LPI-labile plasma iron in iron overload

Labile plasma iron (LPI) represents a component of non-transferrin-bound iron (NTBI) that is both redox-active and chelatable, capable of permeating into organs and inducing tissue iron overload. It appears in various types of hemosiderosis (transfusional and non-transfusional) and in other iron-overload conditions. Sustained levels of LPI could over time compromise organ (e.g. heart) function and patient survival. With the advent of methods for measuring LPI in the clinical setting, it has become possible to assess the implications of LPI in the management of iron overload based on regimens of iron chelation. As LPI is detected primarily in patients with transfusional iron overload and other forms of hemosiderosis, we review here regimens of iron chelation with deferrioxamine and deferiprone (separately or combined) in terms of their efficacy in minimizing daily exposure to LPI in thalassemia major and thalassemia intermedia patients.     

Liver iron concentration, stainable iron, and total body storage iron

Liver iron concentration has been determined chemically in 154 liver biopsies and the findings compared with the routine histological assessment of stainable parenchymal iron, performed by an independent observer. There was a significant correlation between liver iron concentration and histochemical grading but the relationship did not have a normal linear form. Absence of stainable iron corresponded to liver iron concentrations below the mean value for control male subjects (77 μg/100 mg dry liver). In general grade 1 siderosis corresponded to liver iron concentrations in the upper part of the control range and grade 2 siderosis to marginally elevated values. The transition from grade 2 to grade 3 (submaximal) siderosis represented a sharp increase in liver iron concentration and as grade 3 siderosis corresponded to a wide range of chemical values it is also the most difficult histochemical grade to interpret in quantitative terms. Grade 4 siderosis invariably indicated heavy iron excess.

There was a close correlation between liver iron concentration and measurements of total body storage iron obtained by quantitative phlebotomy in patients with idiopathic haemochromatosis and by determination of DTPA-chelatable body iron in a variety of iron-loading disorders.

     

Carbonyl iron therapy for iron deficiency anemia

To determine if elemental carbonyl iron powder is safe and effective therapy for iron deficiency anemia, 20 nonanemic and 32 anemic volunteers were studied. Single doses of 1,000 to 10,000 mg of carbonyl iron (15 to 150 times the 65 mg of iron in the usual dose of ferrous sulfate) were tolerated by nonanemic volunteers with no evidence of toxicity and only minor gastrointestinal side effects. Anemic volunteers (menstruating women who had previously donated blood) were treated with several regimens providing 1,000 to 3,000 mg of carbonyl iron daily in one to three doses for 8 to 28 days. After 12 weeks anemia was corrected in 29 of 32 patients, and serum ferritin was greater than 12 micrograms/L in 14. Hemoglobin regeneration proceeded at a rate similar to that described for therapy with oral iron salts and parenteral iron dextran. There was no evidence of hematologic, hepatic, or renal toxicity, but mild gastrointestinal side effects occurred in a majority of anemic volunteers. Carbonyl iron is an effective, inexpensive treatment for iron deficiency anemia, is accompanied by tolerable side effects and may have an advantage over therapy with iron salts by substantially reducing or eliminating the risk of iron poisoning in children.     

Nutritional iron requirements and food iron absorption

To prevent nutritional iron deficiency, sufficient iron must be absorbed from the diet to meet the normal physiological requirements. Daily iron losses in males are about 1 mg (14 micrograms kg-1), while the average additional requirements incurred in women include menstruation (0.6 mg), pregnancy (2.7 mg) and lactation (less than 0.3 mg). Requirements during pregnancy are not evenly distributed and increase to between 5-6 mg in the last trimester of pregnancy, which is more than can be absorbed from even an optimal diet. While the amounts absorbed are affected by the iron content of the diet, the composition of the latter is even more relevant. About one-quarter of the iron in haem proteins is absorbed regardless of the other components in the diet, while non-haem iron absorption is subject to the interplay of promoting and inhibiting substances in the diet. Thus diets rich in enhancers of non-haem iron absorption, chiefly meat and/or ascorbic acid, have high iron bioavailability (about 3 mg d-1) while diets in which inhibitors, such as polyphenols and phytates, predominate are poor sources of iron (less than 1 mg d-1). Examination of the relative proportions of promoters and inhibitors of iron absorption in individual foodstuffs and the measured iron absorption from them may be useful in predicting the overall iron bioavailability from mixed diets.     

Relationship among plasma iron, plasma iron turnover, and reticuloendothelial iron release

A circadian rhythm was demonstrated in 10 males and 10 females with respective mean decreases in plasma iron concentration at 18 hr of 62% and 47% of morning values. Ferrokinetic studies performed on 5 normal males and 5 normal females showed a more rapid disappearance rate and lower plasma iron turnover in the evening. Parallel studies were done on 6 normal males in the morning and 4 normal males in the evening of the release of reticuloendothelial iron at 8 and 18 hr after intravenous injection of 59Fe chondroitin ferrous sulfate. The 6-hr release in the morning was 54.1% and in the evening 25.9%. Composite data from morning and evening showed a correlation between plasma iron level and plasma iron turnover (r = 0.76, p less than 0.001). A similar correlation existed between the plasma iron level and the percent of radioiron released from the reticuloendothelial system (r = 0.67, 0.02 less than p less than 0.05). These data are consistent with a fluctuating iron release from the reticuloendothelial cell in normal subjects, which would account for the diurnal variation in plasma iron.     

Body iron metabolism and pathophysiology of iron overload

Iron is an essential metal for the body, while excess iron accumulation causes organ dysfunction through the production of reactive oxygen species. There is a sophisticated balance of body iron metabolism of storage and transport, which is regulated by several factors including the newly identified peptide hepcidin. As there is no passive excretory mechanism of iron, iron is easily accumulated when exogenous iron is loaded by hereditary factors, repeated transfusions, and other diseased conditions. The free irons, non-transferrin-bound iron, and labile plasma iron in the circulation, and the labile iron pool within the cells, are responsible for iron toxicity. The characteristic features of advanced iron overload are failure of vital organs such as liver and heart in addition to endocrine dysfunctions. For the estimation of body iron, there are direct and indirect methods available. Serum ferritin is the most convenient and widely available modality, even though its specificity is sometimes problematic. Recently, new physical detection methods using magnetic resonance imaging and superconducting quantum interference devices have become available to estimate iron concentration in liver and myocardium. The widely used application of iron chelators with high compliance will resolve the problems of organ dysfunction by excess iron and improve patient outcomes.     

铁过载检测与祛铁治疗

临床上对于低危骨髓增生异常综合征(myelodysplastic syndromes,MDS)、再生障碍性贫血(aplastic anemia,AA)以及β珠蛋白生成障碍性贫血等疾病的患者来说,输血治疗是挽救其生命和     

Regulation of iron absorption and storage iron turnover

The regulation of iron supply to plasma was studied in male rate. Repeated exchange transfusions were first carried out with plasma from iron-deficient or iron-loaded animals. There was no recognizable effect on the amount of iron entering the plasma as evidenced by plasma iron concentration or iron absorption by recipient animals. In other studies, iron compounds having different tissue distribution were injected. Subsequent iron release was greater from reticuloendothelial cells than from other iron-loaded tissues. When requirements for transferrin iron were increased by exchange transfusion with high reticulocyte blood, within minutes there was a doubling of the rate of tissue iron donation. It was concluded from these studies that (1) iron turnover in the plasma is primarily determined by the number of tissue receptors for iron, particularly those of the erythron, (2) that the amount of iron supplied by each donor tissue is dependent on the output of other donor tissues, and (3) that a humoral mechanism regulating iron exchange is unlikely in view of the speed of response and magnitude of changes in plasma iron turnover. It is proposed that there is some direct mechanism that determines the movement of iron from donor tissues to unsaturated transferrin binding sites.     

A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia

Iron deficiency anemia (IDA) is common in many chronic diseases, and intravenous (IV) iron offers a rapid and efficient iron correction. This trial compared the efficacy and safety of iron isomaltoside and iron sucrose in patients with IDA who were intolerant of, or unresponsive to, oral iron. The trial was an open‐label, comparative, multi‐center trial. Five hundred and eleven patients with IDA from different causes were randomized 2:1 to iron isomaltoside or iron sucrose and followed for 5 weeks. The cumulative dose of iron isomaltoside was based on body weight and hemoglobin (Hb), administered as either a 1000 mg infusion over more than 15 minutes or 500 mg injection over 2 minutes. The cumulative dose of iron sucrose was calculated according to Ganzoni and administered as repeated 200 mg infusions over 30 minutes. The mean cumulative dose of iron isomaltoside was 1640.2 (standard deviation (SD): 357.6) mg and of iron sucrose 1127.9 (SD: 343.3) mg. The primary endpoint was the proportion of patients with a Hb increase ≥2 g/dL from baseline at any time between weeks 1‐5. Both non‐inferiority and superiority were confirmed for the primary endpoint, and a shorter time to Hb increase ≥2 g/dL was observed with iron isomaltoside. For all biochemical efficacy parameters, faster and/or greater improvements were found with iron isomaltoside. Both treatments were well tolerated; 0.6% experienced a serious adverse drug reaction. Iron isomaltoside was more effective than iron sucrose in achieving a rapid improvement in Hb. Furthermore, iron isomaltoside has an advantage over iron sucrose in allowing higher cumulative dosing in fewer administrations. Both treatments were well tolerated in a broad population with IDA.     

Hepcidin response to acute iron intake and chronic iron loading in dysmetabolic iron overload syndrome

Background: The pathogenesis of dysmetabolic iron overload syndrome (DIOS) is still unclear. Hepcidin is the key regulator of iron homeostasis controlling iron absorption and macrophage release. Aim: To investigate hepcidin regulation by iron in DIOS. Methods: We analysed urinary hepcidin at baseline and 24 h after a 65 mg oral iron dose in 24 patients at diagnosis and after iron depletion (n=13) and compared data with those previously observed in 23 healthy controls. Serum iron indices, liver histology and metabolic data were available for all patients. Results: At diagnosis, hepcidin values were significantly higher than in controls (P<0.001). After iron depletion, hepcidin levels decreased to normal values in all patients. At baseline, a significant response of hepcidin to iron challenge was observed only in the subgroup with lower basal hepcidin concentration (P=0.007). In iron‐depleted patients, urinary hepcidin significantly increased after oral iron test (P=0.006). Conclusions: Ours findings suggest that in DIOS, the progression of iron accumulation is counteracted by the increase in hepcidin production and progressive reduction of iron absorption, explaining why these patients develop a mild–moderate iron overload that tends to a plateau.     

Treatment of iron deficiency anemia with intravenous iron preparations

OBJECTIVE: We aimed to determine the effects of intravenous iron therapy on blood parameters in pediatric patients who do not tolerate oral iron therapy for any reason. PATIENTS AND METHODS: The patient group consisted of candidates for elective operations requiring blood transfusions in order to raise hemoglobin (Hb) concentrations rapidly and for whom oral iron administration is useless and compliance with long-term treatment is definitely impossible due to sociocultural factors. Sixty-two children were included in the study. Venous blood samples were taken at diagnosis, and after 1 week and 1, 2 and 3 months. Hb, hematocrit, erythrocyte indices (mean erythrocyte volume, mean erythrocyte Hb and mean erythrocyte Hb concentration), serum iron (SI) levels, iron binding capacity, transferrin receptor (CD71) and serum ferritin levels were measured. Iron sucrose was used as an intravenous iron preparation. RESULTS: All children showed improvements in iron deficiency anemia. A statistically significant elevation occurred between the time of diagnosis and week 1 (p<0.05) in nearly all parameters. SI was raised until at least 1 month of therapy. There was no significant difference between transferrin receptors measured before and after the intravenous iron therapy. Ferritin did not exceed the values achieved in the 1st month. Mild side effects were encountered in only 8 (12.9%) patients. Treatment was not discontinued because of side effects in any case. The patients in the control group were given an oral form containing ferroglycine sulfate. CONCLUSION: Intravenous iron therapy can replace oral therapy in patients whose blood parameters must be raised rapidly and in situations where oral iron administration would not be appropriate for any reason. However, reinforcement with oral iron therapy or additional intravenous doses would be appropriate.     

The labile iron pool of hepatocytes in chronic and acute iron overload and chelator-induced iron deprivation.

BACKGROUND: The cytosolic labile iron pool (LIP) is a transitory, catalytically active compartment that has been implicated in cell iron homeostasis and in metal-induced cytotoxicity.Aims: We attempted to define LIP levels in living hepatocytes derived from chronic overloaded rats and from normal hepatocytes either acutely loaded with iron or depleted by chelation. METHODS: LIP levels were measured in living rat hepatocytes derived from normal and iron-fed rats. RESULTS: Steady-state LIP levels in untreated hepatocytes ( approximately 0.2 microM) were raised by 1.8-fold following iron loading and were reduced by 0.66-fold by short-term chelation treatment. Changes in LIP were accompanied by the corresponding changes in iron-responsive protein (IRP) activity and ferritin levels, that, in rat hepatocytes isolated from chronically loaded animals, raised by approximately 19-fold. CONCLUSIONS: Whereas ferritin levels provide an index of long-term or cumulative iron loading, LIP measurements provide an "instantaneous" parameter of iron availability within hepatocytes. The latter was associated with the cell chelatable pool in cells derived from normal and iron-loaded animals, both of which showed similar accessibility to iron chelators.     

Intravenous iron therapy restores functional iron deficiency induced by infliximab

Background and aimsInfliximab (IFX) and iron sucrose (FeS) are of high value in inflammatory bowel disease (IBD). We aimed to assess the relative role of both therapies in IBD related anaemia and their safety when used in combination.MethodsIBD patients with anaemia receiving a first series of FeS infusions in addition to IFX were prospectively followed. We investigated serum kinetics of erythropoietin (EPO), soluble transferrin receptors (sTFRs) and vascular endothelial growth factor (VEGF).ResultsData analysis included 87 patients of whom 49.4% achieved the target Hb level of 12.0 g/dL. IFX resulted in a significant increase of EPO and sTFR compared to baseline pre-IFX levels (p = 0.029 and p = 0.005 respectively) and after a 12-week combined FeS and IFX treatment, EPO and sTFR levels dropped significantly compared to pre-FeS levels (p < 0.001 for both). Infusion related adverse events were recorded in 2 IFX treated patients (2.3%, 0.7% of the infusions) and were mild. Disease activity and quality of life were not affected.ConclusionsIn anaemic IBD patients treated with IFX, combined administration of FeS is safe. Infliximab significantly increases serum EPO and sTFR levels resulting in an increased functional iron deficiency, which is restored after combined treatment with I.V. iron sucrose.