Erythroid Iron Research Articles

Regulation of iron absorption in iron loaded subjects with end stage renal disease: effects of treatment with recombinant human erythropoietin and reduction of iron stores.

The effects on iron absorption of variation in erythroid activity, haemoglobin and iron stores were studied in six anaemic dialysis-dependent subjects in whom iron stores were increased from previous red cell transfusions. Gastrointestinal mucosal uptake and whole body retention of oral iron were measured at the beginning of the study, after starting treatment with recombinant erythropoietin (but before significant increase in haemoglobin), after partial correction of anaemia, after further reduction of iron stores by repeated phlebotomy, and when erythropoiesis decreased from the discontinuation of treatment with erythropoietin. Between successive measurements, valid comparisons were made in five subjects. Correction of anaemia decreased whole body retention of iron through decreased mucosal uptake (P = 0.032). Further reduction in iron stores through repeated phlebotomy whilst the increase in haemoglobin was maintained by treatment with erythropoietin, tended to increase whole body retention of iron through an increase in mucosal transfer (P = 0.010). With initial enhancement of erythropoiesis in anaemic iron-loaded subjects there was no change in any measured component of iron absorption. However, after correction of anaemia and reduction of iron stores, a decrease in erythropoiesis was associated with decreased whole body iron retention in all subjects through decreased mucosal transfer (P = 0.028). The data suggest that anaemia upregulates mucosal iron uptake, and that erythroid activity upregulates mucosal transfer but that this latter effect may be counter-balanced by iron overload which downregulates mucosal transfer.

A prognostic classification of myelofibrosis with myeloid metaplasia.

The dependence of survival time on a set of prognostic factors was explored by means of Cox's regression model in 137 cases of myelofibrosis with myeloid metaplasia (MMM). The following parameters recorded at diagnosis proved to be important independent indicators of a poor prognosis: a higher value for age, a lower value for Hb concentration, a higher value for immature myeloid cells in peripheral blood (IMC), a lower value for total erythroid iron turnover (TEIT), and a bone marrow red cell aplasia (RCA). A prognostic classification tree was constructed whose terminal nodes (risk groups), described by simple logical conditions upon important indicators, were characterized by significantly different expected survival. The two extreme risk groups lend themselves to a simple, but complete description. The low-risk group (19.7% of the sample) comprises cases who had the diagnosis of MMM before age 45 and a number of IMC constantly lower than 24%. The actuarial proportion of patients surviving at 15 years was 100%. The high-risk group (29.9% of cases) comprises patients with age greater than 45 and Hb lower than 13 g/dl, associated with RCA, or with a relatively decreased erythropoiesis (TEIT lower than 2 times the normal) or with IMC greater than 24%. Seven out of the 11 who died within this group developed blastic crisis. Median survival time of the group was 69 months.

Classification of anaemia on the basis of ferrokinetic parameters.

Quantitative information on abnormalities of erythropoiesis and mechanisms of anaemia has been obtained in 136 anaemic patients by means of ferrokinetic studies. To derive a functional classification of anaemia based on ferrokinetic parameters, agglomerative hierarchical cluster analysis and principal coordinate analysis were utilized as techniques for unsupervised classification. Two main clusters were found and named anaemia with low potential erythropoiesis and with high potential erythropoiesis, since the most discriminant parameter between them was total erythroid iron turnover, a measure of total erythropoietic activity. A value of total erythropoiesis equal to 4 times the normal was found to discriminate these two types of anaemia in 94% of cases. Within the group with low potential erythropoiesis, three clusters showing different qualitative disturbances of erythropoiesis were singled out. Among patients with high potential erythropoiesis, two clusters were found. A value of effective erythropoiesis equal to 2.5 times the normal was shown to have a high discriminant power between these clusters. This threshold level distinguished between patients having ineffective erythropoiesis or peripheral haemolysis as the major mechanism of anaemia. The present functional classification of anaemia provides a complete picture of the different pathogenetic mechanisms and may represent the basis for a more rational diagnostic approach to erythroid disorders.

Turnover in the transferrin iron pool during the hypoferremic phase of experimental Neisseria meningitidis infection in mice.

Mouse transferrin was used to specifically label the plasma transferrin iron pool for studies of iron kinetics in normal mice and infected mice during the hypoferremic phase of experimental meningococcal infection. The plasma transferrin iron pool of normal mice was found to be very dynamic, with a half-life of iron in the pool of 0.7 h. Iron left the plasma pool, entered the bone marrow, and was released into the blood in erythrocytes. Iron from the transferrin pool also entered the liver and spleen and was presumably in the reticuloendothelial system components of these organs. Most of the iron that had been supplied as transferrin iron was found in erythrocytes by 48 h after injection. Studies with mice infected with Neisseria meningitidis strain M1011 revealed similar kinetics for transferrin iron. There was no redistribution of iron within the various iron pools as a result of infection. Iron turnover in the plasma transferrin pool during the hypoferremic phase was similar to control rates, and iron leaving the pool entered its normal erythroid compartments. The lack of accelerated turnover of plasma iron and the finding that plasma iron was not rerouted to storage compartments during the hypoferremic phase provided good evidence that lactoferrin and leukocytic endogenous mediator were not directly involved in redirecting transferrin iron. Our evidence has implicated an impaired return of reticuloendothelial system-processed iron to the transferrin pool during the hypoferremic response. This appears to be a logical point in the erythroid iron cycle for host-mediated iron sequestration, as the reticuloendothelial system is involved in iron storage and may regulate iron levels in the plasma transferrin pool under normal conditions.

A distributed model of iron kinetics for clinical assessment of normal-abnormal erythropoietic activity.

The use of mathematical models of iron metabolism has been recognized as an essential tool for analyzing ferrokinetic data. Multicompartment models, however, did not make it possible to describe marrow iron kinetics, taking into account that marrow erythroid cells uptake iron from the plasma according to their maturity.

The anemia of chronic disorders: studies of marrow regulation and iron metabolism

Marrow regulation and iron metabolism were evaluated in 17 patients with mild or moderate anemia associated with chronic disorders. In addition, whole blood P50 and red cell 2,3-diphosphoglycerate (DPG) levels were measured. The study group consisted of seven patients with non-hematologic malignancies, nine with infection or inflammation, and one with idiopathic hypoproliferative anemia. The mean whole blood P50 and DPG levels were elevated to 28.5 +/- 1.9 mm Hg and 7.03 +/- 0.83 mumole/ml packed RBC, respectively, as compared to normal values of 26.6 +/- 0.6 mm Hg and 4.83 +/- 0.33 mumole/ml packed RBC. Erythropoietin (ESF) excretion was variable (1.1–28.7 IRP U, day), clearly elevated above normal in only three patients and, within the study group, bore no relation to hematocrit. While nine of the 17 subjects had ESF excretion rates within the 95% limits predicted by hematocrit, the remaining eight had lower than expected values. No significant differences in ferrokinetics, ESF excretion, or hematologic profile were found between patients with malignancy and those with inflammation. Marrow transit times correlated inversely with both serum and urine ESF activity (r = -0.57, p less than 0.02; and r = -0.63, p less than 0.01, respectively), indicating that the marrow reticulocyte release response to ESF stimulation was unimpaired. Erythroid iron turnovers were unrelated to serum or urinary ESF activity but were significantly correlated with serum iron levels expressed as microgram/100 ml whole blood (r = 0.56, p less than 0.02). These studies suggest that there is an intraerythrocytic response to the anemia in this group of patients, document that reduced ESF production is not a uniform finding with the anemia of chronic disorders, and provide evidence that the marrow proliferative response to anemia is limited in many patients primarily by the availability of iron.

The Anemia of Chronic Disorders: Studies of Marrow Regulation and Iron Metabolism

Marrow regulation and iron metabolism were evaluated in 17 patients with mild or moderate anemia associated with chronic disorders. In addition, whole blood P50 and red cell 2,3-diphosphoglycerate (DPG) levels were measured. The study group consisted of seven patients with non-hematologic malignancies, nine with infection or inflammation, and one with idiopathic hypoproliferative anemia. The mean whole blood P50 and DPG levels were elevated to 28.5 +/- 1.9 mm Hg and 7.03 +/- 0.83 mumole/ml packed RBC, respectively, as compared to normal values of 26.6 +/- 0.6 mm Hg and 4.83 +/- 0.33 mumole/ml packed RBC. Erythropoietin (ESF) excretion was variable (1.1-28.7 IRP U, day), clearly elevated above normal in only three patients and, within the study group, bore no relation to hematocrit. While nine of the 17 subjects had ESF excretion rates within the 95% limits predicted by hematocrit, the remaining eight had lower than expected values. No significant differences in ferrokinetics, ESF excretion, or hematologic profile were found between patients with malignancy and those with inflammation. Marrow transit times correlated inversely with both serum and urine ESF activity (r = -0.57, p less than 0.02; and r = -0.63, p less than 0.01, respectively), indicating that the marrow reticulocyte release response to ESF stimulation was unimpaired. Erythroid iron turnovers were unrelated to serum or urinary ESF activity but were significantly correlated with serum iron levels expressed as microgram/100 ml whole blood (r = 0.56, p less than 0.02). These studies suggest that there is an intraerythrocytic response to the anemia in this group of patients, document that reduced ESF production is not a uniform finding with the anemia of chronic disorders, and provide evidence that the marrow proliferative response to anemia is limited in many patients primarily by the availability of iron.

Improvement in the anemia of chronic renal failure with fluoxymesterone.

Fluoxymesterone was administered to 14 severely anemic patients with chronic renal failure stabilized with maintenance hemodialysis. Clinically, significant improvement in erythropoiesis was seen within 3 to 6 months of androgen therapy in 13 of the 14 patients, as reflected by a reduction in transfusion requirements and an increase in hematocrit value. The increase in effective erythropoiesis was documented by the erythroid iron turnover and was accompanied usually by either an increase in measurable serum levels of erythropoietin or a reduction in the marrow transit time, suggesting that the androgen acted primarily by stimulating erythropoietin production. This response did not depend on the presence of residual renal tissue. In the doses given (10 mg/day for women; 30 mg/day for men), fluoxymesterone therapy was unassociated with significant toxicity.

The effect of total nephrectomy on hematopoiesis in patients undergoing chronic hemodialysis.

Abstract Routine hematologic measurements, erythrokinetic studies, and serum erythropoietic-stimulating factor (ESF) assays were perforMed before and after bilateral nephrectomy in 8 patients undergoing chronic hemodialysis. In addition, average hematocrit values and transfusion requirements were determined on these and 19 other patients prior to and after removal of the kidneys. The results indicate that hematocrit values decrease and transfusion requirements increase after the kidneys are removed, even though the patients had severe renal failure requiring regular dialysis prior to surgery, and the level of azotemia did not change. These findings are accompanied by decreased total and erythroid iron utilization. Red cell survival times, while shorter than normal, were not changed significantly. ESF was not detectable in the plasma of any patient prior to nephrectomy, but was detectable in 1 patient after the kidneys were removed when the hematocrit reached a very low level. These findings suggest that bilateral nephrectomy so adversely affects erythropoiesis that the procedure should be recommended only for control of severe hypertension, for other specific indications, or at the time of renal transplantation.