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Introduction: Hereditary hemochromatosis is an autosomal recessive disorder of iron absorption, leading to organ dysfunction. C282Y gene homozygosity is implicated in 80%-95% of cases of hereditary hemochromatosis. The clinical penetrance of this genotype remains unclear. The purpose of the study was to better describe the clinical penetrance and disease progression of C282Y homozygotes., Methods: This is a retrospective study of all individuals in Newfoundland and Labrador, Canada, homozygous for the C282Y mutation from 1999 to 2009. Using electronic health records, laboratory values, phlebotomy status, radiologic reports, and clinic records were recorded up to November 2017. Iron overload status was classified via the HealthIron study. SPSS Version 19.0 (IBM Corporation) was used for descriptive statistics. Predictors of disease penetrance were assessed with logistic regression; a Student t test was used for continuous variables, and χ tests were used for categorical variables., Results: Between 1999 and 2009, 360 individuals tested positive for C282Y/C282Y. The mean age of diagnosis was 49.1 years. Three hundred six individuals had adequate follow-up for analysis (mean 11.6 years). End-organ damage was observed in 18.3%, with 5.8% developing liver disease. End-organ damage was more frequently observed in men 24.3% vs 10.5% (P < 0.05). Clinical penetrance in postmenopausal women approached that of men 18.3%., Discussion: This is the largest reported cohort of C282Y homozygotes, followed for an extended duration of time in North America. The findings reflect outcomes in routine clinical practice and suggest that C282Y homozygosity uncommonly causes end-organ damage and liver disease.

Objective: The study evaluates the long-term deferasirox treatment of adult and pediatric patients with chronic transfusional iron overload in clinical practice., Methods: In this non-interventional study, patients were observed for up to 3 years from initiation of deferasirox treatment both prospectively and retrospectively for up to 1 year prior to enrollment. The primary end points were the proportion of patients with ≥1 notable increase in serum creatinine (SCr), and ≥1 notable increase in alanine aminotransferase (ALT)., Results: Overall, 120 patients were enrolled and 51 completed the study, with a limited 3-year dropout rate of 12.5% due to adverse events (AEs). Increase in SCr > 33% above baseline and the age-adjusted ULN (upper limit of normal) was observed in 14 patients (95%CI, 7.1-19.2). The ALT levels >5 × ULN was observed in 1 patient. Most frequent AEs reported during treatment with deferasirox include gastrointestinal disturbances., Conclusions: The long-term treatment with deferasirox was manageable in most transfusion-dependent patients with no unexpected safety findings. Regular monitoring and an adjusted deferasirox dosing strategy per local labels allowed continued iron chelation treatment and control of transfusional iron in the majority of patients on study.

Objective: The aim of this study was to evaluate the vitamin D-PTH axis in thalassemia major (TM) in relation to hepatic siderosis liver iron content., Design and Participants: In this case-controlled observational study, vitamin D-PTH axis was studied in 158 TM and 84 age and ethnicity-matched healthy nonthalassemic controls attending University College Hospital, London. Patients were classified as 25-hydroxy vitamin D (25-OHD) insufficient and sufficient if the value was less than or greater than 50 nmol/L, respectively. 25-OHD data were evaluated in relation to markers of iron load in TM., Results: In TM, 25-OHD insufficiency was 8-fold higher than the control group (odds ratio [OR], 8.1; 95% confidence interval [CI], 4.3-15.0; P<0.001). Similarly, serum PTH (P<0.001), calcium (P<0.001), and phosphate levels (P<0.05) were also significantly lower in TM compared with the controls. In TM, serum ferritin of >2500 μg/L (OR, 5.3; 95% CI, 2.3-12.3; P<0.01), liver iron of >7 mg/g dry weight (OR, 8.8; 95% CI, 3.5-10.3; P<0.001), and serum alanine aminotransferase of >50 IU/L (OR, 9.7; 95% CI, 4.0-23.5; P<0.001) were independent risk factors for low 25-OHD levels., Conclusions: Our results suggest that TM had a 8-fold higher risk of 25-OHD insufficiency compared with the controls. This was likely to be associated with hepatic hemosiderosis.

Idiopathic pulmonary hemosiderosis is primarily a disorder of childhood, which is characterized by hemoptysis, iron deficiency anemia, and diffuse parenchymal infiltrates on chest x-ray secondary to recurrent attacks of alveolar hemorrhage. It can be diagnosed by showing hemosiderin laden macrophages in bronchoalveolar lavage fluid after other specific causes of diffuse alveolar hemorrhage are definitely excluded. A 5-year-old male patient was admitted to our clinic with sudden-onset pallor during iron therapy given for anemia. While he was being investigated for clinical and laboratory signs mimicking hemolytic anemia, he developed cough and dyspnea. He had infiltrates on chest x-ray and scattered patchy infiltrates in both lungs on high-resolution computed tomography. Hemosiderin laden macrophages were identified in fasting gastric juice and bronchoalveolar lavage fluid. The patient was diagnosed with idiopathic pulmonary hemosiderosis and started corticosteroid therapy.

An increase of the serum ferritin may appear as an incidental finding in asymptomatic patients in the routine laboratory examination. On the one hand, ferritin reflects the iron stores of the body and can therefore indicate an iron overload of various causes. On the other hand, it is an acute phase protein and thus increases in inflammatory and malignant diseases. We aim to describe an approach to the incidental finding hyperferritinemia with possible evaluation strategy and to explain the most important differential diagnoses.

Renal hypoplasia due to a congenitally reduced number of nephrons progresses to chronic kidney disease and may cause renal anemia, given that the kidneys are a major source of erythropoietin in adults. Hypoplastic kidney (HPK) rats have only about 20% of the normal number of nephrons and develop CKD. This study assessed the renal function and hematologic changes in HPK rats from 70 to 210 d of age. HPK rats demonstrated deterioration of renal excretory function, slightly macrocytic erythropenia at all days examined, age-related increases in splenic hemosiderosis accompanied by a tendency toward increased hemolysis, normal plasma erythropoietin levels associated with increased hepatic and decreased renal erythropoietin production, and maintenance of the response for erythropoietin production to hypoxic conditions, with increased interstitial fibrosis at 140 d of age. These results indicate that increases in splenic hemosiderosis and the membrane fragility of RBC might be associated with erythropenia and that hepatic production of erythropoietin might contribute to maintaining the blood Hgb concentration in HPK rats.

Background: Intensive transfusion schedule and iron-chelating therapy prolonged and improved quality of life in patients with β-thalassemia (β-T) major. However, this led to an increased risk of developing impaired glucose tolerance or diabetes. In this study we analyzed variables associated with the occurrence of impaired glucose tolerance or diabetes in patients with β-T major., Methods: 388 Sardinian patients were included. Age, gender, duration of chelation therapy, body mass index, and markers of pancreatic and extrapancreatic autoimmunity were analyzed., Results: Multiple logistic regression analysis showed that anti-thyroid peroxidase (TPO) antibodies (Ab) (OR = 3.36; p = 0.008) and male gender (OR = 1.98; p = 0.025) were significantly associated with glucose impairment, while the other variables were not. Ferritin levels were significantly higher in TPOAb positive compared to TPOAb negative patients (4870 ± 1665 μg/L versus 2922 ± 2773 μg/L; p < 0.0001)., Conclusions: In patients with β-T major a progressive damage of insulin-producing cells due to secondary hemosiderosis appears to be the most reasonable mechanism associated with glucose metabolism disorders. The findings need to be confirmed with additional well designed studies to address the question of whether TPOAb may have a role in the management of these patients.

The ferrokinetic indices of blood serum of rats with acetaminophen-induced hepatitis under the conditions of alimentary deprivation of protein were assessed in the work. Research was conducted on 4 groups of animals: 1 - control; 2 - rats maintained on low-protein diet; 3 - rats with acute acetaminophen-induced hepatitis, maintained on full-value ration, 4 - rats with acute acetaminophen-induced hepatitis, maintained under the conditions of alimentary deprivation of protein. The serum iron content of and serum iron binding capacity were determined colorimetrically,% of the transferrin iron saturation - as a ratio of serum iron concentration to maximal iron binding capacity of serum transferrin. The presence of hemosiderin inclusions and the character of hemosiderosis were determined in the liver sections, stained by Perls method. Qualitative determination of C-reactive protein in blood serum was carried out by immunoenzymatic method. It is shown, that in protein-deficiency rats any significant changes of iron metabolism indices and hemosiderin accumu- lation weren't observed. At the same time in rats with acetaminophen-induced hepatitis the 5-fold increase of the serum iron content against the background non-significant increase of serum iron binding capacity and the 2-fold increase of the transferrin iron saturation is established. Simultaneously in the hepatocytes and reticuloendothelial system cells the accumulation of hemosiderin in the low dispersion form is observed, equating the second degree of hemosiderosis on the background emerging of C-reactive protein in serum. In protein-deficiency rats with toxic liver injury an abrupt increase of serum iron against the background reduction of the total serum iron binding capacity and maximal saturation of transferrin by iron ions is observed. It is established, that for animals from current group the third degree of mixed type hemosiderosis and the intensification of the inflammatory reaction in liver is characterstic. Conclusion was made, that alimentary deprivation of protein under the conditions of toxic liver injury is the critical factor for structural-functional state of liver, being accompanied by the iron metabolism disturbances, development of hemosiderosis and intensification of the inflammatory reaction in liver. Research results may be used for the biochemical rationale of the therapeutic approaches for the elimination and correction of the toxic liver injury consequences.

Rational: Although notification of post-transfusion hemosiderosis is mandatory since 1994 among the French hemovigilance network, it is so far largely under reported., Patients and Methods: We screened 42,443 patients hospitalized for blood diseases in France in 2009 and 2010 and determined which patients had received more than 20 PRC. Among them, we selected those having at least one measure of serum ferritin, and subsequently those which ferritin was greater than or equal to 1000 ng/mL., Results: Three thousand eight hundred and twelve patients (9%) received more than 20 PRC, 1935 (4.5%) had a ferritin assay, which was increased in 1216 patients (2.9%). Eight hundred and eighty-one patients underwent an hemovigilance report form. Forty-nine percent had low-risk myelodysplasia or acute leukemia, 7% hemoglobinopathies. Hemosiderosis was asymptomatic for 680 patients (77%), serious 188 (88%) and life-threatening for 11 (1%). Two patients died of terminal heart failure. The most severe hemosiderosis (≥ grade 2) were low-risk myelodysplasia and idiopathic aplastic anemia. Ninety-two percent of thalassemia patients and 46% of sickle cell anemia patients received an iron chelator. For low-risk myelodysplastic syndromes and idiopathic aplastic anemia, 228 of the 317 patients whose treatment is known and who could benefit from iron chelation (72%) have not received it., Conclusion: These results encourage seeking optimal transmission of information (over 20 CGR) to the clinician, and prolonging hemovigilance action towards a more comprehensive statement of post-transfusion hemochromatosis., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Idiopathic pulmonary hemosiderosis is a rare disorder that can occur at any age and is characterized by the triad of hemoptysis, iron deficiency anemia and diffuse pulmonary infiltrates. The clinical course is exceedingly variable especially in children and a substantial proportion of this age group is undiagnosed. It is probably due to the fact that iron deficiency anemia may be the first and the only manifestation of IPH, preceding other symptoms and signs by several months and IPH is not considered as a rare cause of anemia, unless the typical triad is present. We present a case of IPH in a 13-year-old girl, treated for several months with persistent iron deficiency anemia, without response to therapy.

The combination of marked hypersideremia, hypertransferrinemia, and monoclonal gammopathy of underdetermined significance (MGUS) should alert clinicians to the possible presence of an anti-transferrin immunoglobulin, an uncommon acquired disorder also defined as transferrin-immune complex disease (TICD). The authors have previously described a case of TICD with 100% transferrin saturation and liver iron overload. However, the findings in the few cases so far reported are heterogeneous, and the presence of high transferrin saturation and liver iron overload is not universal. In this article, the authors have described the identification of two additional patients with anti-transferrin monoclonal gammopathy, hypersideremia, and hypertransferrinemia, but with incomplete transferrin saturation and no hepatic iron overload. The autoantibodies were purified by using transferrin as affinity bait and characterized. One subject showed a high-titer monoclonal anti-transferrin IgM with a κ-type light chain. This finding is the first observation of IgM autoantibodies against transferrin. The other patient developed the disease after pregnancy. In this study, monoclonal antibody was an IgG mounting a κ-type light chain with altered molecular weight. These results highlight that transferrin might induce the development of a monoclonal immune response of different classes and specificity. The identification, in a single hematologic center, of three different subjects with anti-transferrin monoclonal gammopathy suggests that the disease probably represents a still underdiagnosed condition. From a clinical standpoint, these patients must be followed up both as MGUS and as hemochromatosis., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Chronically increased intestinal iron uptake in genetic hemochromatosis (HC) may cause organ failure. Whilst iron loading from blood transfusions may cause dilated cardiomyopathy in conditions such as thalassemia, the in-vivo prevalence of myocardial siderosis in HC is unclear, and its relation to left ventricular (LV) dysfunction is controversial. Most previous data on myocardial siderosis in HC has come from post-mortem studies., Methods: Cardiovascular magnetic resonance (CMR) was performed at first presentation of 41 HC patients (58.9 ± 14.1 years) to measure myocardial iron and left ventricular (LV) ejection fraction (EF)., Results: In 31 patients (genetically confirmed HFE-HC), the HFE genotype was C282Y/C282Y (n = 30) and C282Y/H63D (n = 1). Patients with other genotypes (n = 10) were labeled genetically unconfirmed HC. Of the genetically confirmed HFE-HC patients, 6 (19%) had myocardial siderosis (T2* <20 ms). Of these, 5 (83%) had heart failure and reduced LVEF which was correlated to the severity of siderosis (R2 0.57, p = 0.049). Two patients had follow-up scans and both had marked improvements in T2* and LVEF following venesection. Myocardial siderosis was present in 6/18 (33%) of patients with presenting ferritin ≥ 1000 μg/L at diagnosis but in 0/13 (0%) patients with ferritin <1000 μg/L (p = 0.028). Overall however, the relation between myocardial siderosis and ferritin was weak (R2 0.20, p = 0.011). In the 10 genetically unconfirmed HC patients, 1 patient had mild myocardial siderosis but normal EF. Of all 31 patients, 4 had low LVEF from other identifiable causes without myocardial siderosis., Conclusion: Myocardial siderosis was present in 33% of newly presenting genetically confirmed HFE-HC patients with ferritin >1000 μg/L, and was the commonest cause of reduced LVEF. Heart failure due to myocardial siderosis was only found in these HFE-HC patients, and was reversible with venesection. Myocardial iron was normal in patients with other causes of LV dysfunction.

Iron-induced cardiotoxicity remains the leading cause of morbidity and mortality in patients with transfusion-dependent β-thalassemia major. Heart failure in these patients, which may be reversible but has a poor prognosis, is characterized by myocardial iron deposition-related early diastolic dysfunction. Amino-terminal pro-brain natriuretic peptide (NT-proBNP) is a sensitive biomarker for the detection of asymptomatic left ventricular dysfunction. In this study, we prospectively evaluated plasma NT-proBNP levels in 187 adult patients aged 19-54 years with β-TM. Possible correlations with the proposed recently cardiac iron concentration based on an equation derived from heart T2* assessment by MRI: [Fe] = 45.0 × [T2*](-1.22) with [Fe] in milligrams per gram dry weight and T2* in milliseconds were explored. We found that: 143 patients had no cardiac hemosiderosis, defined as [Fe] < 1.1 mg/g dry weight, corresponding to T2* > 20 ms and 44 patients had cardiac hemosiderosis, defined as [Fe] > 1.2mg/g dry weight. The main results of the study showed that: a) NT-proBNP levels were markedly increased in thalassemic patients (152.2 ± 190.1 pg/mL, ranged from 6.0 to 1336.0 pg/mL compared to normal control levels 40.1 ± 19.7 pg/mL, p < 0.001, b) NT-proBNP levels were significantly higher in patients with cardiac hemosiderosis compared to patients without cardiac hemosiderosis (185.1 ± 78.0 vs 128.9 ± 20.2 pg/mL, p < 0.05), c) NT-proBNP levels correlated with [Fe] values (r = 0.387, p < 0.001). This correlation was significant in patients with cardiac hemosiderosis (r = 0.520, p < 0.001), but not in patients without cardiac hemosiderosis (p > 0.1), and d) no significant correlation was found between NT-proBNP levels and left ventricular ejection fraction values, (p > 0.3). Our study demonstrated for first time the significant association of NT-proBNP levels and cardiac iron concentration in patients with β-thalassemia major linking blood chemistry and imaging techniques. Multicenter studies of these parameters during iron chelation therapies are needed to validate their association and further exploit its clinical use., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To assess whether black blood T2* cardiovascular magnetic resonance is superior to conventional white blood imaging of cardiac iron in patients with thalassaemia major (TM)., Materials and Methods: We performed both conventional white blood and black blood T2* CMR sequences in 100 TM patients to determine intra and inter-observer variability and presence of artefacts. In 23 patients, 2 separate studies of both techniques were performed to assess interstudy reproducibility., Results: Cardiac T2* values ranged from 4.5 to 43.8 ms. The mean T2* values were not different between black blood and white blood acquisitions (20.5 vs 21.6 ms, p=0.26). Compared with the conventional white blood diastolic acquisition, the coefficient of variance of the black blood CMR technique was superior for intra-observer reproducibility (1.47% vs 4.23%, p<0.001), inter-observer reproducibility (2.54% vs 4.50%, p<0.001) and inter-study reproducibility (4.07% vs 8.42%, p=0.001). Assessment of artefacts showed a superior score for black blood vs white blood scans (4.57 vs 4.25; p<0.001)., Conclusions: Black blood T2* CMR has superior reproducibility and reduced imaging artefacts for the assessment of cardiac iron, in comparison with the conventional white blood technique, which make it the preferred technique for clinical practice.

Background: Diffuse alveolar hemorrhage (DAH) of unknown cause has been characterized as idiopathic pulmonary hemosiderosis (IPH). IPH is a rare disease, which has a high prevalence in children and shows a poor prognosis. However, in adults, since there are few reports about collective cases, the details remain to be determined., Methods: Between January 2003 and June 2008, consecutive adult patients strictly defined as unknown cause DAH by chest images, fiberoptic bronchoscopy, autoantibody testing, and exclusion of systemic disease were enrolled. We investigated the clinical characterization and course of the enrolled patients., Results: Nine patients were included. All patients were middle-aged men (56.1 ± 4.2 year-old) with sudden onset. They did not present with anemia (the hemoglobin level was 13.9 ± 0.5 g/dL) despite the quantity of bleeding. In bronchoalveolar-lavage fluid analysis, the cell count was increased (7.6 ± 1.6×10(5) cells/mL) with neutorophilia (33.3 ± 13.3%). The illness resolved within 2 weeks with or without corticosteroid therapy. All of the patients were alive without recurrence during the follow-up period (45.2 ± 6.2 months) after diagnosis., Conclusion: Adult IPH patients showed good prognosis. However, the present patients are clinically slightly different from the previously characterized IPH.

In Germany and Central Europe, congenital disorders leading to secondary hemochromatosis are rare. The majority of these patients are treated in peripheral medical institutions. As a consequence, the experience of each institution in the treatment of secondary hemochromatosis in patients with congenital anemia is limited. Recent developments concerning new chelating agents, their combination for intensified chelation and new possibilities to diagnose and monitor iron overload have important consequences for the management of patients with secondary hemochromatosis and increase its complexity enormously. Therefore, the development of a guideline for rational and efficient diagnostics and treatment was necessary. The new guideline was developed within a formal consensus process and finally approved by a consensus conference with participants from both the pediatric and adult German hematology societies (GPOH and DGHO). Apart from general information and recommendations, the guideline contains 9 consensus statements on diagnostics (iron status, siderotic complications, chelator side-effects), the start of chelation, indications for intensified chelation, iron elimination in specific disorders, and iron elimination after stem cell transplantation. Here, these consensus statements are presented and discussed in detail. For the complete text of the guideline, please visit the AWMF homepage at http://www.leitlinien.net ., (© Georg Thieme Verlag KG Stuttgart · New York.)

Aim: to reveal the determinants of the development of iron overload in patients with acute leukemias (AL) and aplastic anemia (AA)., Subjects and Methods: The investigation included 104 patients, including 64 with various types of AL, 31 with AA, and 9 with myelodysplastic syndromes (MDS). A group affiliation and an erythrocyte phenotype were determined from rhesus system antigens in all the patients and the HFE gene was studied to identify mutations. For control of siderosis, the authors determined serum iron (SI) by a colorimetric technique, by applying the kits of the AGAT firm (Russia), serum ferritin (SF) by an immunoradiometric method, by using the kits of Immunotech (Czechia). The volume of transfusion was estimated in the period of June 2007 to November 2009., Results: There is evidence for a relationship between the higher level of SF and the number of transfusions. SF was 1046.1 microg/l in patients, H63D heterozygous carriers who had received less than 10 packed red blood cell transfusions and 2856 microg/l in those who had 20 transfusions (p < 0.005). HFE gene mutation carriage accelerates iron accumulation and is an additional risk factor for siderosis. In patients with transfusion chimeras and a rare phenotype in terms of rhesus antigens, packed red blood cell transfusion results in a much more increase in iron stores., Conclusion: The most important factor of iron overload acceleration is no specific choice of packed red blood cells for patients with rare combinations of red blood cell antigens and for those with artificially induced chimeras.

Background: The goal of this study was to determine the predictive value of cardiac T2* magnetic resonance for heart failure and arrhythmia in thalassemia major., Methods and Results: We analyzed cardiac and liver T2* magnetic resonance and serum ferritin in 652 thalassemia major patients from 21 UK centers with 1442 magnetic resonance scans. The relative risk for heart failure with cardiac T2* values <10 ms (compared with >10 ms) was 160 (95% confidence interval, 39 to 653). Heart failure occurred in 47% of patients within 1 year of a cardiac T2* <6 ms with a relative risk of 270 (95% confidence interval, 64 to 1129). The area under the receiver-operating characteristic curve for predicting heart failure was significantly greater for cardiac T2* (0.948) than for liver T2* (0.589; P<0.001) or serum ferritin (0.629; P<0.001). Cardiac T2* was <10 ms in 98% of scans in patients who developed heart failure. The relative risk for arrhythmia with cardiac T2* values <20 ms (compared with >20 ms) was 4.6 (95% confidence interval, 2.66 to 7.95). Arrhythmia occurred in 14% of patients within 1 year of a cardiac T2* of <6 ms. The area under the receiver-operating characteristic curve for predicting arrhythmia was significantly greater for cardiac T2* (0.747) than for liver T2* (0.514; P<0.001) or serum ferritin (0.518; P<0.001). The cardiac T2* was <20 ms in 83% of scans in patients who developed arrhythmia., Conclusions: Cardiac T2* magnetic resonance identifies patients at high risk of heart failure and arrhythmia from myocardial siderosis in thalassemia major and is superior to serum ferritin and liver iron. Using cardiac T2* for the early identification and treatment of patients at risk is a logical means of reducing the high burden of cardiac mortality in myocardial siderosis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00520559.

Hepatic hemosiderosis is one of the most common postmortem findings in captive callitrichid species. Noninvasive evaluation of hematologic iron analytes has been used to diagnose hepatic iron storage disease in humans, lemurs, and bats. This study evaluated the relationship between hematologic iron analyte values (iron, ferritin, total iron binding capacity, and percent transferrin saturation) and hepatic hemosiderosis in callitrichids at the Wildlife Conservation Society's Central Park and Bronx Zoos. Results revealed that both ferritin and percent transferrin saturation levels had strong positive correlations with hepatic iron concentration (P<0.001, r=0.77, n=20; P<0.001, r=0.85, n=10, respectively). Serum iron levels positively correlated with hepatic iron concentration (P=0.06, r=0.56, n=11), but this finding was not significant. Serum total iron binding capacity did not significantly correlate with hepatic iron concentration (P=0.47, r=0.25, n=10). Both ferritin and hepatic iron concentration positively correlated with severity of hepatic iron deposition on histology (P<0.05, r=0.49, n=21; P<0.001, r=0.67, n=21, respectively). This study suggests that ferritin, serum iron concentration, and percent transferrin saturation are convenient, noninvasive, antemortem methods for assessing severity of hemosiderosis in callitrichids.

Since 1962, desferrioxamine (deferoxamine, DFO) has been utilized for the treatment of secondary hemosiderosis. For about 30 years, DFO therapy has been performed as nightly continuous subcutaneous infusion. About 20 years ago, the first oral iron chelator (deferiprone, DFP) was presented. Concerns about potential side effects were responsible for the late acceptance and license of this drug which is limited to the use as second-line therapy for patients with thalassemia major. During recent years, chelation therapy and its evaluation started to progress rapidly. Clinical research and drug development as well as the introduction of new methods for the assessment of iron overload contributed to these advances. By using cardiac T2 (*) MRI it was possible to examine the specific effect of a chelator on myocardial siderosis. Clinical studies using this method indicated superiority of DFP compared to DFO with respect to the treatment of myocardial siderosis. Several retrospective and first prospective clinical trials seem to confirm this observation. In parallel, treatment strategies based on the combination of DFO and DFP have been developed. Using both drugs simultaneously or sequentially, additive and synergistic effects contribute to the fast elimination of iron from different organs at risk for siderotic damage. Deferasirox (DSX) is a recently developed oral chelator which shows good efficacy and tolerability in patients with transfusional hemosiderosis due to various underlying disorders. Long-term studies will define the future importance of DSX for iron chelation treatment. For the first time, there is a choice between three commercially available chelating agents for patients with transfusional iron overload. This will allow a highly effective, individually tailored treatment hopefully leading to a fundamental improvement of patients' life expectancy and quality.

Background: It is common for alcoholic patients to have excess iron accumulation in the liver, which may contribute to the development of alcoholic liver disease (ALD). However, the mechanism of hepatic iron uptake in ALD is still obscure. Recently, a novel iron-regulatory hormone hepcidin was found that suppresses the absorption of iron from the small intestine and the release of iron from macrophages. To elucidate the contribution of hepcidin toward the hepatic excess iron accumulation in ALD, we examined whether alcohol loading affects hepcidin expression both in ALD patients and in an ethanol-fed mouse model., Methods: Serum prohepcidin concentration was quantified by enzyme-linked immunosorbent assay. Hepatic hepcidin-1 and hepcidin-2 mRNA expressions in mouse liver were evaluated by quantitative real-time reverse-transcriptase polymerase chain reaction method. The protein expression of prohepcidin in mouse liver was examined immunohistochemically by rabbit antimouse prohepcidin antibody., Results: Serum prohepcidin concentration in ALD was significantly lower than that in healthy subjects (p<0.001). Especially, serum prohepcidin concentrations were decreased in the patients whose serum ferritin value was high. In the ethanol-fed mouse model, hepatic hepcidin-1 mRNA expression was significantly lower than that in control (p=0.04). Prohepcidin was expressed in the cytoplasm of hepatocytes of mice liver tissue sections, and its expression was decreased after ethanol loading., Conclusion: Alcohol loading down-regulates hepatic hepcidin expression and leads to the increase of iron absorption from the intestine.

Idiopathic pulmonary hemosiderosis (IPH) is a very rare disorder of unknown etiology characterized by recurrent or chronic hemorrhage and accumulation of hemosiderin in the lung parenchyma. It is most common in children but can occur in adults. Clinical manifestations of the disease include iron deficiency anemia without any known cause, pulmonary symptoms such as hemoptysis, dyspnea and cough, and parenchymal lesions on chest X-ray. The clinical course of the disease may vary from patient to patient however, in general, the prognosis of the disease is worse. Treatment is symptomatic and supportive. Corticosteroids and other immune suppressive agents were used for the therapy of IPH. Since it is seen rarely in adults and the clinical course of the disease vary from patient to patient we presented an adult male patient with IPH responded well to steroid therapy clinically and radiologically.

Routine monitoring of body iron stores is an essential component of overall management for the patient on hemodialysis. Adequate iron levels are important for the prevention and treatment of iron-deficiency anemia, which is associated with reduced physical functioning, cardiovascular disease, and poor quality of life. Hemodialysis patients are at especially high risk for iron-deficiency anemia, owing to continuous blood losses and supraphysiologic levels of erythropoiesis driven by recombinant human erythropoietin therapy. Unfortunately, the accurate determination of iron status in these patients can be a challenging task, which is made more difficult by inflammation, infections, and the large number of comorbid conditions that can affect commonly used indices of body iron stores. Despite their limitations, transferrin saturation (TSAT) and serum ferritin remain the cornerstones of iron status assessment. Because these values can be altered by a number of non-iron-related factors, it is necessary to go beyond these measures and draw upon additional sources of information to determine the patient's iron status. Other important factors to consider when assessing the need for iron therapy include evidence of underlying inflammatory processes that may block iron mobilization and distort the standard iron indices, the results of alternative iron indices, and the patient's recent history of iron administration. Frequently, the response to a gram of intravenous (i.v.) iron is a safe and effective way to determine the role of iron deficiency in the anemia of the problematic patient. The chronic inflammatory state associated with malnutrition and clinical or subclinical infections substantially increases the risk of misdiagnosing the patient with iron overload and may place the patient at risk of iron deficiency owing to inappropriate withdrawal of i.v. iron therapy. To avoid the risks of withholding iron therapy, the nephrologist must keep this relationship in mind whenever serum ferritin testing suggests replete iron stores, whereas TSAT testing suggests insufficient iron availability.

Intravenous (i.v.) iron and recombinant human erythropoietin (EPO), like all other medications, are associated with the risk of adverse events. Historically, the primary concern with iron therapy has been the possibility of iron overload, which exposes the individual to the effects associated with nontransferrin-bound iron. Experience with EPO use has demonstrated an association with hypertension and with the upregulation of a number of markers of inflammation. The impact of these potential adverse effects merits careful analysis, given that both i.v. iron and EPO are designed for long-term use in a patient population at high risk for infection and cardiovascular disease. However, the incidence of iron overload and the risks associated with nontransferrin-bound iron have dramatically been reduced since the introduction of EPO therapy, and no data exist that demonstrate a definitive association between i.v. iron and an increased risk of morbidity related to infection or cardiovascular disease. On the other hand, EPO use is associated with hypertension, endothelial dysfunction, and prothrombotic and inflammatory states in hemodialysis patients. Risks associated with hypertension can be minimized by using the lowest effective EPO dose, which may be achieved through the regular use of i.v. iron. Judicious use of both i.v. iron and EPO may optimize cardiovascular outcomes.

The incidence of cardiomyopathy was monitored in a 6-year follow-up study involving 56 transfused thalassemia patients treated with deferoxamine (DFO), deferiprone (L1) or their combination. During this period, five female patients on regular subcutaneous or intravenous DFO presented with cardiac complications. Three patients suffered congestive heart failure and the other two arrhythmias. Four of the five patients maintained serum ferritin levels of about 1 mg/L or below and the fifth about 1.5 mg/L for several years prior to the cardiomyopathy. Cardiac magnetic resonance imaging (MRI) T2* and T2 was performed in four patients after the cardiomyopathy, identifying the presence of moderate-to-heavy siderosis. The treatment of the five patients has since changed, involving mainly the use of L1. Low serum ferritin levels appear to be misleading for detecting cardiac iron overload and this may increase the risk of cardiomyopathy. The MRI T2 and T2* relaxation time measurements are a more accurate method of detecting cardiac iron overload. Chelation therapy using L1 or appropriate L1/DFO combinations can reduce cardiac iron overload and the mortality rate in thalassemia patients.

Background and Aims: It has been postulated that the HFE C282Y mutation (linked to human leukocyte antigen [HLA]-A3-B7 haplotype) is not only responsible for hereditary hemochromatosis; HLA class I alleles would also contribute to the disease pathogenesis. In addition, H63D mutation linked to HLA-A29-B44 would also be pathogenetic, particularly in the Mediterranean Basin and throughout the world. However, sporadic porphyria cutanea tarda (s-PCT) has also been linked to these HFE mutations. In the present work, we have studied HFE mutations and HLA genes to test these hypotheses., Methods: C282Y and H63D mutations together with HLA genetic typing have been performed in Spanish hereditary hemochromatosis (n = 98) and PCT (n = 63) patients. The etiologic fraction (delta) has been used to determine the absolute strongest gene linkage to both diseases., Results: The Spanish frequent HLA-A29-B44 haplotype is not significantly associated to the H63D mutations in hereditary hemochromatosis patients (although it is found more frequently in patients than in controls). Sporadic porphyria cutanea tarda patients do not show a significant association to H63D mutations, although it is also more frequent than in controls; however, compound H63D/C282Y subjects seem to bear a significant risk to s-PCT. Allelic C282Y (and not H63D) frequencies show a significant association with s-PCT., Conclusions: The postulated additional risk of hereditary hemochromatosis given by class I HLA antigens may be secondary to the HFE gene linkage disequilibrium with certain class I alleles or to the existence of other neighboring genetic pathogenetic factors in our Spanish sample.

Purpose: To evaluate the accuracy of magnetic resonance (MR) imaging in the quantification of hepatic iron concentration., Materials and Methods: Between April 1999 and June 2001, 112 patients were recruited prospectively. All had undergone liver biopsy and hepatic iron concentration quantification with spectrophotometry, followed by MR imaging. MR imaging involved use of four gradient-echo sequences and one spin-echo sequence. Signal intensity (SI) was measured on images obtained with each sequence by means of regions of interest placed in the liver and paraspinal muscle to obtain the liver-to-muscle SI ratio. The relationship between hepatic iron concentration and SI ratio for each sequence was analyzed with multiple linear regression. Receiver operating characteristic analysis was performed to find the diagnostic thresholds., Results: Sixty-eight patients had normal hepatic iron levels (<36 micromol/g), 23 had hemosiderosis (36-80 micromol/g), and 21 had hemochromatosis (>80 micromol/g). With all sequences, an inverse linear relationship between iron concentration and SI ratio was apparent. The authors generated a mathematic model to estimate the iron concentrations from MR imaging data (r = 0.937). For estimated concentrations of more than 85 micromol/g, the positive predictive value for hemochromatosis was 100%; for those less than 40 micromol/g, the negative predictive value for hemochromatosis was 100%. For estimated concentrations of more than 58 micromol/g, the positive predictive value for iron overload was 100%; for those less than 20 micromol/g, the negative predictive value for iron overload was 100%., Conclusion: MR imaging is a useful and noninvasive diagnostic tool for quantification of hepatic iron concentration., (Copyright RSNA, 2003)

Objective: To evaluate a secondary liver iron overload and its fate in children who are treated conventionally for acute lymphoblastic leukemia and to assess whether serum soluble transferrin receptor (sTfR) is useful in detecting iron load., Methods: Liver siderosis was estimated histologically from liver biopsy specimens of 30 children (aged 2.6-17.6 years) close to or at the end of therapy using total iron score (TIS). Serum iron parameters and sTfR were measured at the same time and in 22 patients 1 to 3 years after therapy., Results: In 19 (63%) of 30 patients, liver TIS was >15, indicating at least moderate iron overload. Serum ferritin, iron, and transferrin iron saturation levels were highest and transferrin level lowest in the patients with the highest liver iron content. Serum sTfR levels did not differ significantly between the patients with varying amounts of liver iron. TIS correlated most significantly positively with serum ferritin (r(S) = 0.899), transferrin iron saturation (r(S) = 0.764), and the amount of transfused red blood cells (r(S) = 0.783). Serum iron parameters normalized in most patients during the follow-up. In 3 (14%) of 22 patients, serum ferritin level remained high (>1000 microg/L)., Conclusions: Long-term iron overload is detected in at least 14% of children after therapy for acute lymphoblastic leukemia. Serum sTfR is an inappropriate marker for liver iron overload, whereas ferritin seems to be the most useful serologic marker for it.

Background: For the long-term survival of iron-loaded patients, early and well adjusted treatment with iron chelators is of crucial importance, especially in children. Basis of the adequate treatment are appropriate diagnostic parameters which are capable to monitor the range of the individual iron burden., Patients: In the time period between 1989 and 2001, the status of iron loading was investigated in 1112 patients with post transfusion siderosis., Methods: The iron concentration in liver and spleen was quantified by SQUID-biosusceptometry. Using these values, the whole body iron stores were calculated., Results and Discussion: Based on a large number of patients with secondary siderosis, the benefit of SQUID-biosusceptometry for non-invasive liver iron quantification was evaluated retrospectively. In patients under treatment with deferoxamin, a new therapeutic DFO-index was defined which respects liver iron concentration instead of serum ferritin. This results in a more reliable information about DFO overdosing in a given patient.

The exact differential diagnosis of iron overload syndromes is mandatory as important therapeutic consequences may derive from a correct diagnosis, especially when hemochromatosis is present. To facilitate diagnostic and therapeutic decisions algorithms and probabilistic calculations based on different frequencies of clinical symptoms and typical laboratory findings of the diseases in question have been proposed. Overestimation and/or underestimation of clinical symptoms and/or laboratory findings in using such calculations, however, may lead to incorrect diagnosis and therapy as demonstrated in this case. We report on a 62-year-old patient with arthralgia, pathologic glucose metabolism, brown skin pigmentation and excessively elevated ferritin and transferrin saturation levels, which initially were interpreted as signs of the assumed underlying disease (hemo-chromatosis) based on a high initial suspicion level and further corroborated by Bayesian probability analysis yielding a probability 99.0 % for the presence of hemochromatosis. Because of this high probability and the patient's wish for treatment phlebotomy was started, but stopped after having obtained negative results of genetic testing and normal quantitative liver iron values. The diagnosis of hemochromatosis had to be revised and symptoms and laboratory findings of this patient were found to be compatible with chronic fatty liver and pathologically altered iron metabolism due to chronic alcohol intake which the patient has initially concealed. The joint pain was explained in terms of chronic degenerative bone destruction, the impaired glucose tolerance seen as the consequence of obesity and the skin pigmentation was ascribed to sun exposure due to the patient's outdoor activities as a hobby farmer not evaluated during initial presentation. The implications and importance of unbiased history taking, critical interpretation of clinical symptoms and laboratory findings in using probabilistic calculations and diagnostic decision analysis are emphasized and the different mechanisms of iron metabolism in hemochromatosis and hemosiderosis are discussed.

Background: idiopathic pulmonary haemosiderosis (IPH) is a rare disorder characterized by intermittent, diffuse alveolar bleeding. The pathogenesis of the diseases is unclear, although an association with milk or gluten hypersensitivity has been described, and an immune-mediated damage of alveolar capillaries has been suggested. A previous report showed the release of histamine after cow's milk intake in a newborn with cow's milk intolerance and IPH., Methods and Results: here, we report the detection of serum histamine-releasing activity (HRA) in a 30-year-old woman with IPH. The serum taken during an active phase of the disease induced histamine release from basophils of two normal donors; conversely, when the patient was receiving prednisone and azathioprine, and the disease was in remission, the serum HRA was reduced. Serum fractions with a MW lower than 100 kDa displayed an enhanced HRA; in contrast, serum fractions with MW above 100 kDa were not able to induce histamine release, suggesting that the activity was due to a cytokine and not to an immunoglobulin., Conclusions: the detection of serum HRA provides further evidence that the immune system is activated in the course of IPH and supports an immunologic basis for the alveolar capillary damage, which is responsible for alveolar bleeding.

At present, about 300 patients in Germany suffer from thalassemia major. In 1990, a multicenter study was introduced to identify all thalassemic patients in Germany as well as to establish a uniform therapy protocol, including follow-up diagnostic procedures. After 6 years of study, the data of 203 patients were analyzed. The majority originate from endemic regions around the Mediterranean Sea. The median age of the patients is 13.8 years (range 1-37.5 years). At present, about 20% of the patients are older than 21 years. Regarding transfusion therapy, a shortening of the average transfusion interval to 3 weeks in most cases occurred. Throughout the entire period, median baseline hemoglobin concentrations of 10.0 g/dl were observed. The evaluation of serum ferritin levels revealed considerable differences, depending on the patients' age. Thalassemic patients in the first decade of life generally presented with good therapeutic results; serum ferritin levels were below 1800 ng/ml in 76/102 patients (75%) upon entry into the study. In contrast, 51/98 patients (52%) older than 10 years had ferritin levels above 2500 ng/ml. More than half of all treated patients presented with siderotic complications such as cardiac disease in 20/157 (13%), liver disease in 32/157 (21%), impaired glucose metabolism in 22/157 (14%), hypogonadism in 39/66 (59%), and hypothyroidism in 38/157 (24%) who were under treatment at the time of first survey. Since the situation concerning siderosis and the lack of compliance proved to be particularly difficult with adolescent patients, further efforts should concentrate on this age-group.

At present, about 300 patients with thalassemia major are living in Germany. Starting in 1991, a multicenter study in Germany has concentrated on identifying all patients suffering from thalassemia as well as on establishing a uniform therapy protocol including follow-up diagnostic procedures. After six years of study, the data of 198 patients suffering from thalassaemia major were analysed. The majority of these patients originate from endemic regions around the Mediterranean Sea. The patient's median age is 13.8 years (range 1-37.5 yrs.). At present, about 20% of patients are older than 21 years. Regarding transfusion therapy, a shortening of the average transfusion interval to 3 weeks in most cases occurred. Throughout the entire period, median baseline haemoglobin concentrations of 10.0 g/dl could be observed. The evaluation of serum ferritin levels revealed considerable differences depending on patients age. 60% of patients in the first decade of life showed good therapeutic results with serum ferritin levels below 1800 ng/ml. In contrast, 52% of patients older than ten years presented with ferritin levels above 2500 ng/ml. During the observation, a decreasing number of patients with ferritin levels above 2500 ng/ml was observed in patients aged 15 to 21 years of age. The situation of patients aged 9 to 15 years proved to be more problematic. More than half of all treated patients presented with siderotic complications as cardiac disease in 13%, liver disease in 21%, impaired glucose metabolism in 14%, hypothyroidism in 24% and hypogonadism in 59% of all patients. These values did not change considerably during the observation apart from an increase of cardiac disorders to 20%. Since the situation concerning siderosis and the lack of compliance proved to be particularly difficult in adolescent patients, further efforts has to concentrate on this age group.

Neutrophils (PMNs) from patients with secondary iron overload have an increased iron and ferritin content as well as a phagocytosis defect. Several serum components might be incriminated in the cellular iron accumulation. We therefore compared the effects on the PMN phagocytosis of total serum as well as the ferritin and transferrin fractions of serum derived from patients with thalassemia major and healthy control subjects. An incubation system of PMNs was developed. PMN phagocytosis was measured before and after incubation. Total serum from patients with thalassemia induced a defect that was prevented by co-incubation with deferoxamine (DFO). Gel-filtration chromatography was performed to separate the serum fraction containing transferrin and albumin from that containing ferritin. The transferrin-albumin fraction had no effect on PMN phagocytosis. On the contrary, the ferritin fraction of normal serum was deleterious to PMN phagocytosis, and the same fraction from thalassemic serum decreased PMN phagocytosis even more. Co-incubation with DFO or catalase improved this defect. Moreover, a cellular increase in the L-type subunit of ferritin was observed after the incubation of PMNs with the ferritin-containing fraction from thalassemic serum. In conclusion, serum from patients with thalassemia is toxic to PMNs, and this toxicity is due to ferritin-associated iron.

Background: Adverse reactions after ingesting buckwheat are known to be IgE-mediated. Further, hypersensitivity reactions may be involved in some patients with pulmonary hemosiderosis related to cow milk sensitivity. We, however, encountered a patient with pulmonary hemosiderosis related to buckwheat protein without high levels of buckwheat-specific IgE antibodies., Objective: The aim of this study was to investigate the mechanisms., Methods: RAST for anti-buckwheat IgE, skin prick test, skin patch test, and proliferative responses of peripheral blood mononuclear cells to buckwheat were investigated in this patient., Results: RAST values for buckwheat protein were negative, and skin prick test for buckwheat protein also gave negative results. On the other hand, skin patch testing for buckwheat protein elicited positive responses. Further, peripheral blood mononuclear cells of our patient responded to buckwheat protein., Conclusions: Our patient had pulmonary hemosiderosis related to non-immediate buckwheat protein hypersensitivity.

Because of continuous blood transfusions, thalassemia patients are subjected to peroxidative tissue injury by the secondary iron overload. In accordance, analysis of serum from 42 beta-thalassemia patients, aged 4 to 40 years, showed that the mean concentrations of conjugated diene lipid hydroperoxides (CD), lipoperoxides evaluated as malondialdehyde/ thiobarbituric acid (MDA/TBA) adducts, and protein carbonyls increased about twofold with respect to control. Ferritin levels were positively correlated with the amount of MDA (r = .41; P = .007) and showed a positive trend with CD (r = .31; P = .07) and protein carbonyls (r = .35; P = .054), as further evidence of the deleterious effects of high tissue iron levels. Marked changes in the antioxidant pattern were also observed in all patients. Evidence is presented of a net drop in the concentration of ascorbate (-44%), vitamin E (-42%), vitamin A(-44%), beta-carotene (-29%), and lycopene (-67%). On the other hand, an increase of uric acid and bilirubin was observed, whereas serum albumin and glutathione were in the normal range in all patients. As a result, the total serum antioxidant potential, measured as trolox equivalent antioxidant capacity appeared significantly decreased by 14%. Serum levels of vitamin E were inversely correlated with ferritin (r = -.45; P = .003), suggesting a major consumption of this antioxidant under iron overload. Nontransferrin bound iron (NTBI) was in the range 4.5 to 54.8 micrograms/dL (mean, 21.8 +/- 13.9). Although NTBI had a positive trend with ferritin (r = .37, P = .03), no clear correlation was found with either MDA or vitamin E. A mild to severe hepatic damage, as assessed by serum transaminases, was shown in 24 of 42 patients. Serum levels of vitamin E (r = -.49, P = .015), vitamin A (r = -.48, P = .016) and lycopene (r = -.47, P = .020), were inversely correlated with the levels of transminases. On the other hand, lipid-soluble antioxidants in thalassemia patients were depleted to the same extent in hepatitis C virus (HCV)-infected (31 subjects) and in HCV-uninfected (10 subjects), while in the normal range in serum from 30 nonthalassemic patients with HCV-related chronic hepatitis. These results point out that the iron-induced liver damage in thalassemia may play a major role in the depletion of lipid-soluble antioxidants. The variations of the parameters evaluated in the present study were not correlated with the age of the patients. Our results suggest that the measurement of peroxidation products, matched with evaluation of antioxidants, may be a simple measure of iron toxicity in thalessemia, in addition to the conventional indices of iron status.

The rapidity and duration of the response of non-transferrin-bound iron (NTBPI) to chelation therapy are largely unknown and have important implications for the design of optimal chelation regimens. Methodology was developed to measure simultaneously NTBPI, deferoxamine (DFO), and its major metabolite. NTBPI was present in all but 2 of 28 thalassaemia major (TM) patients who had received conventional subcutaneous DFO the previous night, suggesting a short duration of NTBPI clearance by DFO. The detailed kinetics of NTBPI were therefore studied in response to intravenous DFO at 50 mg/kg/27 h for 48 hours and compared in 17 regularly transfused TM and 8 untransfused thalassaemia intermedia (TI) patients to determine the influence of hypertransfusion and iron overload on NTBPI response. Before DFO infusion, NTBPI was present in all patients and was significantly higher in TI (4.52 +/- 0.53 mumol/L) than TM (2.92 +/- 0.03 mumol/L; P = .03). NTBPI values in TM correlated with transferrin saturation (r = .6, P = .03) but not with serum ferritin. Removal of NTBPI by intravenous DFO is in a biphasic manner. The initial rapid rate constant (alpha) was similar in TI (1.5 hour-1) and TM (1.6 hour-1), but the subsequent beta phase was slower (0.04 hour-1) in TI when compared with TM (0.4 hour-1, P = .002). Detectable NTBPI persisted during the beta phase, particularly in TI, despite an excess of plasma DFO also being present (steady state 8 mumol/L). On cessation of DFO infusion, NTBPI reappearance was rapid; the kinetics also being biphasic. The rapid initial rate constant (alpha = 2.5 hour-1) lasted less than 30 minutes and was approximately equal to the summation of the initial rate constant for removal of DFO (1.8 hour-1) and its major metabolite (0.6 hour-1). This was followed by a slower return to pretreatment levels, usually between 6 and 12 hours, which was faster in TI than in TM. This marked NTBPI lability supports the use of continuous rather than intermittent DFO in high risk patients.

Fifteen iron-overloaded thalassaemia major (TM) patients and two homozygous sickle cell patients (SCD) were treated continuously for 7d each week with the novel 48 h continuous subcutaneous (s.c.) desferrioxamine (DFX) delivery device (code C1083, Baxter) and 10 TM patients received the 24 h continuous intravenous (i.v.) DFX delivery device (code C1071). The 27 patients had previously received conventional s.c. DFX for 8-10h on 5 or more days each week. The serum non-transferrin bound iron (NTBI) levels fell significantly in both groups within 12h of commencing the continuous infusion. In the s.c. group the mean level fell from 4.2 to 2.0 mumol/l (P = 0.001), whereas in the i.v. group the mean level fell from 3.6 to 0.1 mumol/l (P = 0.006) the initial levels being measured 12h after stopping conventional s.c. DFX. After 4 weeks there was a significant fall in serum ferritin in both groups (P = 0.009). The new DFX delivery device is effective at removing toxicfree iron from plasma and reducing body iron. Moreover, it is preferred by patients with much improved compliance compared to the conventional s.c. DFX pump.

Nineteen children and adolescents receiving repeated transfusions and subcutaneous desferrioxamine treatment were investigated in an attempt to quantitate iron overload non-invasively. Before patients were started on desferrioxamine individual relationships were correlated for 12 to 36 months between transfused iron, absorbed iron estimated gastrointestinally, and increasing serum ferritin concentrations. Patients with inflammation, increased liver enzymes, or haemolysis were excluded from analysis. The relationship between the variables could be described by a logarithmic regression curve (y = transfused iron [plus eventually gastrointestinally absorbed iron] = iron overload = a+b log [x = serum ferritin]) for each individual patient. All patients showed close correlation (R2) between x and y (median R2 of 0.909, 0.98, and 0.92 in thalassaemia, aplastic anaemia, and sickle cell anaemia patients, respectively). When started on desferrioxamine, current serum ferritin concentrations were used to derive the iron overload from each individual regression curve. The derived estimated iron overload ranged from 0.6 g to 31 g. Left ventricular dilatation was observed in three patients with beta thalassaemia and in one patient with aplastic anaemia with median iron overload of 20.7 (14.1-31.3) g and 24.0 g respectively. Hypothyroidism was found in four patients with beta thalassaemia and one patient with aplastic anaemia with iron overload between 14.7 (6.8 and 26.1) g and 15.1 g respectively. Human growth hormone deficiency was detected in three patients with beta thalassaemia with an iron overload of 4.2 (3.5-6.8) g; all three patients had excellent desferrioxamine compliance.

Biochemical evidence of iron overload (transferrin saturation greater than 60% and/or serum ferritin concentration greater than 1000 micrograms/L) was observed in 16% of patients admitted to an alcohol withdrawal unit. No subjects in an age and sex matched control group showed such biochemical changes. Whilst changes in serum ferritin concentration closely correlated with aspartate aminotransferase activity and could be explained by alcohol induced liver damage, the increased transferrin saturation was not similarly explained. In nine patients withdrawal of alcohol resulted in a decrease in transferrin saturation and serum ferritin, the former due to a reduction in serum iron concentration. In patients with high alcohol intake biochemical measures of iron status may be misleading and a decrease in both transferrin saturation and serum ferritin concentration after withdrawal of alcohol may help to rule out the possible diagnosis of hereditary haemochromatosis.

Haemodialysis patients with iron overload sometimes develop resistance to erythropoietin therapy due to 'functional iron deficiency'. It is known that this resistance may be overcome by iron supplementation; however, the latter could worsen haemosiderosis. Therefore, we treated four iron-overloaded haemodialysis patients who had developed relative resistance to erythropoietin (among whom three had features of 'functional iron deficiency') with ascorbic acid (500 mg intravenously after haemodialysis, 1-3 times a week). The erythropoietin doses were voluntarily kept unchanged during the study. After a latency of 2-4 weeks, haematocrit and haemoglobin had increased respectively from 26.5 +/- 0.7 to 32.7 +/- 0.4 vol% and from 8.8 +/- 0.3 to 10.8 +/- 0.2 g/dl (means +/- SEM, P < 0.001). While serum ferritin remained unchanged, transferrin saturation increased from 27 +/- 7 to 54 +/- 12% (P < 0.05), suggesting that ascorbic acid supplementation had allowed mobilization of iron from tissue burdens. In one patient, haematocrit declined after withdrawal of vitamin C and increased again after rechallenge. Also, ascorbate supplementation was continued after the study in two patients and allowed the erythropoietin doses to be decreased, 8 and 11 weeks, respectively, after the start of the trial. When a control group of seven patients with normal iron status and without resistance to erythropoietin were challenged in the same manner with ascorbate, no elevation of haematocrit or transferrin saturation was noted. We conclude that ascorbate supplementation may circumvent resistance to erythropoietin that sometimes occurs in iron-overloaded patients, in particular, in the setting of 'functional iron deficiency'.