPO) deficiency, prompting trials of recombinant EPO to reduce red cell transfusion during chemotherapy. We have investigated these phenomena by serial estimations of reticulocytes and sEPO in 11 autologous marrow transplant recipients. sEPO reached two to five times baseline 0 to 5 days after transplant but the inverse relationship between sEPO and haematocrit was maintained. Observed to expected log sEPO (Epo ratio) rose and fell in parallel with sEPO, remaining greater than 1.0 throughout. A progressive fall in reticulocyte count during chemotherapy was followed by an increase during engraftment. The strong inverse relationships between reticulocytes and Epo ratio in the 10 days after initiating chemotherapy support the hypothesis that loss of EPO-receptor bearing erythroid precursors allows a rise in sEPO during chemotherapy. The elevation of Epo ratio levels during engraftment indicates that it is the availability of EPO-sensitive progenitors, rather than the supply of EPO, that limits the rate of resumption of erythropoiesis after high-dose chemotherapy.