Secondary Iron Overload Research Articles

Iron body stores in patients treated with red-cell transfusions

Background: Consequence of chronic transfusion therapy is a secondary iron overload, which adversely affects the heart, liver and endocrine glands. This can be minimized by iron chelating therapy. The assessment of iron overload is essential to assign and adjust this treatment. Serum ferritin is a widely used marker for the estimation of iron stores. However, a variety of conditions alter the relationship between serum ferritin levels and body iron stores. Soluble transferrin receptors in serum (sTfR) reflect the degree of erythropoiesis and the status of body iron. The data on usage of serum transferrin receptors for the assessment of iron overload are sparse. The purpose of our work was to estimate iron overload in transfusion dependent patients and to assess the combinative value of serum transferrin receptors and ferritin in prediction of iron load. Methods: Serum levels of iron, transferrin saturation, ferritin and sTfR were evaluated for 36 transfusion dependent patients. Twenty of them had myelodysplastic syndrome (MDS). Body iron (mg/kg) was calculated from the sTfR/ferritin ratio with the use of regression formula developed by Cook et al. Levels of serum parameters and calculated body iron were compared with estimated iron overload. We used absolute number of transfused units of blood as a measure of iron overload. Results: Serum ferritin above 1000 ug/L and above 2000 ug/L was found in 69 % and in 47 % of transfusion dependent patients. For MDS patients these levels were found in 85 % and 65 %. Concentration of sTfR was lower in the group of patients than it was in control group of healthy people (p = 0.001). We found a significant inverse correlation between sTfR and transferrin saturation. The estimated iron overload correlates well with serum ferritin (n = 0.66, p 1000 ug/L and good prognosis (subgroup of MDS) should need intensification of chelating treatment. In this study we didn’t find any advantages of calculating body iron in comparison to measuring serum ferritin levels for the estimation of iron overload.

HFE gene in primary and secondary hepatic iron overload.

Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe (HFE) gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and non-alcoholic fatty liver diseases and porphyria cutanea tarda. We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis.

Correlation between Dose-Dependent Reductions in Serum Transaminase (ALT) and Serum Ferritin Levels during Long-Term Chelation Therapy with Deferasirox (Exjade®, ICL670).

Introduction: Hepatic siderosis, a result of chronic transfusion therapy, leads to hepatocellular injury and progression to chronic liver disease. Increases in serum transaminase levels are indicative of progressive liver damage. The effect of deferasirox (Exjade®, ICL670), a novel, once-daily oral chelator, on liver iron content and pathology in chronically transfused patients has been assessed in Phase II and III clinical studies. A sub-analysis of pooled data from the planned 4-year extension of two pivotal studies sought to correlate the long-term changes in serum ALT levels with those of serum ferritin in iron-overloaded patients during treatment with deferasirox.Methods: In these two clinical studies, 480 patients with β-thalassemia (β-thal), myelodysplastic syndromes (MDS), Diamond-Blackfan anemia (DBA), and other transfusion-dependent anemias received deferasirox at 5, 10, 20 or 30 mg/kg/day according to baseline liver iron concentrations for 12 months. In the extension phases, doses were titrated according to patient response, with dose escalation for patients who did not receive sufficient drug in the core study to reduce iron burden. Serum ferritin and ALT levels were assessed at baseline and monthly during the core and extension phases. For this analysis, serum ferritin and ALT levels were analyzed in the combined patient groups who received deferasirox 5 and 10 mg/kg/day, and in those who received 20 and 30 mg/kg/day.Results: Throughout the entire period, deferasirox at 20 and 30 mg/kg/day resulted in a negative iron balance in transfused patients with secondary iron overload. Changes from baseline to week 128 (2.5 years) for serum ferritin and ALT levels are presented. The figure shows that deferasirox at 20 and 30 mg/kg/day decreased median serum ferritin. These decreases were mirrored by decreases in ALT, with a Spearman's rank-correlation 0.67. Patient numbers shown are baseline/week 128. A number of patients had not reached week 128 of treatment at the time of data cut-off. [Display omitted] Decreases in ALT were also observed after dose escalation in the extension phase in patients originally assigned deferasirox 5 and 10 mg/kg/day. There were no consistent relevant changes in other biochemical liver parameters, such as serum aspartate transaminase, in this patient population.Conclusions: With long-term follow-up of this large patient population, correlation between decreases in serum ferritin and ALT levels was high, indicating an association between iron burden and liver dysfunction, and further emphasizing the potential beneficial effect of deferasirox on hepatic function.

Iron Does Not Cause Arrhythmias in the Guinea Pig Model of Transfusional Iron Overload.

Cardiac events, including heart failure and arrhythmias, are the major cause of death in patients with b-thalassemia. Although cardiac arrhythmias in humans are believed to result from iron overload, excluding confounding factors in the human population is difficult. The purpose of these studies was to evaluate the development of cardiac arrhythmias using the guinea pig model of secondary iron overload. Electrocardiograms were recorded via surgically implanted telemetry devices in guinea pigs loaded intraperitoneally with iron dextran and controls. Cardiac and liver iron concentrations were significantly elevated in the iron loaded animals when compared to control, and were in the range of those reported for humans with thalassemia. Arrhythmias were noted infrequently in both iron loaded and control guinea pigs. No life threatening arrhythmias were detected in either group. These data suggest that iron alone may be insufficient to cause cardiac arrhythmias, and that arrhythmias detected in individuals with iron overload may be the result of a complex interplay of factors.

Summary of Long-Term Renal Safety Data in Transfused Patients with Secondary Iron Overload Receiving Deferasirox (Exjade®, ICL670).

^Renal Safety Board (RSB) memberIntroduction: Deferasirox has been evaluated in a series of 1-year clinical trials in patients with a variety of transfusion-dependent anemias. Mild, non-progressive increases (ie initial rises, then stabilization) in serum creatinine >33% above baseline were observed in approximately one-third of patients receiving deferasirox. Following completion of the core trials, patients have entered 4-year extension phases to evaluate the long-term safety and efficacy of deferasirox. This is an analysis of renal function in patients receiving deferasirox in two ongoing extension phases.Methods: Initial deferasirox dose was assigned by baseline iron burden in the core trials, and tailored to meet individual patient needs in the extension phases. Serum creatinine and urinary protein/creatinine ratios were measured monthly. Creatinine increases >33% above baseline on ≥2 consecutive values, ≥7 days apart, were selected by the RSB for dose review.Results: Of the 480 patients who initially received deferasirox, 387 entered the extension phases and 334 were on treatment at the time of analysis; the median duration of treatment was 2.5 years. In patients who started on deferasirox 20 and 30 mg/kg/day, non-progressive, dose- and iron intake-dependent creatinine increases were noted by week 4 (Figure). In patients who initially received deferasirox 5 and 10 mg/kg/day, a small, non-progressive increase also occurred near week 52, coinciding with dose escalation to 20 or 30 mg/kg/day. These patterns were consistent irrespective of age or underlying anemia. Similar trends were observed with creatinine clearance. Of the 480 patients, creatinine levels increased marginally above the upper limit of normal (ULN) at some point during the 2.5-year observation period in 12.1%. With or without dose reduction, most (72.4%) returned <ULN, 5% fluctuated around ULN and 15.5% stabilized slightly >ULN. No follow-up information was available in 7.1% of patients at the time of data cut-off. [Display omitted] These non-progressive creatinine increases were generally reversible with dose modification/interruption. In 36 episodes of treatment interruption, preceded by creatinine increases >33% above baseline, overall median creatinine levels decreased from 77.8 to 62.8 μmol/L. Levels fell below the <33% limit in 25 episodes, and decreased rapidly but remained >33% above baseline in the remaining 11, where treatment was either resumed early or the patient was off-treatment at the time of analysis. Ten patients (1.0%) had urinary total protein/creatinine ratio >1.0 at two consecutive visits.Conclusions: This 2.5-year analysis of renal function in patients receiving deferasirox confirms that early changes in creatinine/creatinine clearance observed in 1-year core trials are non-progressive with continued treatment. The small changes in creatinine/creatinine clearance noted when patients were dose-escalated from 5/10 mg/kg/day at the end of the core trials, were also non-progressive. These changes were manageable with appropriate dose modification.

SI33 Implications and Management of Iron Overload in Myelodysplastic Syndromes

According to evidence‐ and consensus‐based practice guidelines, the majority of patients with myelodysplastic syndrome (MDS) should receive supportive therapy at present. Once anemia is symptomatic, red cell transfusions are the mainstay of therapy. The life expectancy of patients with isolated erythroid dysplasia aged 70 years or older is not significantly shorter than that of the general population; avoiding disease complication is therefore very important in these individuals. Recently we demonstrated that the development of red cell transfusion‐dependency significantly affects survival of MDS patients (Malcovati et al. J Clin Oncol 2005; 23: 7594–603). This partly reflects the severity of bone marrow failure; however, development of secondary iron overload significantly worsens survival of transfusion‐dependent patients. Considering patients with transfusion needs, iron overload (defined as serum ferritin above 1000 ng mL−1) is developed after receiving a median number of 20–25 RBC units. The effect of iron overload is mainly noticeable among patients with refractory anemia, who have a longer survival and therefore are more prone to develop the adverse effects of iron overload. In contrast, secondary iron overload does not affect the survival of patients with refractory cytopenia, who have a median survival of about 50 months. The negative effect of iron overload is significantly associated with serum ferritin levels, with a 40% increase in hazard for every 500 ng mL‐1 of increase in serum ferritin. According to the currently available therapeutic guidelines iron chelation should be considered once a patient has received 20–50 units of red cells, but only in patients for whom long‐term transfusion therapy is likely, or when an allogeneic stem cell transplantation is planned. The target serum ferritin concentration should be &lt;1000 ng mL‐1. Desferrioxamine 20–40 mg kg‐1 per day should be administered by 12 h subcutaneous infusion or by two daily subcutaneous bolus administrations for 5 days per week. Recently, deferasirox (ICL670) has proved to be an effective oral iron chelator in patients with thalassemia major and in those with MDS. In 2005, the USA Food and Drug Administration has approved deferasirox for treatment of chronic iron overload due to multiple blood transfusions. A European Medicines Agency (EMEA) decision is waited in 2006.

Association between serum ferritin and the insulin resistance syndrome in a representative population

Unexplained hepatic iron overload with increased serum ferritin (SF) values has been associated with the insulin resistance syndrome (IRS), defined by the presence of one or more of the following criteria: increased body mass index (BMI), diabetes, hyperlipidemia or hypertension. However, as yet the association between IRS and SF in a representative population has not been investigated. The study subjects participated in a nationwide epidemiological survey on metabolic disorders in the adult German population. The 1200 probands included in this study are representative of the German population. To eliminate major causes of secondary iron overload, 114 (9.5%) subjects with excessive alcohol consumption and 16 (1.5%) subjects with serological evidence for hepatitis B or C were excluded. For all remaining 1070 probands, complete clinical data of SF, HbA1c, known diabetes, BMI, cholesterol, high-density lipoprotein-cholesterol and blood pressure were available. SF values were significantly increased in men and women with high BMI (> 25 kg/m2), increased cholesterol (> 200 mg/dl), and increased systolic (> 160 mmHg) blood pressure, in women with diabetes, and in men with increased diastolic (> 95 mmHg) blood pressure. Furthermore, there was a significant correlation between the number of IRS criteria and SF. This study shows a significant correlation between SF and the presence of IRS criteria in a large representative population. Interestingly, the severity of the IRS seems to be associated with increased SF levels suggesting a causal connection. Further studies are required to investigate the pathophysiological mechanism and consequences of increased SF levels in patients with IRS.

Iron-Chelating and Free-Radical Scavenging Activities of Microwave-Processed Green Tea in Iron Overload

Secondary iron overload is found in β-thalassemia (thal) patients because of increased dietary iron absorption and multiple blood transfusions. Excessive iron catalyzes free-radical generation, leading to oxidative damage and vital organ dysfunction. Non-transferrin-bound iron (NTBI) detected in thalassemic plasma is highly toxic and chelatable. Though used to treat iron overload, desferrioxamine (DFO) and deferiprone (L1) also have adverse effects. Green tea (GT) shows many pharmacological effects, particularly antioxidative and iron-chelating capacities. This study was performed to investigate the ability of GT extracts to reduce plasma NTBI concentration and oxidative stress in vitro. The Fe3+ was found to bind to GT crude extract and form a complex. Green tea crude extract time- and dose-dependently decreased plasma NTBI concentration and counteracted the increase of oxidative stress in both Fe 2+-EDTA-treated human plasma and erythrocytes. Green tea is a bifunctional natural product that could be relevant for management of iron overload and oxidative stress.

Heavy smoking and liver

Smoking causes a variety of adverse effects on organs that have no direct contact with the smoke itself such as the liver. It induces three major adverse effects on the liver: direct or indirect toxic effects, immunological effects and oncogenic effects. Smoking yields chemical substances with cytotoxic potential which increase necro-inflammation and fibrosis. In addition, smoking increases the production of pro-inflammatory cytokines (IL-1, IL-6 and TNF- alpha) that would be involved in liver cell injury. It contributes to the development of secondary polycythemia and in turn to increased red cell mass and turnover which might be a contributing factor to secondary iron overload disease promoting oxidative stress of hepatocytes. Increased red cell mass and turnover are associated with increased purine catabolism which promotes excessive production of uric acid. Smoking affects both cell-mediated and humoral immune responses by blocking lymphocyte proliferation and inducing apoptosis of lymphocytes. Smoking also increases serum and hepatic iron which induce oxidative stress and lipid peroxidation that lead to activation of stellate cells and development of fibrosis. Smoking yields chemicals with oncogenic potential that increase the risk of hepatocellular carcinoma (HCC) in patients with viral hepatitis and are independent of viral infection as well. Tobacco smoking has been associated with suppression of p53 (tumour suppressor gene). In addition, smoking causes suppression of T-cell responses and is associated with decreased surveillance for tumour cells. Moreover, it has been reported that heavy smoking affects the sustained virological response to interferon (IFN) therapy in hepatitis C patients which can be improved by repeated phlebotomy. Smoker's syndrome is a clinico-pathological condition where patients complain of episodes of facial flushing, warmth of the palms and soles of feet, throbbing headache, fullness in the head, dizziness, lethargy, prickling sensation, pruritus and arthralgia.

Peroxidative stress and antioxidant enzymes in children with β‐thalassemia major

Regular blood transfusions and secondary iron overload make thalassemic erythrocytes prone to peroxidative injury. Although some reports suggest endogenous free radical damage in thalassemia, there remains discrepancy in the status of antioxidant enzymes. The aim of this study was to evaluate the extent of lipid peroxidation and status of antioxidant enzyme in children with beta-thalassemia. Fifty transfusion-dependent beta-thalassemics were subjected to analysis of lipoperoxides as malondialdehyde (MDA), nitric oxide (NOx), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GPx) along with serum iron and ferritin, liver functions and uric acid. Plasma MDA was analyzed to indicate the oxidative parameters, whereas the erythrocyte SOD, GPx, and plasma NOx were measured to show the antioxidant status of the children. All these parameters in 30 non-anemic healthy controls attending the child health promotion clinic of hospital were also studied. All the patients were iron overloaded. Markers of free radical injury such as MDA and antioxidant enzyme SOD and NOx levels were significantly elevated in thalassemic children while mean GPx levels were decreased in patients compared to controls (P < 0.001). All these markers significantly correlated with serum ferritin levels. There was no significant difference in levels of GSH measured but it correlated with serum iron levels. Our study results suggest that iron overload causes peroxidative damage in beta-thalassemia and antioxidant systems try to compensate for reducing lipid peroxidation to lower tissue damage.

The Effect of Transfusion Dependency and Secondary Iron Overload on Survival of Patients with Myelodysplastic Syndrome.

According to evidence- and consensus-based practice guidelines (Haematologica 2002; 87:1286–306), red cell transfusion is the therapy of choice for the majority of patients with myelodysplastic syndrome (MDS) and symptomatic anemia. Previous studies have shown that widespread organ dysfunction can result from transfusion iron overload developing in non-thalassemic adults (Schafer et al, N Engl J Med 1981; 304:319–24; Cazzola et al, Blood 1988; 71:305–12). In this study, we evaluated the effect of transfusion dependency and secondary iron overload on survival of MDS patients classified according to WHO criteria. Four hundred and sixty-seven consecutive patients with a diagnosis of de novo MDS made at the IRCCS Policlinico San Matteo, University of Pavia Medical School, Pavia, Italy, between 1992 and 2002 were retrospectively evaluated and reclassified according to the WHO criteria. The effects that developing transfusion dependency or secondary iron overload had on survival were evaluated by applying Cox proportional hazards regression with time-dependent covariates. Transfusion-dependent patients had a significantly shorter overall survival (OS) and leukemia-free survival (LFS) than did patients who did not become transfusion-dependent (HR=2.16, P<.001 and HR=2.02, P<.001, respectively). Transfusion burden, calculated as the number of transfusions per month, was found to have a significant effect on both OS (HR=1.35, P<.001) and LFS (HR=1.75, P<.001). These effects were maintained after accounting for cytogenetics. We then assessed the survival of transfusion-dependent and non-transfused patients considering non-leukemic death as an end-point. In the first 50 months of follow-up transfusion-dependent patients had a significantly worse survival than those who did not require transfusions (HR=1.98, P=.01). Cardiac failure was significantly more frequent in transfusion-dependent patients (P=.01). Focusing the analysis on WHO subgroups, transfusion requirement affected both the OS and LFS of patients with RA, RARS or MDS with del(5q) (HR=1.54, P<.001 and HR=1.44, P=.05, respectively), and of those with RCMD or RCMD-RS (HR=1.87, P=.04 and HR=1.54, P=.02, respectively), while it showed no effect on the survival of RAEB patients. Finally, we evaluated the prognostic value of patients with MDS developing iron overload during their follow-up. The development of secondary iron overload significantly affected survival (P<.001) with a HR of 1.36 for every 500 ng/mL increase in serum ferritin. The effect of iron overload was maintained after adjusting for transfusion burden (HR=1.30, P=.003). With respect to WHO subgroups, the effect of secondary iron overload was still present in patients with RA/RARS (HR=1.51, P<.001), while it was not significant in those with RCMD/RCMD-RS (HR=1.34, P=.20). In conclusion, these findings show that the development of transfusion dependency significantly worsens the survival of MDS patients. Although this poor prognosis partly reflects the severity of bone marrow failure, our observations also suggest that development of secondary iron overload per se can worsen survival of transfusion-dependent patients. These individuals may therefore considerably benefit from therapeutic approaches aimed at reducing transfusion needs and/or at preventing secondary iron overload.

Quantitative evaluation of oxidative stress status on peripheral blood in β‐thalassaemic patients by means of electron paramagnetic resonance spectroscopy

High oxidative stress status (OSS) is known to be one of the most important factors determining cell injury and consequent organ damage in thalassaemic patients with secondary iron overload. Using an innovative hydroxylamine 'radical probe' capable of efficiently trapping majority of oxygen-radicals including superoxide we measured, by electron paramagnetic resonance (EPR) spectroscopy, OSS in peripheral blood of 38 thalassaemic patients compared with sex-/age-matched healthy controls. Thalassaemic patients showed sixfold higher EPR values of OSS than controls. Significantly higher EPR values of OSS were observed in those with a severe phenotype (thalassaemia major, transfusion-dependent) with respect to mild phenotype (sickle-cell/beta-thalassaemia, not transfusion-dependent) or thalassaemia intermedia. In patients with thalassaemia major, EPR values of OSS were positively correlated with serum ferritin and with alanine aminotransferase levels. In patients with sickle cell/beta-thalassaemia, there was no correlation between EPR value of OSS and all parameters considered. The type of chelating therapy (desferrioxamine or deferiprone) did not have an effect on EPR value of OSS. In conclusion, EPR 'radical probe' seems to be a valid innovative method to determine total OSS in patients affected by thalassaemia and might be used for evaluating new strategies of chelation, new chelators, or the efficacy of antioxidant formula.

Transfusional hemosiderosis and combined chelation therapy in sickle thalassemia

Although the indications for transfusions in sickle cell syndromes are well listed, and chronic transfusion has become practicable since the recent advances in chelation therapy have essentially eliminated the risk of secondary iron overload, multi-transfused, non-compliant to long-term chelation therapy patients confront the complication of iron overload and secondary hemosiderosis. In thalassemia major patients, combined therapy with desferrioxamine and deferiprone has maximized tissue iron removal and may reduce the overall occurrence of hemosiderotic heart failure. Despite this, safety and contradictions of chelating agents are still controversial. The aim of this report is to present the results of this combination in a long-term transfused sickle beta-thalassemic patient suffering from severe heart failure and liver dysfunction.

Pathways for the regulation of body iron homeostasis in response to experimental iron overload

Secondary iron overload is a frequent clinical condition found in association with multiple blood transfusions. To gain insight into adaptive changes in the expression of iron genes in duodenum, liver and spleen upon experimental iron overload we studied C57BL/6 mice receiving repetitive daily injections of iron-dextran for up to 5 days. Iron initially accumulated in spleen macrophages but with subsequent increase in macrophage ferroportin and ferritin expression its content in the spleen decreased while a progressive storage of iron occurred within hepatocytes which was paralleled by a significant increase in hepcidin and hemojuvelin expression. Under these conditions, iron was still absorbed from the duodenal lumen as divalent metal transporter-1 expressions were high, however, most of the absorbed iron was incorporated into duodenal ferritin, while ferroportin expression drastically decreased and iron transfer to the circulation was reduced. Experimental iron overload results in iron accumulation in macrophages and later in hepatocytes. In parallel, the transfer of iron from the gut to the circulation is diminished which may be referred to interference of hepcidin with ferroportin mediated iron export, thus preventing body iron accumulation.

Junge Patientin mit Diabetes mellitus, kleinknotiger Leberzirrhose, hoher Transferrin-Sättigung und negativem HFE-Test

A 28 year young female presented to our hospital for further evaluation with recently diagnosed diabetes mellitus, hyperpigmentation of the skin, hepato- and splenomegaly, thrombocytopenia and an elevated transferrin saturation (96 %), but a negative test for HFE gene mutations such as C282Y and H63D. Using the mini-laparascopic technique we diagnosed a smallnodular liver cirrhosis with an iron overload. This is the clinical presentation of one subtype of the so called Non-HFE-hemochromatosis, the juvenile hemochromatosis (HFE2). Other causes of primary and secondary iron overload have been ruled out. Different from the HFE-positive hemochromatosis (HFE 1) in which the gene defect is located on chromosome 6, the defect in HFE 2 is located on chromosome 1. The underlying genetic defect has been localized within recently identified HJV gene. Phlebotomy is the treatment of choice, to be performed until the ferritin level is lower than 50 microg/l. If liver cirrhosis is present in hemochromatosis, the overall risk of developing heptatocellular carcinoma is 20 times higher than in the normal population. Therefore it is suggested to perform an ultrasound examination of the liver and an AFP-test every 6 months, whereas an MRI-scan should be performed once a year, as a basis for further treatment options.

Liver cirrhosis as a consequence of iron overload caused by hereditary nonspherocytic hemolytic anemia

Nonspherocytic hereditary anemias are occasionally accompanied by significant iron overload but the significance for the development of chronic liver disease is not clear. We described two cases of patients with chronic liver disease and severe iron overload due to chronic hereditary hemolysis. Both patients have had signs of liver cirrhosis and severe hemolysis since childhood. A hereditary pyruvate kinase deficiency (PKD) was discovered as the underlying reason for the hemolysis. Sequencing of the pyruvate kinase gene showed a mutation within exon 11. Liver histology in both patients revealed cirrhosis and a severe iron overload but primary hemochromatosis was excluded by HFE-gene analysis. An iron reduction therapy with desferrioxamine led to significant decrease of serum ferritin and sustained clinical improvement. PKD-induced hemolysis may cause severe iron overload even in the absence of HFE-genotype abnormalities. This secondary iron overload can lead to chronic liver disease and cirrhosis. Therefore, the iron metabolism of PKD patients has to be closely monitored and iron overload should be consequently treated.

Liver iron concentration and fibrosis in a cohort of transfusion-dependent patients on long-term desferrioxamine therapy

Secondary iron overload is associated with significant mortality and morbidity. Although new, less invasive techniques are becoming available, the most acceptable and readily accessible way to assess iron overload is to measure hepatic iron by liver biopsy. In this study, we report on serial liver biopsies (at least 2) in a cohort of transfusion-dependent patients (49) on long-term desferrioxamine treatment. There was no significant change in liver iron concentrations (LIC) even in the medication-compliant patients, although there was an upward trend (not statistically significant) in the poorly compliant patients. Fibrosis was present in both HCV RNA-positive and -negative patients, but was more common in positive patients and there was also a significant relationship between fibrosis and hepatic iron concentration. Liver iron levels appear to be maintained in patients who are compliant to desferrioxamine treatment, but overall there is little evidence of significant improvement in liver iron in these patients and in the group as a whole.

Safety of Liver Biopsies in Children with Transfusional Iron Overload.

Secondary iron overload, caused by chronic transfusions, is common among patients who have chronic hemolytic disorders, especially sickle cell disease and thalassemias. Accurate assessment of the hypertransfused patient's body iron burden is important in deciding when and whether to start chelation therapy in order to prevent iron -related toxicities such as heart failure and endocrine abnormalities. The gold standard to measure iron content is through a liver biopsy. Though shown to be safe, many physicians are still reluctant to use this invasive approach in children to evaluate liver iron content.Study Design: A retrospective chart review of chronically transfused patients at Texas Children's Hospital (1998–2003) was performed to assess possible biopsy complications, including pain, hemorrhage, bilious peritonitis, puncturing of other organs, and bacterial infections, in patients with hemolytic disorders. The study was approved by the Institutional Review Board.Results: There were 65 biopsies, 43 patients had one biopsy and 11 patients had two biopsies. 56 % were male, 44 % were female; 52% (28/54) were African American, 15 % (8/54) were Oriental/Asian, and 22 % (12/54) were Hispanic. 30 patients (56%) had sickle cell disease, 16 (30%) thalassemias, 5 (14%) other forms of anemia, 1 patient had leukemia, and 1 had lymphoma with the sickle cell trait. Eight of these patients (15%) are not on or have never been on chelation therapy, 11 (20%) used to be on chelation therapy, 35 (65%) are currently on chelation therapy. The average age when the first biopsy was performed was 11 years (range 2 to 18.9 years); and the average age at the time of the second biopsy was 12.7 years (range, 5.8 to 21.1 years). The reasons for their biopsies included possible iron overload due to hypertransfusions, pre-bone marrow transplant evaluation, and elevated liver enzymes. The average serum ferritin level before biopsy was 2681.8 ng/mL ranging from 348 to 35,332 ng/mL, and the average liver iron content (LIC) determined through biopsy was 12,278 ug/g dry wt. Ultrasound guidance was used for all 65 biopsies; 46 (71%) biopsies were done percutaneously, 8 (12%) laparoscopically, and 6 (10%) through an open procedure. There were no complications during the biopsy. There were no major and only 5 minor complications after the biopsy: 3 patients (5%) had transient abdominal pain at the biopsy site which subsided over a couple of days, and 2 (3%) had a fever with other (non-biopsy-related) complications requiring an increased hospital stay.Conclusions: Liver biopsies in the pediatric population are safe and feasible and they should be considered for the accurate assessment of iron content in chronically transfused patients. Certain factors contributing to the success of the biopsies include having an experienced physician, using ultrasound guidance, and fully informing the patient or patient's parents about the biopsy before the procedure.

Iron Chelators in Cancer Chemotherapy

Iron chelators may be of value as therapeutic agents in the treatment of cancer. They may act by depleting iron, a necessary nutrient, and limiting tumor growth. Alternatively or additionally, they may form redox-active metal complexes that cause oxidative stress via production of reactive oxygen species, damaging critical intracellular targets and thereby eliciting a cytotoxic response. Studies in vitro have evaluated the structure-activity relationships and mechanism of action of many classes of iron chelators, including desferrioxamine (DFO), pyridoxal isonicotinoyl hydrazone (PIH) analogs, desferrithiocin (DFT) analogs, tachpyridine, the heterocyclic carboxaldehyde thiosemicarbazones, and O-Trensox. Animal studies have confirmed the antitumor activity of several chelators. Dexrazoxane has been approved for use in combination with doxorubicin, and its effectiveness in allowing higher doses of doxorubicin to be administered is, in part, based on the interactions of both drugs with iron. Clinical trials of the antitumor activity of chelators have been largely limited to DFO, which has been extensively studied as a consequence of its approved use for treatment of secondary iron overload. While the modest antitumor effects of DFO are encouraging, it is likely that more effective iron chelators may be identified.

Association of Liver Hemangiosarcoma and Secondary Iron Overload in B6C3F1 Mice?The National Toxicology Program Experience

Association of Liver Hemangiosarcoma and Secondary Iron Overload in B6C3F1 Mice?The National Toxicology Program Experience