Ferritin in bone marrow and serum in iron deficiency and iron overload

Summary Nonheme iron and ferritin in the bone marrow and serum ferritin was investigated in patients with iron deficiency anaemia or iron overload. As controls served patients without any disturbance of the iron metabolism.There is a precise correlation between the nonheme iron and ferritin in the bone marrow of patients with and without disturbance of iron metabolism. A correlation was also found between the ferritin in the bone marrow and the serum. Nonheme iron and ferritin in the bone marrow and serum ferritin was decreased in patients with iron deficiency anaemia. Conversely, the same parameters were increased in patients with iron overload.     

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.     

Non-transferrin-bound iron and hepatic dysfunction in African dietary iron overload

BACKGROUND: Circulating iron is normally bound to transferrin. Non-transferrin-bound iron (NTBI) has been described in most forms of iron overload, but has not been studied in African dietary iron overload. This abnormal iron fraction is probably toxic, but this has not been demonstrated. METHODS: High-pressure liquid chromatography was used to assay serum NTBI in 25 black African subjects with iron overload documented by liver biopsy and in 170 relatives and neighbours. Levels of NTBI were correlated with indirect measures of iron status and conventional liver function tests. RESULTS: Non-transferrin-bound iron (> 2 micromol/L) was present in 43 people, 22 of patients of whom underwent liver biopsy and 21 relatives and neighbours. All but four of these had evidence of iron overload on the basis of either liver biopsy or elevated transferrin and serum ferritin concentrations. Among all 195 subjects, the presence of NTBI in serum was independently related to elevations in alanine and aspartate aminotransferase activity and bilirubin concentration. This relationship between serum NTBI and hepatic dysfunction was confirmed in the subgroup of 25 subjects with iron overload documented by liver biopsy. Non-transferrin-bound iron correlated significantly with elevations in alanine and aspartate aminotransferase activities after adjustment for hepatic iron grades, inflammation and diet. CONCLUSIONS: Non-transferrin-bound iron was found to be commonly present in African patients with dietary iron overload and to correlate with transferrin saturation and serum ferritin concentration. The independent relationship between NTBI and elevated liver function tests suggests that it may be part of a pathway leading to hepatic injury.     

Pituitary iron and volume predict hypogonadism in transfusional iron overload

Hypogonadism is the most common morbidity in patients with transfusion‐dependent anemias such as thalassemia major. We used magnetic resonance imaging (MRI) to measure pituitary R2 (iron) and volume to determine at what age these patients develop pituitary iron overload and volume loss. We recruited 56 patients (47 with thalassemia major, five with chronically transfused thalassemia intermedia and four with Blackfan‐Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Hypogonadism was defined clinically based on the timing of secondary sexual characteristics or the need for sex hormone replacement therapy. Patients with transfusional iron overload begin to develop pituitary iron overload in the first decade of life; however, clinically significant volume loss was not observed until the second decade of life. Severe pituitary iron deposition (Z > 5) and volume loss (Z < ?2.5) were independently predictive of hypogonadism. Pituitary R2 correlated significantly with serum ferritin as well as liver, pancreatic, and cardiac iron deposition by MRI. Log pancreas R2* was the best single predictor for pituitary iron, with an area under the receiving operator characteristic curve of 0.88, but log cardiac R2* and ferritin were retained on multivariate regression with a combined r² of 0.71. Pituitary iron overload and volume loss were independently predictive of hypogonadism. Many patients with moderate‐to‐severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. The subset of hypogonadal patients having preserved gland volumes may also explain improvements in pituitary function observed following intensive chelation therapy. Am. J. Hematol. 2011. © 2011 Wiley Periodicals, Inc.     

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.     

Serum iron and iron stores in non-anemic patients with fibromyalgia

The aim of the study was to assess iron serum levels and markers of iron stores in non-anemic fibromyalgia (FM) patients and to evaluate their impact on the prevalence and clinical manifestations of FM patients. Eighty-four patients with primary FM and 87 controls were investigated. Demographic and clinical data were collected from all participants. All patients completed the fibromyalgia impact questionnaire (FIQ). Patients evaluated the effect of the disease on their daily activity (DA) and judged the severity (DS) of the disease on a 0–10 scale. Venous blood was tested for serum iron, transferrin, ferritin, and soluble transferrin receptors (sTfR). Iron deficiency was defined if any of the following were present: serum iron <40 μg/dL, serum ferritin levels <10 ng/mL, or sTfR levels >28.1 nmol/L. Analysis at a cutoff level of serum ferritin levels ≤30 ng/mL and sTfR/ferritin ratio was also performed. Hemoglobin, iron, transferrin, sTfR, ferritin levels, and sTfR/ferritin ratios did not differ between the groups. The mean FIQ score was 57.13 ± 20.21 and the DA and DS scores were 6.79 ± 2.97 and 6.74 ± 3.09, respectively. No correlations were found between the parameters studied and the FIQ or its ten individual items. Thirty-eight controls (43.7%) and 23 FM patients (27.4%) had ferritin levels of ≤30 (p < 0.04). Within the FM group, lower levels were associated with lower total FIQ score and FIQ subscale scores. Patients with FM do not have reduced serum levels of iron or surrogate markers of iron stores. At present, there is no evidence to support iron supplementation in the treatment of FM.     

Serum iron and total iron binding capacity in leprosy patients

Serum Iron and Total Iron Binding capacity were estimated on the sera collected from 45 leprosy patients attending the out-patient department of the Central JALMA Institute for Leprosy, Agra. The Sera from 15 healthy subjects were included in the study as controls. Hypoferraemia was observed in lepromatous leprosy and was particularly marked during the reactive phase. Further investigations to elucidate the pathogenesis of anaemia in leprosy are being planned.     

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.     

Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload

BACKGROUND & AIMS: Imbalances of iron homeostasis are accompanied by alterations of intestinal iron absorption. The identification of divalent-metal transporter 1 (DMT1) and ferroportin 1 (FP1) has improved our understanding of transmembrane iron trafficking. To gain insight into the regulatory properties of these transporters in the duodenum, we studied their expression in patients with hereditary hemochromatosis (HFE-associated and non-HFE-associated), secondary iron overload, and iron deficiency. METHODS: DMT1, FP1 messenger RNA (mRNA), and protein expression were analyzed in duodenal biopsy specimens from patients by means of TaqMan real-time polymerase chain reaction, Western blotting technique, and immunohistochemistry. RESULTS: DMT1 and FP1 mRNA levels are positively correlated with each other in all patient groups (P < 0.001). Moreover, DMT1 and FP1 mRNA levels were significantly increased in patients with iron deficiency, HFE and non-HFE hemochromatosis, whereas they were unchanged in patients with secondary iron overload. Alterations in DMT1 and FP1 mRNA levels were paralleled by comparable changes in the duodenal expression of these proteins. In patients with normal iron status or iron deficiency, significant negative correlations between DMT1, FP1 mRNA, and serum iron parameters were found, which were absent in subjects with primary hemochromatosis. CONCLUSIONS: DMT1 and FP1 are centrally involved in iron uptake/transfer in the duodenum and in the adaptive changes of iron homeostasis to iron deficiency and overload.     

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.     

Small-dose iron tolerance test and body iron content in normal subjects

Abstract: The small-dose iron tolerance test (SD-ITT) was performed in 37 healthy subjects (20 females and 17 males). The area under the curve (AUC) of serum iron variations after the test dose (10 mg of iron as iron sulphate) was corrected by the expected plasma iron disappearance rate, the expected subject's plasma volume and the measured spontaneous time-dependent serum iron variations, and was used as a summary measure of the outcome, Q-ITT. Q-ITT correlated strictly with the maximum serum iron increase (SImax). Q-ITT gave positive (greater than zero) values in only 14 out of the 37 subjects (11 females and 3 males). Serum ferritin proved to be the best discriminating parameter between positive and non-positive subjects, and was inversely correlated with Q-ITT in the positive ones. In 2 male subjects, aged 43 and 34 years, SD-ITT proved to be highly sensitive to the progressive decrease of mobilzable body iron content during repeated venesections. In these patients the threshold for a positive test result was obtained at values lower than 1050 and 950 mg of body iron content, respectively. The threshold-dependent sensitivity, simplicity, and repeatability of this method favor its becoming a useful technique for studying the up-regulation of iron absorption in normal subjects and in pathological conditions.     

Ineffective erythropoiesis and regulation of iron status in iron loading anaemias

The definition ‘iron loading anaemias’ encompasses a group of inherited and acquired anaemias characterized by ineffective erythropoiesis, low hepcidin levels, excessive iron absorption and secondary iron overload. Non‐transfusion‐dependent β‐thalassaemia is the paradigmatic example of these conditions that include dyserythropoietic and sideroblastic anaemias and some forms of myelodysplasia. Interrupting the vicious cycle between ineffective erythropoiesis and iron overload may be of therapeutic benefit in all these diseases. Induction of iron restriction by means of transferrin infusions, minihepcidins or manipulation of the hepcidin pathway prevents iron overload, redistributes iron from parenchymal cells to macrophage stores and partially controls anaemia in β‐thalassaemic mice. Inhibition of ineffective erythropoiesis by activin ligand traps improves anaemia and iron overload in the same models. Targeting iron loading or ineffective erythropoiesis shows promise in preclinical studies; activin ligand traps are in clinical trials with promising results and may be useful in patients with ineffective erythropoiesis.     

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.

     

Storage iron decrease rates and their clinical significance in iron deficiency anemia patients following intravenous iron therapy

A simple method was devised for determination of the storage iron decrease rate (SID) and the number of days to a recurrent state of iron deficiency. Several patients with iron deficiency anemia were given intravenous doses of iron, and their serum ferritin levels were periodically assayed. A serum ferritin decrease curve was plotted semi-logarithmically; back-extrapolation of that curve yielded the period of days (D) from the starting day of iron supplement therapy to the day by which serum ferritin had decreased to 12 ug/l. The amount of administered iron that was initially stored and eventually lost during period D was calculated by subtracting the amount of iron utilized for hemoglobin increase (R) from the total amount of iron administered (T) to each patient. R was calculated from values for patient body weight and change in hemoglobin concentration prior to and after therapy. SID values were obtained from the following formula: SID = (T-R)/mg/day. SID rates and the number of days to a state of recurrent iron deficiency were measured in 12 patients. SID rates ranged from 0.8 to 9.8 mg/day, and were larger in those patients who exhibited heavier blood loss. A correlation was observed between SID values and the half-times for serum ferritin decrease, as expressed by the equation, Y = 248.5X0.129 (r = 0.129). SID values reflected the negative iron balance of each patient. That observation suggested it should be possible to select a more appropriate intravenous iron does for individual patients if their SID values are taken into full account.     

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.     

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