Higher Serum Iron Levels Research Articles

Erythropoietin and iron-restricted erythropoiesis

Twenty five years ago, Finch summarized knowledge gained primarily from studies of normal individuals, patients with hereditary hemolytic anemias, and patients with hemochromatosis [1]. Under conditions of basal erythropoiesis in normal subjects, plasma iron turnover (as an index of marrow erythropoietic response) is little affected, whether transferrin saturation ranges from very low to very high levels. In contrast, the erythropoietic response in individuals with congenital hemolytic anemia, in whom erythropoiesis is chronically raised up to sixfold over basal levels [2], is affected (and limited) by serum iron levels and by transferrin saturation [3]. Patients with hemochromatosis who underwent serial phlebotomy were observed to mount erythropoietic responses of up to eightfold over basal rates, attributed to the maintenance of very high serum iron and transferrin saturation levels in these patients [4], whereas normal individuals were shown to have difficulty providing sufficient iron to support rates of erythropoiesis greater than three times basal rates [5]. These observations led Finch to identify a "relative iron deficiency" state, also known as "functional iron deficiency," which he defined as circumstances in which increased erythron iron requirements exceed the available supply of iron [6]. In another clinical setting, patients undergoing autologous blood donation represent a model for perisurgical blood loss and the erythropoietic response. Insights gained over the last 20 years regarding the relationship between erythropoietin, iron, and erythropoiesis, along with implications for clinical management, will be reviewed.

Haematological measurements and iron levels in HIV-infected Gambian subjects

Results Anaemia was not found in the healthy HIV negative controls. There was however, significant higher proportion of anaemic subjects with low CD4 count < 200 cells/μl compared with other categories of subjects in both infections (44% for HIV-1 [p = 0.03] and 56% for HIV-2 [p = 0.003]). Serum iron levels were normal in all healthy control subjects and of higher levels than in both HIV infections. The proportion of individuals with less than normal serum ferritin values was higher in each of the categories of CD4 T cell counts in HIV-1 than in HIV-2 infection but was not statistically significant. Unlike serum iron level, no association was found between Hb, RDW and ferritin with CD4 counts in both HIV-1 and HIV-2 infection. Conclusion Anaemia is common in HIV-1 and HIV-2 infections when CD4 T cells declined to < 200 cells/μl but higher serum iron level is found in asyptomatic HIV-2 infection. from 2006 International Meeting of The Institute of Human Virology Baltimore, USA. 17–21 November, 2006

Serum Iron and Body Fat Distribution in a Multiethnic Cohort of Adults Living in New York City

Objective To examine the relationship between serum iron and body composition in a multiracial adult cohort. Methods The analysis consisted of 670 participants on whom blood analysis and anthropometric data were available. The participants were recruited as part of the Rosetta Study (1990-2000), which was designed to assess body composition in a multiethnic cohort of healthy adults. Fasting iron level was measured as part of a biochemistry panel. Dual x-ray absorptiometry was used to assess fat mass. Anthropometric measures included waist circumference and body mass index (BMI; calculated as kg/m 2) as an index of abdominal adiposity and overall body fatness, respectively. Results In the study cohort the mean age was 54±17 years and 60.9% were overweight or obese (BMI ≥25). Men had higher serum iron levels (94.91±34.52 μg/dL [16.99±6.18 μmol/L] vs 82.17±32.62 μg/dL [14.71±5.84 μmol/L]) and larger waist circumference (91.98±11.87 cm vs 85.24±12.37 cm) compared with women ( P<0.001). Iron was inversely correlated with BMI ( r=−0.23, P<0.001), waist circumference ( r=−0.19, P<0.05), and fat mass ( r=−0.19, P<0.05) among Hispanic women but not among African-American, white, or Asian women or in men of any race/ethnic group. Conclusions The results of this study show an inverse association of measures of body fat distribution and total fat mass with serum iron level in Hispanic women. Studies designed to explore how micronutrients are used by the body at varying degrees of body fatness could provide useful information on the micronutrient-related comorbidities of obesity.

SURVEY AND CLINICAL APPLICATION OF SERUM IRON, TOTAL IRON BINDING CAPACITY, TRANSFERRIN SATURATION, AND SERUM FERRITIN IN CAPTIVE BLACK AND WHITE RUFFED LEMURS (VARECIA VARIEGATA VARIEGATA)

Serum samples from 63 clinically normal captive black and white ruffed lemurs (Varecia variegata variegata) were analyzed to survey serum iron, total iron binding capacity, transferrin saturation, and serum ferritin levels. Data analysis showed no differences in these analytes attributable to sex, but significantly higher levels of serum iron, transferrin saturation, and serum ferritin in older animals. The survey data were examined in light of two black and white ruffed lemurs that were treated for iron overload with serial phlebotomies. Prior to therapy, both phlebotomized lemurs had excess hepatic iron deposition, but had serum iron, transferrin saturation, and serum ferritin below the upper limits observed in the survey animals, suggesting that some clinically normal animals included in the survey may have accumulated excess systemic iron. Serial phlebotomy therapy reduced serum iron, transferrin saturation, and serum ferritin in both animals. Three years after the conclusion of therapy in the one remaining case, serum iron and transferrin saturation have risen substantially, whereas serum ferritin has risen slightly. Serum iron, transferrin saturation, and serum ferritin may be useful predictors of systemic iron stores in this species, though the correlation between these parameters and systemic iron stores needs to be determined.

Serum Iron Levels and Hepatic Iron Overload in Nonalcoholic Steatohepatitis and Chronic Viral Hepatitis

Our objective was to determine the effect of serum iron levels and hepatic iron overload on hepatocellular damage in nonalcoholic steatohepatitis (NASH) and to compare this with chronic viral hepatitis. Twenty-five patients who had elevated transaminase levels on at least two occasions, without any evidence of viral and autoimmune hepatitis and diabetes, without a history of significant alcohol use, and with a liver biopsy consistent with NASH were enrolled in the study. Twenty-five patients with chronic viral hepatitis (13 patients with chronic hepatitis C and 12 with chronic hepatitis B) who were not under any antiviral treatment were taken as controls. Metabolic factors were studied in the NASH and chronic hepatitis groups. Biopsy specimens were stained with hematoxylin-eosin, and the grade of steatosis and the stage of fibrosis were evaluated as I, II, or III, I being mild and III being severe. Iron overload in the hepatic tissue was studied by Prussian blue staining. Serum ALT, AST, ALP, GGT, globulin, and ferritin levels were comparable in both steatohepatitis and chronic viral hepatitis groups. However, patients with chronic hepatitis had a lower albumin level and a higher serum iron level, with higher transferrin saturation. Among patients with NASH, mild, moderate, and severe steatosis was found in 7, 10, and 8 patients, respectively. Inflammatory infiltration was grade I in 24 patients and grade III in 1 patient. Fibrosis was mild in 12 patients and 13 patients had no fibrosis. Among patients with chronic viral hepatitis, inflammatory infiltration of grade I was seen in 11 patients, grade II in 11 patients, and grade III in 3 patients. Fibrosis was mild in 9 patients, moderate in 13 patients, and severe in 2 patients; 1 patient had no fibrosis. Compared to patients with NASH, those with chronic viral hepatitis cases had more severe inflammatory infiltration and fibrosis (P < 0.01). While five patients with chronic viral hepatitis had mild iron overload, patients with NASH had no hepatic paranchymal iron overload. Neither NASH nor chronic viral hepatitis revealed a relationship between hepatic iron overload and disease activity. This suggests that the iron overload actually may be a result of hemachromatosis gene mutation. The absence of hepatic parenchymal iron overload in the NASH group and only mild iron accumulation in the chronic hepatitis group may be explained by a lower frequency of the gene mutation in our country.

Hb Stara Zagora: A New Hyper-Unstable Hemoglobin Causing Severe Hemolytic Anemia

We describe a new hyper-unstable β chain variant (codons 137–139, − 6 bp) in a 2-year-old Bulgarian boy. The abnormal hemoglobin (Hb) is associated with severe hemolytic anemia as a consequence of its hyper instability. The child was admitted to the Pediatric Clinic (Faculty of Medicine, Stara Zagora, Bulgaria) at the age of 2 months. Because of anemia (Hb 6.9 g/dL) and high serum iron level (58 μM/L) the child was transfused. However, a month later his Hb level had dropped to 7.5 g/dL, and since then he has been on a regular monthly blood transfusion regimen. Hemoglobin analysis of a blood sample collected 2 months after the last transfusion at the age of 2 years, revealed no abnormalities except for the presence of inclusion bodies after incubation of peripheral blood with brilliant cresyl blue. Sequencing of the β-globin gene revealed heterozygosity for a 6 bp deletion (–TGGCTA) at codons 137 [the second and third base pair (bp)], 138 and 139 (the first bp), forming a new codon at position 137 (GAT). This event eliminates three amino acids (Val-Ala-Asn) and introduces a new residue (Asp). It creates a new restriction site for HphI. The parents and his dizygotic twin brother had no history of hemolysis. The paternity of the child was confirmed by DNA analysis.

Increased serum iron may contribute to enhanced oxidation of low-density lipoprotein in smokers in part through changes in lipoxygenase and catalase

Background: Increased oxidative stress is considered to be causative for cardiovascular disease (CVD) in smokers, but its mechanisms are still unclear. We compared oxidative stress markers between male smokers and male nonsmokers. Methods: Twenty-three healthy men (11 nonsmokers and 12 smokers) were enrolled, and blood samples after 12 h of fasting were collected to assess plasma lipids and oxidative stress markers. The effects of iron loading on 12-lipoxygenase (12-LO) expression and activity in human umbilical vein endothelial cells (HUVECs) were tested in vitro to investigate the relevance of iron to oxidation potential in vivo. Results: Higher levels of plasma-oxidized low-density lipoprotein (LDL) and lipid peroxide (LPO), and higher oxidizability of LDL were observed in smokers than in nonsmokers. Higher levels of serum iron and lower levels of plasma vitamin E were observed in smokers than in nonsmokers. Stepwise multiple regression analysis showed that serum iron was an independent determinant for both plasma-oxidized LDL and lag time of LDL oxidation. Iron loading enhanced 12-LO expression threefold and its activity 1.5-fold. Moreover, iron loading decreased catalase expression by 50% and significantly reduced its activity by 75%. Conclusions: Enhanced oxidative stress in smokers may be due to increased iron levels. Iron-induced modulation of expression and activity of 12-LO and catalase may be relevant to increased iron-related oxidative stress as observed in smokers.

SLC11 family of H+-coupled metal-ion transporters NRAMP1 and DMT1.

NRAMP1 (natural resistance-associated macrophage protein-1) and DMT1 (divalent metal-ion transporter-1) make up the SLC11 gene family of metal-ion transporters that are energized by the H(+) electrochemical gradient. Long known to confer resistance to bacterial infection, NRAMP1 functions at the phagolysosomal membrane of macrophages and neutrophils. NRAMP1 most likely contributes to macrophage antimicrobial function by extruding essential metal ions (including Mn(2+)) from the phagolysosome via H(+)/metal-ion cotransport. An alternative hypothesis in the literature proposes that NRAMP1 concentrate Fe(2+) within the phagolysosome by means of H(+)/Fe(2+) antiport, resulting in the generation of toxic free radicals. DMT1 is expressed widely and accepts as substrates a broad range of transition metal ions, among which Fe(2+) is transported with high affinity ( K(0.5) approximately 2 microM). DMT1 accounts both for the intestinal absorption of free Fe(2+) and for transferrin-associated endosomal Fe(2+) transport in erythroid precursors and many other cell types. DMT1 is up-regulated dramatically in the intestine by dietary iron restriction and, despite high serum iron levels, is not appropriately down-regulated in hereditary hemochromatosis.

The role of iron in erythropoiesis in the absence and presence of erythropoietin therapy.

Preoperative autologous blood donation has served as a model for blood loss anaemia. Studies in these patients, along with clinical trials of i.v. iron and recombinant human erythropoietin (rHuEPO) therapy, have furthered our understanding of the relationship between erythropoietin, iron, and erythropoiesis. With supplemental oral iron, the endogenous erythropoietic response to routine autologous blood donation and to the anaemia of chronic illness has been shown to be modest, but predictable. In more aggressive donation and more severe anaemia, the endogenous erythropoietic response is more substantial, but still predictable. Studies in patients undergoing aggressive phlebotomy whilst receiving rHuEPO demonstrate a wide variation in response to rHuEPO dose. This variability is not related to age or gender and suggests factors such as iron-restricted erythropoiesis may be responsible. Supporting evidence arises from the superior erythropoietic response observed in patients with haemochromatosis. These patients maintain very high serum iron and transferrin saturation levels. In response to serial phlebotomy these patients can mount an endogenous erythropoietin response up to five-times greater than healthy individuals. When treated with rHuEPO, patients with haemochromatosis respond with much greater RBC expansion volumes than patients receiving rHuEPO and iron supplementation. Studies show no difference in the degree of endogenously stimulated erythropoiesis between patients with measurable iron stores and those without. However, when treated with rHuEPO, increased erythropoiesis has been observed in patients with measurable iron stores compared with those without. This suggests that, while oral iron supplementation may be sufficient to keep pace with endogenously stimulated erythropoiesis, it may not be adequate to prevent iron-restricted erythropoiesis during rHuEPO therapy. Some studies have suggested that i.v iron may prevent iron-restricted erythropoiesis during rHuEPO therapy although further research is needed. The availability of better tolerated i.v. iron preparations provides an ideal opportunity to study the value of iron therapy in patients with acute blood loss, particularly those undergoing rHuEPO therapy.

Liver iron accumulation in chronic hepatitis C patients without HFE mutations: relationships with histological damage, viral load and genotype and α-glutathione S-transferase levels

Host and viral factors have been suggested as possible causative factors for the presence of liver iron accumulation in chronic hepatitis C. However, there is no agreement regarding the influence of liver iron accumulation on the biochemical and histological severity of chronic hepatitis C. Moreover, data concerning the relationships between both viral load and genotype and liver iron accumulation are scanty. To evaluate the biochemical, histological and virological assessment of a group of chronic hepatitis C patients without risk factors for iron overload, on the basis of the presence, degree and distribution of liver iron accumulation. Fifty-three chronic hepatitis C patients (34 men, 19 women; age 44 +/- 11 years) with no risk factors for liver iron accumulation and showing no HFE mutations were chosen from a broader cohort of chronic hepatitis C patients. The presence, degree and distribution of liver iron accumulation were assessed using Deugnier's score. Relationships between the presence of liver iron accumulation and grading and staging were carried out separately. Hepatitis C virus RNA serum levels and viral genotype were compared in patients with or without liver iron accumulation. Alpha glutathione S-transferase serum levels were assessed in all patients. Overall, liver iron accumulation was mild and was present in 19 patients (36%). It was associated with male gender (P = 0.0358), and was reflected by high serum iron levels (P = 0.001) and high ferritin levels (P < 0.0001). Hepatitis C virus RNA levels and genotype were not associated with the presence of liver iron accumulation. In multivariate analysis, ferritin was the only variable significantly associated with liver iron accumulation (P < 0.0001). Grading was higher in patients with liver iron accumulation regardless of the site of iron deposition. Fibrosis was present in all patients with iron overload; these patients were more frequently cirrhotic. Moreover, patients with mesenchymal or mixed deposition had higher staging than patients with hepatocytic or no iron deposition. This feature was reflected by higher alpha-glutathione S-transferase levels. Liver iron accumulation is mild in chronic hepatitis C patients without HFE mutations and is mainly reflected by serum ferritin levels. Viral characteristics do not seem to play a role in iron deposition. Liver iron accumulation is associated with higher grading, advanced fibrosis and cirrhosis. Moreover, higher staging is associated with mesenchymal or mixed iron deposition. In these patients, higher alpha-glutathione S-transferase levels seem to reflect more complex damage.

Increase in plasma esterified F2-isoprostanes following intravenous iron infusion in patients on hemodialysis

In epoetin-treated dialysis patients, currently iron is administered by the intravenous route to maintain optimum erythropoiesis. However, rapid infusion of iron in excess of transferrin binding capacity can lead to the availability of unbound iron that can theoretically catalyze peroxidation of lipids, such as low-density lipoprotein (LDL), which when oxidatively modified is proinflammatory and promotes atherogenesis. To address this issue, our study used one of the most specific measures of lipid peroxidation available, namely gas chromatography/mass spectometry (GC/MS) analysis of F2-isoprostanes. Using a prospective design, blood samples were collected 15 minutes before (pre) and 30 minutes after (post) a one-hour infusion of 700 mg bolus of intravenous iron in 22 adult home-hemodialysis patients on a non-hemodialysis day. With iron-dextran infusion, serum iron markedly increased (mean +/- SE, 42 +/- 4 vs. 311 +/- 92 microg/dL, P < 0.0001) and exceeded the transferrin saturation of 100% in 22 out of 22 patients (pre 23 +/- 3 vs. post 165 +/- 8%, P < 0.0001). Plasma concentrations of free F2-isoprostanes did not change significantly following infusion of iron (pre 40 +/- 5 vs. post 39 +/- 6 pg/mL). However, levels of F2-isoprostanes esterified in plasma lipoproteins increased significantly in the postinfusion samples (pre 199 +/- 19 vs. post 233 +/- 25 pg/mL, P < 0.004). Pre-infusion levels of serum iron correlated directly with pre-infusion levels of esterified F2-isoprostanes (r = 0.56, P = 0.008), which persisted in the postinfusion period (r = 0.43, P = 0.04). However, there was no correlation between esterified F2-isoprostanes and serum ferritin levels. In the last four patients in whom blood samples were collected five hours after the intravenous iron infusion, there were further increases in esterified F2-isoprostanes that very closely correlated with postinfusion serum iron levels (r = 0.99, P = 0.013). In a control study, the in vitro addition of iron dextran to blood samples did not increase free or esterified F2-isoprostanes, suggesting that the increase in esterified F2-isoprostanes seen in vivo after iron infusion in patients is not due to a procedural artifact. Collectively our data suggest that high levels of serum iron appearing soon after a large bolus of iron infusion is associated with significant, albeit modest, increases in levels of F2-isoprostanes esterified in plasma lipoproteins that tended to increase with time. Although it is uncertain whether this degree of lipid peroxidation may have deleterious effects, it may be sagacious to explore whether this can be prevented by slow infusion of frequent smaller doses of iron and, if necessary, along with administration of antioxidants.

Iron and infection: Clinical experience

Bacterial infection is a significant cause of morbidity and mortality in hemodialysis patients, and a number of studies have implicated iron overload as a risk factor for bacterial infection in these patients. While the underlying cause of increased susceptibility to bacterial infection is not completely understood, evidence suggests that iron overload alters the chemotactic and phagocytic properties of neutrophils, thereby reducing their ability to kill invading pathogens. T-cell function also appears to be altered. In addition, high levels of serum iron may promote replication and dissemination of bacterial pathogens that use iron as a growth factor. With the introduction of recombinant human erythropoietin therapy for hemodialysis patients, the need for red blood cell transfusions has been reduced and iron overload occurs much less frequently. Several recent studies have indicated that iron overload, which is suspected in the presence of high serum ferritin levels, may no longer be a significant risk factor for infection in hemodialysis patients receiving erythropoietin therapy. Major risk factors for infection in these patients include history of bacterial infection, immunosuppressive therapy, and vascular access via catheters rather than by arteriovenous fistula. In addition, anemia has recently been linked to an increased incidence of bacterial infection, particularly in patients receiving erythropoietin therapy. Therefore, repletion of iron stores and maintenance of iron balance without iron overload may prove to be important factors in reducing the incidence of bacterial infections in hemodialysis patients. However, the relationships between iron levels, anemia, and susceptibility to bacterial infection require further investigation. Am J Kidney Dis 34:s30-s34, 1999. Copyright © 1999 by National Kidney Foundation

'Oversaturation' of transferrin after intravenous ferric gluconate (FerrlecitR) in haemodialysis patients

Chronic haemodialysis causes blood loss and iron-deficiency. This can be corrected with intravenous preparations, e.g. sodium ferric-gluconate (FeGl). In two patents complaints of hypotension and malaise during FeGl infusion coincided with high levels of serum iron and a calculated transferrin iron saturation above 100%. Iron toxicity could be the cause of these complaints. Free iron is known to aggravate the toxicity of free radicals and other reactive oxygen products that are constantly formed in the body. We compared four rates of FeGl infusion with regard to iron parameters. 20 dialysis patients received a total of 26 infusions of FeGl. A rapid infusion of 135 mg (Protocol A (n=10)) or 62.5 mg (Protocol B (n=7)) of FeGl was given during the last 30 min of dialysis. A slow infusion of 125 mg (Protocol C (n=9)) or 62.5 mg (Protocol D (n=10)) was given during 4 or 4.5 h of dialysis. Blood was taken at regular intervals, before, during, and after dialysis for determination of serum iron, transferrin, ferritin, haematocrit, total protein, albumin, and lactate dehydrogenase (LDH). Transferrin saturation was calculated from transferrin and serum iron. With rapid infusion A (125 mg) the highest levels of serum iron (median 120 (range 40-159) micromol/l) and transferrin saturation (207 (84-331)%) were seen at the end of the infusion. These were significantly higher than the peak levels with B, C, and D (P</=0.03). With rapid infusion B (62.5 mg), peak levels were intermediately high (serum iron 61 (50-96) micromol/l; transferrin saturation 118 (91-174)%). With slow infusion C (125 mg) similar peak levels were seen (serum iron 83 (43-106) micromol/l; transferrin saturation 141 (88-172)%). With slow infusion D (62.5 mg), the lowest peak levels were seen (serum iron 38 (31-55) micromol/l; transferrin saturation 78 (43-92)%). These levels were significantly lower than those with A, B and C (P<=0.002). Only with D all patients showed a transferrin saturation lower than 100%. Ferritin was increased before the next dialysis in all patients. LDH was not significantly elevated during any infusion. The commonly used rapid infusion rate (A) of FeGl causes 'oversaturation' of transferrin. This is compatible with iron toxicity due to free iron which may explain our patients' complaints. Free iron cannot be measured directly. LDH as a crude measure of cell damage was not elevated. Better measurements to prove free iron toxicity, like lipid peroxides, are not yet readily available. Infusion during a longer period at a lower dose (D) is effective and eliminates 'Oversaturation' of transferrin and probably the danger of iron toxicity.

Influence of iron status in the response to the deferoxamine test.

The study presented here was carried out to evaluate the possible relationship between serum iron and iron transferrin saturation with the response to the deferoxamine test in 86 chronic renal failure patients undergoing hemodialysis. The deferoxamine test was performed as a diagnostic tool for aluminum intoxication. Basal serum aluminum levels correlated with: (1) serum aluminum levels after the infusion of deferoxamine (r = 0.45; P < 0.05); (2) serum iron levels (r = -0.26; P < 0.05), and; (3) iron transferrin saturation (r = -0.33; P < 0.05). The increase in serum aluminum levels after deferoxamine administration (DAI) showed a negative relationship with serum iron levels (r = -0.23; P < 0.05) and iron transferrin saturation (r = -0.26; P < 0.05). The correlations improved when analysis of this study included only those patients with high serum iron levels or high iron transferrin saturation (r = -0.55). Patients with low probability of having aluminum overload (serum iron levels < 40 micrograms/L and DAI < 150 micrograms/L) had significantly higher values of serum iron, iron transferrin saturation, and serum ferritin levels compared with those patients with a high probability of having aluminum overload (serum aluminum levels > 40 micrograms/L and DAI > 150 micrograms/L). The study presented here suggests that patients who have indicators of iron repletion would tend to have lower increases in serum aluminum levels after the challenge with deferoxamine and presumably a higher incidence of false negative results with the deferoxamine test. These findings indicate that iron measurements must be always taken into account when interpreting the deferoxamine test.

Lower extremity manifestations of vibrio vulnificus infection

Vibrio vulnificus is a potentially lethal marine bacterium that has not been previously described in podiatric literature. A review of the microorganism's characteristics, susceptible patient population, and lower extremity manifestations of infection is presented. V. vulnificus is found as part of the normal flora of the Gulf of Mexico, Atlantic, and Pacific coastal waters and is often isolated from the filter feeding shellfish of these regions. Its pathogenicity is generally reserved for the immunocompromised host, and is specifically related to disease states which exhibit high serum iron levels. V. vulnificus infections present in two distinct clinical syndromes: primary sepsis secondary to raw oyster ingestion, or localized infection from wound exposure to V. vulnificus-inhabited salt water. Both syndromes demonstrate characteristic skin lesions of the trunk and extremities that present as hemorrhagic bullae and progress to necrotic ulcerations. Although V. vulnificus infection is rare, its extreme virulence in patients suffering from a chronic disease process and its manifestation of characteristic lower-extremity lesions require the podiatric physician to be able to recognize and treat such a condition.

Serum bleomycin-detectable iron in patients with thalassemia major with normal range of serum iron.

"Free" iron, a potentially radical-generating low mass iron, and not found in normal human blood, was increased in the serum of blood-transfused thalassemia major patients seen in the Yangon General Hospital, Yangon, Myanmar (Burma). The low mass iron was detected by the bleomycin assay. Fifty-one blood samples were analyzed (from 28 males and 23 females). High "free" iron was detected in 47 sera samples from thalassemia patients. Serum ferritin, which reflects the body store iron, was higher than the normal range (10-200 ng/ml) in 49 patients. On the other hand, serum iron of 39 sera samples fell within the normal range (50-150 micrograms/dl). Four were less than 50 micrograms/dl and eight were more than 150 micrograms/dl. Almost all the patients' sera of normal or higher serum iron level contained "free" iron. Thus, almost all the sera from thalassemic patients from Myanmar contain bleomycin-detectable iron, even when serum iron is within the normal range. In developing countries where undernutrition is prevalent (serum albumin in these patients was 3.6 +/- 0.4 g/dl, P < 0.0001 vs. control value of 4.0 - 4.8 g/dl), normal serum iron does not preclude the presence of free iron in the serum.

Significance of serum iron levels as a biochemical marker in pregnancy-induced hypertension

OBJECTIVE: To determine the changes in serum iron levels, if any, as a biochemical marker of pregnancy-induced hypertension (PIH). METHOD: Fifty-four primigravidas with PIH formed the study group and 20 normotensive primigravidas comprised the control group in a prospective study. Serum iron levels were estimated at diagnosis of PIH, at termination of pregnancy and in the postpartum period. Data was analyzed using Student's t-test, the X 2-test and regression analysis. RESULTS: Subjects with PIH were found to have higher serum iron levels at diagnosis of PIH (recruitment value) and at termination of pregnancy than the controls ( P < 0.001). Serum iron levels in the PIH subjects decreased markedly in the postpartum period simultaneously with the clinical recovery from PIH. Serum iron values of ≥ 110 gg/dl was found to differentiate PIH from normotensive pregnancies with a sensitivity and specificity of 89% and 90%, respectively. CONCLUSIONS: Changes in serum iron levels correlated with the clinical course of PIH and appeared to be a uniform and specific biochemical marker of PIH although its correlation with the severity of PIH was found to be poor.

Distribution of radioiron in larval lampreys, Petromyzon marinus L., following administration of 55ferrous citrate

Light microscopic autoradiography and quantitative tissue analyses were used to examine the distribution of radioiron in larvae (ammocoetes) of the lamprey Petromyzon marinus L. over time following the injection of 55ferrous citrate (55Fe). It was found that a single intraperitoneal injection of 55Fe is an efficient method of introducing iron into ammocoetes, and radioiron retention within the body remained high throughout the 28-d experiment. Immediately after radioiron administration the isotope was transported in the serum fraction of the blood to sites of iron storage and elimination. The liver is the most important target organ for iron in ammocoetes, and radioiron acquired from the alimentary canal, skin, carcass, and blood contributed to the initial increase in this organ. Data indicated only temporary storage in the liver; between 3 and 16 d, radioiron was redistributed by the blood to the skin, kidney, alimentary canal, and carcass. Biliary transport of radioiron from the liver to the lumen of the anterior intestine may also explain the lowering of iron concentrations in the liver and the rise in levels in the alimentary canal during this interval. The redeposition of 55Fe in the liver at 16 d may signify longer-term storage of the metal in this organ. There is movement of radioiron in and out of the carcass tissues over time, and most of the radioactivity is localized in the adipose tissue. The epithelial cells of the proximal tubules of the kidney absorb and concentrate the radioiron presumably present in the glomerular filtrate. This concentration probably reflects both the absorption of iron bound to ferritin and a mechanism necessary for maintaining the high serum iron levels of ammocoetes. The release of mucus from iron-laden mucous cells of the skin and exfoliation of radioiron-laden epithelial cells in specific regions of the posterior intestine are possible routes for iron elimination. However, percent incorporation of the injected radioactivity was still high at the end of the experiment, indicating that iron excretion in ammocoetes is relatively low or that it is a slow process. These data support the notion that lampreys provide a useful animal model for the study of iron metabolism in vertebrates.

An Improved Method for Determining the Microbial Inhibitory Activity of Serum and Its Application to the Study of Patients with Leukemia

Numerous investigators have demonstrated that derangements in serum transferrin and iron can contribute to susceptibility to infection, but the complexity and imprecision of assays have impeded both research and development of clinical testing in this area. This article describes an automated assay for measuring the microbial inhibitory activity of transferrin in serum and its use in patients with acute myelogenous leukemia (AML) and in normal controls. The assay measured the ability of heat-inactivated serum to inhibit the growth of an antibiotic-resistant strain of Pseudomonas aeruginosa. The serum dilutions were prepared in a special low iron chemically defined broth. An inhibition index, the reciprocal of the serum dilution producing 50% inhibition of bacterial growth when compared with the growth in broth alone, was determined. The results showed the serum from the patients with leukemia had a significantly lower inhibition index than that of controls (16 +/- 11 vs. 35 +/- 13, P less than 0.01). In addition, they had higher serum iron levels (162 +/- 65 vs. 75 +/- 27, P less than 0.01), lower serum transferrin levels (231 +/- 65 vs. 309 +/- 71, P less than 0.01), and higher percentage saturation of transferrin with iron (59 +/- 21 vs. 20 +/- 8, P less than 0.01) than did controls. Because the assay uses equipment available in many clinical laboratories, it could be developed for routine use as an index of susceptibility to infection in selected patients.

Model of reticuloendothelial iron metabolism in humans: abnormal behavior in idiopathic hemochromatosis and in inflammation

Iron transport in the reticuloendothelial (RE) system plays a central role in iron metabolism, but its regulation has not been characterized physiologically in vivo in humans. In particular, why serum iron is elevated and RE cells are much less iron-loaded than parenchymal cells in idiopathic hemochromatosis is not known. The processing of erythrocyte iron by the RE system was studied after intravenous (IV) injection of 59Fe heat-damaged RBCs (HDRBCs) and 55Fe transferrin in normal subjects and in patients with iron deficiency, idiopathic hemochromatosis, inflammation, marrow aplasia, or hyperplastic erythropoiesis. Early release of 59Fe by the RE system was calculated from the plasma iron turnover and the 59Fe plasma reappearance curve. Late release was calculated from the ratio of 59Fe/55Fe RBC utilization in 2 weeks. The partitioning of iron between the early (release from heme catabolism) and late (release from RE stores) phases depended on the size of RE iron stores, as illustrated by the inverse relationship observed between early release and plasma ferritin (P less than .001). There was a strong correlation between early release and the rate of change of serum iron levels during the first three hours in normal subjects (r = .85, P less than .001). Inflammation produced a blockade of the early release phase, whereas in idiopathic hemochromatosis early release was considerably increased as compared with subjects with similar iron stores. Based on these results, we describe a model of RE iron metabolism in humans. We conclude that the RE system appears to determine the diurnal fluctuations in serum iron levels through variations in the immediate output of heme iron. In idiopathic hemochromatosis, a defect of the RE cell in withholding iron freed from hemoglobin could be responsible for the high serum iron levels and low RE iron stores.