Aims To develop and validate a non-invasive method for measuring myocardial iron in order to allow diagnosis and treatment before overt cardiomyopathy and failure develops.Methods and Results We have developed a new magnetic resonance T2-star (T2*) technique for the measurement of tissue iron, with validation to chemical estimation of iron in patients undergoing liver biopsy. To assess the clinical value of this technique, we subsequently correlated myocardial iron measured by this T2* technique with ventricular function in 106 patients with thalassaemia major. There was a significant, curvilinear, inverse correlation between iron concentration by biopsy and liver T2* (r=0(.)93, P <0(.)0001). Inter-study cardiac reproducibility was 5(.)0%. As myocardial iron increased. there was a progressive decline in ejection fraction (r=0(.)61, P <0(.)001). All patients with ventricular dysfunction had a myocardial T2* of < 20 ms. There was no significant correlation between myocardial T2* and the conventional parameters of iron status, serum ferritin and liver iron. Multivariate analysis of clinical parameters to predict the requirement for cardiac medication identified myocardial T2* as the most significant variable (odds ratio 0(.)79, P <0(.)002).Conclusions Myocardial iron deposition can be reproducibly quantified using myocardial T2* and this is the most significant variable for predicting the need for ventricular dysfunction treatment. Myocardial iron content cannot be predicted from serum ferritin or liver iron, and conventional assessments of cardiac function can only detect those with advanced disease. Early intensification of iron chelation therapy, guided by this technique. should reduce mortality from this reversible cardiomyopathy. (C) 2001 The European Society of Cardiology.

Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload

Iron-chelating therapy and the treatment of thalassemia

Background The prognosis of patients with homozygous β-thalassemia (thalassemia major) has been improved by transfusion and iron-chelation therapy. We analyzed outcome and prognostic factors among patients receiving transfusions and chelation therapy who had reached the age at which iron-induced cardiac disease, the most common cause of death, usually occurs. Methods Using the duration of life without the need for either inotropic or antiarrhythmic drugs as a measure of survival without cardiac disease, we studied 97 patients born before 1976 who were treated with regular transfusions and chelation therapy. We used Cox proportional-hazards analysis to assess the effect of prognostic factors and life-table analysis to estimate freedom from cardiac disease over time. Results Of the 97 patients, 59 (61 percent) had no cardiac disease; 36 (37 percent) had cardiac disease, and 18 of them had died. Univariate analysis demonstrated that factors affecting cardiac disease-free survival were age at the start of che...

https://www.nejm.org/doi/pdf/10.1056/NEJM199409013310903

Survival in medically treated patients with homozygous beta-thalassemia.

The UK Thalassaemia Register records births, deaths and selected clinical data of patients with thalassaemia who are resident in the UK. A study of survival and causes of death was undertaken which aimed to include the possible impact of T2* cardiovascular magnetic resonance (CMR). The Register was updated to the end of 2003, copies of death certificates were obtained, and causes of death in beta thalassaemia major were extracted. In addition, patients who had T2* CMR assessment of cardiac iron load and/or received the oral iron chelator deferiprone were identified from clinical records. The main causes of death were anaemia (before 1980), infections, complications of bone marrow transplantation and cardiac disease due to iron overload. From 1980 to 1999 there were 12.7 deaths from all causes per 1,000 patient years. Forty per cent of patients born before 1980 had T2* cardiovascular magnetic resonance between 2000 and 2003, and 36% of these patients were prescribed deferiprone before end of 2003. In 2000–2003, the death rate from all causes fell significantly to 4.3 per 1,000 patient years (-62%, p < 0.05). This was mainly driven by the reduction in the rate of deaths from iron overload which fell from 7.9 to 2.3 deaths per 1,000 patient years (-71%, p < 0.05). Since 1999, there has been a marked improvement in survival in thalassaemia major in the UK, which has been mainly driven by a reduction in deaths due to cardiac iron overload. The most likely causes for this include the introduction of T2* CMR to identify myocardial siderosis and appropriate intensification of iron chelation treatment, alongside other improvements in clinical care.

/pdf/improved-survival-of-thalassaemia-major-in-the-uk-and-304fxnv1g5.pdf

Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance

Protection against tissue damage in vivo by desferrioxamine: what is its mechanism of action?

The main iron chelator used for transfusional iron overload is desferrioxamine, which is expensive, has toxic side effects, and has to be given subcutaneously. An orally active iron chelator is therefore required. The effects of oral 1,2-dimethyl-3-hydroxypyrid-4-one on urinary iron excretion were studied in eight patients who had received multiple transfusions: four had myelodysplasia and four beta thalassaemia major. Different daily doses of the drug up to 100 mg/kg/day, alone or in combination with ascorbic acid, were used. In three patients with thalassaemia the effect of the drug was compared with that of subcutaneous desferrioxamine at the same daily dose. In all eight patients a single dose of oral 1,2-dimethyl-3-hydroxypyrid-4-one resulted in substantial urinary iron excretion, mainly in the first 12 hours. Urinary iron excretion increased with the dose and with the degree of iron loading of the patient. Giving two or three divided doses over 24 hours resulted in higher urinary iron excretion than a single dose of the same amount over the same time. In most patients coadministration of oral ascorbic acid further increased urinary iron excretion. 1,2-Dimethyl-3-hydroxypyrid-4-one caused similar iron excretion to that achieved with subcutaneous desferrioxamine at a comparable dose. In some cases the iron excretion was sufficiently high (maximum 99 mg/day) to suggest that a negative iron balance could be easily achieved with these protocols in patients receiving regular transfusions. No evidence of toxicity was observed on thorough clinical examination or haematological and biochemical testing in any of the patients. None of the patients had any symptoms that could be ascribed to the drug. These results suggest that the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one is as effective as subcutaneous desferrioxamine in increasing urinary iron excretion in patients loaded with iron. Its cheap synthesis, oral activity, and lack of obvious toxicity at effective doses suggest that it should be developed quickly and thoroughly tested for the management of transfusional iron overload.

Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one.

Cardiac scintigraphy has been performed in 60 β-thalassaemia major patients aged 8-35 years who received regular blood transfusions and subcutaneous desferrioxamine (DFX) chelation. Fifty-seven showed

High incidence of cardiomyopathy in beta-thalassaemia patients receiving regular transfusion and iron chelation: reversal by intensified chelation.

Liver biopsies were performed on 51 regularly transfused patients with beta thalassaemia, age range 5-36 (mean 18.6) years, who had received regular subcutaneous desferrioxamine (DFX) treatment for periods between one and eight years (40 for eight years). The biopsy specimens were examined by light microscopy and immunofluorescence for hepatitis B virus surface and core antigens (HBsAg and HBcAg), and the iron content was determined chemically. The results were compared with serum ferritin concentration and aspartate transaminase (AST) activity and with hepatitis B virus serology. Biopsy specimens, in which chemical liver iron had been determined in 12, were also available from 17 patients. Mean serum ferritin (+/- SD) had fallen from 5885 (3245) micrograms/l to 1638 (976) micrograms/l in 36 patients after eight years9 chelation, while mean (+/- SD) liver iron concentration had fallen from 2945 (900) micrograms/100 mg dry weight to 857 (435) micrograms/100 mg dry weight in 12 of them. All biopsy specimens examined were negative for HBs and HBc antigens. The presence of histological features of hepatitis was associated with increased liver iron content, increased fibrosis, and with progression of fibrosis between the two biopsies. Procollagen III peptide was assayed in 28 patients but did not correlate with the degree of hepatitis, fibrosis, or with chemical liver iron content. We conclude that with regular subcutaneous DFX, mean concentrations of serum ferritin and liver iron are maintained in these patients at about five and 10 times the normal value, respectively, and that progression of liver damage is more likely to be due to viral hepatitis, presumably related to the parenterally transmitted non-A, non-B agents than to iron overload.

https://jcp.bmj.com/content/jclinpath/40/11/1353.full.pdf

Iron state and hepatic disease in patients with thalassaemia major, treated with long term subcutaneous desferrioxamine.

Auditory neurotoxicity occurred in 13 (26%) of 50 evaluable patients receiving long term desferrioxamine chelation. In five of these patients, all of whom were receiving high doses of desferrioxamine, the toxicity caused deafness. These five patients were treated with subcutaneous calcium diethylene triamine pentacetic acid (Ca-DTPA) with zinc supplements instead of desferrioxamine, and their hearing improved during periods of seven to 19 months. Their serum ion concentrations remained unchanged. We suggest that all patients receiving long term desferrioxamine should have audiometric assessments at 6-12 monthly intervals. Ca-DTPA with oral zinc supplements should be considered as alternative to desferrioxamine as an iron chelating treatment in patients with auditory neurotoxicity.

https://adc.bmj.com/content/archdischild/64/1/77.full.pdf

M A Aldouri

Papers

Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one.

High incidence of cardiomyopathy in beta-thalassaemia patients receiving regular transfusion and iron chelation: reversal by intensified chelation.

Iron state and hepatic disease in patients with thalassaemia major, treated with long term subcutaneous desferrioxamine.

Reversal of desferrioxamine induced auditory neurotoxicity during treatment with Ca-DTPA.

Cardiac complications in homozygous beta-thalassemia.