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The significant morbidity and mortality associated with iron overload can be reduced by effective iron chelation. Magnetic resonance imaging (MRI) provides accurate and reproducible iron load assessment. The aim of this epidemiological study was to assess the prevalence and severity of cardiac and hepatic siderosis by MRI and to evaluate the impact of MRI on clinical management in patients with transfusion-dependent anemia and non-transfusion-dependent thalassemia (NTDT). We enrolled 243 patients with myelodysplastic syndromes (MDS), thalassemia major (TM), NTDT or other chronic anemia. Overall, 10% and 48% had cardiac and hepatic siderosis, respectively. Mean liver iron concentration (LIC) was above target range in all groups; mean myocardial T2* was normal. Hepatic siderosis was more prevalent than myocardial siderosis in patients with MDS, occurring in 54.4% and 4.4% of patients, respectively. As also observed in patients with NTDT or other anemia, hepatic siderosis was present in a large proportion of MDS patients who were chelation naive (57.7%), as well as in patients receiving iron chelation therapy (ICT) (52.4%), despite a lower transfusion load compared with TM. Correlation between LIC and serum ferritin was observed across diseases; however, not all patients requiring ICT could be identified with serum ferritin alone, as serum ferritin underestimated LIC in 4.4% and overestimated LIC in 7.5% of patients. Exploratory analyses showed serum ferritin thresholds for liver siderosis detected by MRI at approximately 300 ng/mL higher in MDS than in TM. Most patients reported low-medium adherence to ICT; MRI assessment led to change in ICT in 46% of evaluable patients, including 52% of MDS patients. Accurate organ iron monitoring by MRI facilitated appropriate initiation of chelation, dose optimization and clinical decision making.Trial registration: ClinicalTrials.gov: NCT01736540.Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.

Asymptomatic urolithiasis is common and of mixed composition in patients with beta-thalassaemia major. Twenty-seven subjects were imaged using dual-energy computer tomography to determine the presence and composition of urolithiasis. The prevalence of urolithiasis was 59% and affected patients generally had multiple stones, often with more than one component: struvite (33%), calcium oxalate (31%) and cystine (22%). Hypercalciuria was present in 78% of subjects and calcium-containing urolithiasis was associated with reduced femoral neck Z scores.Copyright © 2017 Royal Australasian College of Physicians

A cross-sectional survey of 265 adult patients with haematological malignancy, haemoglobinopathy or human immunodeficiency virus was performed to determine the potential risk of infection from animal exposures. One hundred and thirty-seven (52%) owned an animal; the majority were dogs (74%) and cats (39%), but 14% owned birds and 3% reptiles. Eighty percent engaged in behaviour with their animals that potentially put them at risk of zoonotic infections. The most frequent behaviours were picking up animal faeces 72 (52%), cleaning animal areas 69 (50%) and allowing animals to sleep in the same bed 51 (37%). Twenty-eight percent allowed the animal to lick their face. Of all patients, 80 (30%) had been bitten or scratched by an animal. Only 16% of those who owned pets could recall receiving education regarding safe behaviours around animals. These immunocompromised patients are at risk of infection through exposure to pets. Our study highlights the need for increased education of patients regarding how to remain safe around their pets.Copyright © 2017 Royal Australasian College of Physicians

Background: Iron overload can lead to impaired organ function and is associated with significant morbidity and mortality, the risks of which can be reduced by effective long-term iron chelation therapy (ICT) and control of iron loading. Magnetic resonance imaging (MRI) allows accurate, reproducible assessment of iron load and its use may affect clinical management decisions, leading to improved patient care. The epidemiological TIMES study used MRI to assess prevalence and severity of cardiac and hepatic siderosis in a large population of Australian patients with transfusion-dependent anemia or non-transfusion- dependent thalassemia (NTDT). In this analysis of the TIMES study, we report the impact of MRI results on investigator treatment decisions. Aim(s): To determine the prevalence of iron overload by MRI and its impact on the clinical management of iron overload in a population of patients with transfusion- dependent anemia or NTDT. Method(s): Patients with thalassemia major (TM), NTDT (beta thalassemia intermedia, beta thalassemia/Hb E, Hb H disease), myelodysplastic syndromes (MDS) or other chronic anemias were enrolled. Patients with NTDT had serum ferritin (SF) >300 ng/mL; others had a lifetime history of >=20 units red blood cell (RBC) transfusions and SF >500 ng/mL. Past medical history was collected (including red blood cell (RBC) transfusion, ICT and hematologic data). Prospective MRI (FerriScan) was used to determine R2 liver iron concentration (LIC) and myocardial T2* (mT2*). Treatment decisions were assessed and recorded using an investigator questionnaire after evaluation of patient MRI results. Result(s): Of the 243 enrolled patients, 10 and 48% had cardiac and hepatic siderosis, respectively. In all disease groups, mean LIC was above the target range (3-7mg Fe/g dw), while mean mT2* was normal (>=20ms). 65.8% of patients received ICT for >=1 month before or during the study. During the 12- month period prior to the study, 55.9% received deferasirox

Objectives: To assess the effect of iron chelation therapy with deferasirox on cardiac iron and function in patients with transfusion-dependent thalassemia major, sickle cell disease (SCD), and myelodysplastic syndromes (MDS). Method(s): This phase IV, single-arm, open-label study over 53 wk evaluated the change in cardiac and liver iron load with deferasirox (up to 40 mg/kg/d), measured by magnetic resonance imaging (MRI). Result(s): Cardiac iron load (myocardial T2*) significantly improved (P = 0.002) overall (n = 46; n = 36 thalassemia major, n = 4 SCD, n = 6 MDS). Results were significant for patients with normal and moderate baseline cardiac iron (P = 0.017 and P = 0.015, respectively), but not in the five patients with severe cardiac iron load. Liver iron concentration (LIC) significantly decreased overall [mean LIC 10.4 to 8.2 mg Fe/g dry tissue (dw); P = 0.024], particularly in those with baseline LIC >7 mg Fe/g dw (19.9 to 15.6 mg Fe/g dw; P = 0.002). Furthermore, myocardial T2* significantly increased in patients with LIC <7 mg Fe/g dw, but not in those with a higher LIC. Safety was consistent with previous reports. Conclusion(s): Once-daily deferasirox over 1 yr significantly increased myocardial T2* and reduced LIC. This confirms that single-agent deferasirox is effective in the management of cardiac iron, especially for patients with myocardial T2* >10 ms (Clinicaltrials.gov identifier: NCT00673608).Copyright © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Thalassemia is an inherited disorder of ineffective erythropoiesis requiring chronic transfusion therapy in its most severe form. This leads to iron overload, marrow expansion and hormonal complications which are implicated in bone deformity and loss of bone mineral density (BMD). In this 19 year retrospective longitudinal study, the relationships between BMD (determined by dual energy X-ray absorptiometry) and risk factors for osteoporosis in 277 subjects with transfusiondependent thalassemia were examined. The study cohort of 277 subjects, from a single academic center, is unique; it represents one of the largest and certainly longest follow-up of patients with transfusiondependent thalassemia worldwide. The mean age at first review was 23.2 +/- 11.9 years and 43.7% were male. Hypogonadism was present in 28.9% and fractures confirmed in 11.6% of subjects. Lumbar spine (LS), femoral neck (FN) and total body (TB) Z scores were derived. Patients with transfusiondependent thalassemia had a significant longitudinal decline in BMD at the FN and TB. In the uni-and multivariate linear mixed model analysis of BMD and risk factors for bone loss, FN Z score was more consistently significantly compared to the LS and TB. The rate of decline at the FN was 0.02 Z score per year and was 3.85 fold greater in males compared to females. The decline in FN Z score over the last 5 years (years 15-19) was 2.5 fold that of the previous 7 years (years 8-14) and coincided with a change in iron chelator therapy from intravenous desferrioxamine to oral deferasirox. Hemoglobin levels positively correlated with higher TB and LS Z scores. In conclusion, the FN is the preferred site for follow-up of BMD. Transfusing patients (particularly males) to a higher hemoglobin target may improve BMD. A role for deferasirox in bone loss is consistent with previous observations and warrants further study.

Development of an acquired systemic elastopathy resembling pseudoxanthoma elasticum in patients with chronic haemoglobinopathies such as beta thalassaemia major and sickle cell disease is well documented. There is paucity of any comprehensive literature on the radiological manifestations of this entity. This pictorial review aims to describe and illustrate the multi system and multi modality imaging findings of this condition.Copyright © 2015 The Royal Australian and New Zealand College of Radiologists.

Background/Aims: Hemoglobin H (HbH) disease is associated with iron overload, but whether this results in serious cardiac or vascular sequelae is unresolved. Method(s): We identified 39 adult subjects (age 42 +/- 12 years, 13 men) with HbH disease who had undergone echocardiography, 27 of whom had also undergone cardiac and liver magnetic resonance assessment of iron loading using T2*-weighted imaging. Result(s): None of the subjects had a history of heart failure or arrhythmias. There were 13/39 subjects with a ferritin level within the sex-based normal range and only 4/39 had ferritin >1,000 ng/ml. Left ventricular (LV) and left atrial dilatation was common, but LV ejection fraction was normal (>=55%) in all subjects. Age was positively correlated with log ferritin in the 27 nontransfused subjects (r = 0.43) and was inversely correlated with the transmitral E wave and E/A ratio (r = -0.69 and r = -0.79, respectively), but no relation of log ferritin with E or E/A was evident. The peak tricuspid regurgitation velocity was normal in 24/29 subjects for whom this was obtained, and it was no more than mildly elevated in the other 5. None of the tested subjects had an abnormal cardiac T2* reading, but half had evidence of liver iron loading. Conclusion(s): No myocardial iron loading or serious cardiac or vascular sequelae were identified in this cohort with HbH disease.Copyright © 2016 S. Karger AG, Basel.

Deferasirox is an oral iron chelator used widely in the treatment of thalassemia major and other transfusion-dependent hemoglobinopathies. Whilst initial long-term studies established the renal safety of deferasirox, there are now increasing reports of hypercalciuria and renal tubular dysfunction. In addition, urolithiasis with rapid loss of bone density in patients with beta thalassemia major has been reported. We conducted a cross-sectional cohort study enrolling 152 adult patients comprising of beta thalassemia major (81.5%), sickle cell disease (8%), thalassemia intermedia (2%), HbH disease (6.5%) and E/beta thalassemia (2%). Cases were matched with normal control subjects on age, gender and serum creatinine. Iron chelator use was documented and urine calcium to creatinine ratios measured. At the time of analysis, 88.8% of patients were receiving deferasirox and 11.2% were on deferoxamine. Hypercalciuria was present in 91.9% of subjects on deferasirox in a positive dose-dependent relationship. This was not seen with subjects receiving deferoxamine. At a mean dose of 30.2 +/- 8.8 mg/kg/day, deferasirox was associated with an almost 4 fold increase in urine calcium to creatinine ratio (UCa/Cr). Hypercalciuria was present at therapeutic doses of deferasirox in a dose-dependent manner and warrants further investigation and vigilance for osteoporosis, urolithiasis and other markers of renal dysfunction.Copyright © 2016 Elsevier Inc..

Introduction: Thalassemia is a disorder of haemoglobin synthesis requiring regular transfusion therapy in its more severe form. Multiple hormonal complications, in particular hypogonadism and severe osteoporosis, can lead to changes in body composition and bone mineral density (BMD). We investigated the relationship between skeletal muscle mass, fat mass and BMD in subjects with transfusion-dependent thalassemia based on their gonadal status. Method(s): A retrospective cross-sectional cohort study of 186 young adults with transfusion-dependent thalassemia at a single academic centre was analysed. Body composition and BMD (lumbar spine, femoral neck and total body) were measured using Dual energy X-ray absorptiometry (DXA) along with anthropometric measures. Intermuscular adipose free skeletal muscle mass was calculated. The association between muscle, fat and BMD was investigated through uni-, multi- and step-wise regression analyses after adjusting for multicollinearity. Result(s): 43.5% were males and 56.5% were females with a median age of 36.5 and 35.4 years, respectively. Hypogonadism was reported in 44.4% of males and 44.7% of females. Skeletal muscle mass and BMD were positively correlated and were strongest in eugonadal males (0.36<=R2<=0.59) but the association was attenuated in hypogonadal males. Skeletal muscle mass (0.27<= R2<=0.69) and total fat mass (0.26<=R2<=0.55) were positively correlated with BMD in hypogonadal females but the correlation was less pronounced in eugonadal females. Leg lean tissue mass and arm lean tissue mass in males and females, respectively, were most highly correlated to BMD in the stepwise regression analysis. Conclusion(s): Skeletal muscle is positively correlated and accounts for the largest variance in BMD in males regardless of gonadal status. Fat mass and skeletal muscle mass were positively but weakly correlated to BMD in eugonadal females but the association was stronger in the hypogonadal state. Hypogonadism attenuates

Background: beta thalassemia major results in ineffective erythropoiesis. Blood transfusion aims, in part, to suppress this and to limit morbidity from anaemia, bone marrow expansion and extra-medullary hemopoiesis (EMH), thereby increasing survival. According to current international guidelines, males and females are transfused equally. Aim(s): We sought to assess the adequacy of suppression of erythropoiesis in all 126 transfused adult (>18 years) males and females with beta thalassemia major at our centre by: (1) assessing readily available pre-transfusion indices of erythropoiesis, including erythropoietin (EPO) levels; (2) determining the volume of blood transfused per kilogram (kg) and per calculated blood volume; and (3) assessing the incidence of para-spinal EMH masses based on magnetic resonance imaging (MRI). Method(s): We analysed pre-transfusion (i.e., the day of transfusion) hemoglobin (Hb), reticulocyte count, red blood cell count (RCC), nucleated red blood cell (NRBC) count, EPO and ferritin levels in patients receiving stable, regular blood transfusion. Automated and manual NRBC and reticulocyte enumerations were performed. Blood volume was calculated using Nadler's formula. MRI performed to assess cardiac function and hepatic and cardiac iron loading was reviewed for the presence of para-spinal EMH. Result(s): One hundred and sixteen adult patients (51 males and 65 females) provided pre-transfusion blood samples (Table 1). The 10 patients not included were either not available or declined testing. The mean pre-transfusion Hb was 98-99g/l with no difference between males or females (Table 2). Therefore, our data reflect long-standing adherence to current international transfusion recommendations. EPO levels and NRBC count (manual and automated) were significantly higher in males compared to females. RCC, reticulocyte count (manual and automated) and ferritin levels were not different between males and females. Males received less blood per kg of body

Thalassemia is an inherited disorder of alpha or beta globin chain synthesis leading to ineffective erythropoiesis requiring chronic transfusion therapy in its most severe form. This leads to iron overload, marrow expansion, and hormonal complications, which are implicated in bone deformity and loss of bone mineral density (BMD). In this 19-year retrospective longitudinal study, the relationships between BMD (determined by dual-energy X-ray absorptiometry) and risk factors for osteoporosis in 277 subjects with transfusion-dependent thalassemia were examined. The mean age at first review was 23.2+/-11.9 years and 43.7% were male. Hypogonadism was present in 28.9%. Fractures were confirmed in 11.6% of subjects and were more frequent in males (16.5%) compared with females (7.7%). Lumbar spine (LS), femoral neck (FN), and total body (TB) Z-scores were derived. Patients with transfusion-dependent thalassemia had a significant longitudinal decline in BMD at the FN and TB. In the linear mixed-model analysis of BMD and risk factors for bone loss, FN Z-score was more significantly associated with risk factors compared with the LS and TB. The rate of decline at the FN was 0.02 Z-score per year and was 3.85-fold greater in males. The decline in FN Z-score over the last 5 years (years 15 to 19) was 2.5-fold that of the previous 7 years (years 8 to 14) and coincided with a change in iron chelator therapy from desferrioxamine to deferasirox. Hemoglobin (Hb) levels positively correlated with higher TB and LS Z-scores. In conclusion, the FN is the preferred site for follow-up of BMD. Male patients with beta-thalassemia experienced a greater loss of BMD and had a higher prevalence of fractures compared with females. Transfusing patients (particularly males) to a higher Hb target may reduce the decline in BMD. Whether deferasirox is implicated in bone loss warrants further study.Copyright © 2014 American Society for Bone and Mineral Research.

A sensitive, rapid analytical method has been developed for the characterization of human hemoglobin disorders with very small volumes (<1 muL) of blood. As an alternative to conventional enzymatic digestion, a site-specific chemical cleavage method has been established using 0.05% formic acid under microwave-irradiation conditions for short time intervals, for example, less than 10 min. Peptide analysis was performed by MALDI TOF MS and capillary liquid chromatographic ESI MS/MS. The cleavage of the hemoglobin chains with formic acid occurred at either side or at both sides (C- and N-terminal) of aspartic acid residues, but preferentially N-terminally. The method has been applied to blood samples from hemoglobin S carrier heterozygotes and hemoglobin S thalassaemia compound heterozygotes with a reduced expression level of hemoglobin S. Both MALDI TOF MS and ESI MS/MS analysis allowed the identification of the hemoglobin S "signature" peptide. This alternative method of sample preparation is compatible with MS techniques and is expected to significantly contribute to the further development of rapid, robust, reproducible and sensitive analytical methods in proteomics and biomedical diagnostics where protein variant characterization is a crucial factor for biomarker discovery and disease identification. © 2010 American Chemical Society.

Summary: Patients with transfusion-dependent thalassemia have abnormal growth, hormonal deficits, and increased bone loss. We investigated the relationship between skeletal muscle mass, fat mass, and bone mineral density in adult subjects with transfusion-dependent thalassemia based on their gonadal status. Our findings show that hypogonadism attenuates the strength of the muscle-bone relationship in males but strengthens the positive correlation of skeletal muscle mass and fat mass in female subjects. Introduction: Transfusion-dependent thalassemia is associated with a high prevalence of fractures. Multiple hormonal complications, in particular hypogonadism, can lead to changes in body composition and bone mineral density (BMD). We investigated for the first time the relationship between skeletal muscle mass (SMM), fat mass, and BMD in adult subjects with transfusion-dependent thalassemia based on their gonadal status. Method(s): A retrospective cohort study of 186 adults with transfusion-dependent thalassemia was analyzed. Body composition and BMD were measured using dual energy X-ray absorptiometry. The association between skeletal muscle, fat, and BMD was investigated through uni-, multi-, and stepwise regression analyses after adjusting for multicollinearity. SMM was derived using the formula, SMM=1.19xALST-1.65, where ALST is equivalent to the sum of both arm and leg lean tissue mass. Result(s): There were 186 subjects, males (43.5%) and females (56.5%), with a median age of 36.5. Hypogonadism was reported in 44.4% of males and 44.7% of females. SMM and BMD were positively correlated and strongest in eugonadal males (0.36<=R2<=0.59), but the association was attenuated in hypogonadal males. SMM (0.27<=R 2<=0.69) and total fat mass (0.26<=R2<=0.55) were positively correlated with BMD in hypogonadal females, but the correlation was less pronounced in eugonadal females. Leg lean tissue mass and arm lean tissue mass in males and females, respectively, were most hig

beta-thalassemia major causes ineffective erythropoiesis and chronic anemia and is associated with iron overload due to both transfused iron and increased iron absorption, the latter mediated by suppression of the iron-regulatory hormone hepcidin. We sought to determine whether, in beta-thalassemia major, transfusion-mediated inhibition of erythropoiesis dynamically affects hepcidin. We recruited 31 chronically transfused patients with beta-thalassemia major and collected samples immediately before and 4 to 8 days after transfusion. Pretransfusion hepcidin was positively correlated with hemoglobin and ferritin and inversely with erythropoiesis. The hepcidin-ferritin ratio indicated hepcidin was relatively suppressed given the degree of iron loading. Posttransfusion, hemoglobin and hepcidin increased, and erythropoietin and growth differentiation factor-15 decreased. By multiple regression, pre-and posttransfusion hepcidin concentrations were both associated positively with hemoglobin, inversely with erythropoiesis, and positively with ferritin. Although men and women had similar pretransfusion hemoglobin, men had significantly increased erythropoiesis and lower hepcidin, received a lower transfusion volume per liter blood volume, and experienced a smaller posttransfusion reduction in erythropoiesis and hepcidin rise. Age of blood was not associated with posttransfusion hemoglobin or ferritin change. Hepcidin levels in patients with beta-thalassemia major dynamically reflect competing influences from erythropoiesis, anemia, and iron overload. Measurement of these indices could assist clinical monitoring. © 2013 by The American Society of Hematology.

Haemoglobinopathies are autosomal recessive disorders. They are the most common human single-gene disorders and are associated with abnormal globin gene expression, which results in either changes in the quantitative production of the globin chains or their structural aberrations. The majority of amino acid sequence variations are caused by a small number of frequently occurring mutations often with very high regional/ethnic human population dependencies. Pre- and postnatal screening programs are essential for effective diagnosis, counselling, and clinical management of individuals and their families exhibiting haemoglobinopathies. Mass spectrometry is a powerful tool for diagnostic screening programs, but its use for clinical haemoglobinopathy assessment has not been implemented in Australia. This investigation was focused on establishing analytical methods, which allow the unambiguous identification of haemoglobin variants through unique and diagnostically relevant methods for the identification of haemoglobin variant 'signature' peptide(s). In this work, sensitive and rapid analytical methods have been developed for the detection of human haemoglobin disorders using very small volumes (<1 muL) of blood. As an alternative to conventional enzymatic digestion, surfactant-aided enzymatic and microwave-assisted site-specific chemical cleavage methods have been established which allow very rapid proteolysis in less than 10 min. These methods have been applied to fifteen haemoglobin variants with identification of the corresponding haemoglobin variant 'signature' peptides by mass spectrometry. These microwaveassisted and MS-compatible sample preparation methods are expected to significantly contribute to the development of rapid, robust, cost-effective and environmentally benign methods of haemoglobin analysis in population screening studies.

The haemoglobinopathies are common inherited disorders. Although the majority are caused by a small number of frequently occurring mutations, many rare mutations collectively contribute considerably to the clinical burden. Population screening to document genotype and allele frequencies, availability of high throughput technologies, advances in the lower income countries and antenatal screening programmes has led to an increase in data accumulation. However, phenotype data on rare mutations often remains inadequate and based on a single report. A standard system for collecting and reporting genotype and phenotype for rare mutations would assist in clinical management of patients and couples at-risk. We report collective phenotype data for a number of relatively rare mutations identified in long established haemoglobinopathy referral laboratories in three countries. For example, the Codon 22 (C>T) and codon 108 (C>A) alpha2 globin gene mutations have only been reported on single patients.We present data on eight heterozygous/ compound heterozygous patients for each mutation. The alpha1 globin gene codon 108/109(-C) mutation has no documented phenotype data. We present data for seven heterozygous patients. The IVS2-478 (C-A) beta-globinmutation has been reported once in the literature whilst data for fourteen patients are presented. We describe the previously unreported phenotype for compound heterozygous patients for the deletion of HS-40 regulatory element/alpha3.7 deletion, alpha3.7 deletion/alpha3.5 deletion, alpha2 cd22(C>T) /alpha2 cd59(G>A), cd59(G>A) /Hb Constant Spring and Hb Phnom Penh/-SEA. The collective data presented here updates phenotype data significantly and demonstrates the value of combining the experience of multiple laboratories.

Although thalassaemia is highly prevalent in the Asia-Pacific region, clinical data on efficacy and safety profiles of deferasirox in patients from this region are rather limited. Recently, data from the multicentre Evaluation of Patients' Iron Chelation with Exjade (EPIC) study in 1744 patients with different anaemias has provided an opportunity to analyse 1115 thalassaemia patients, of whom 444 patients were from five countries in the Asia-Pacific region (AP) for whom thalassaemia management and choice of iron chelators were similar. Compared to the rest of the world (ROW), baseline clinical data showed that the AP group appeared to be more loaded with iron (3745.0 vs. 2822.0 ng/ml) and had a higher proportion on deferoxamine monotherapy prior to the study (82.9 vs. 58.9%). Using a starting deferasirox dose based on transfusional iron intake and tailoring it to individual patient response, clinical efficacy based on serum ferritin reduction in AP and ROW thalassaemia patients was similar. Interestingly, the AP group developed a higher incidence of drug-related skin rash compared to ROW (18.0 vs. 7.2%), which may indicate different pharmacogenetic backgrounds in the two populations. Our analysis confirms that, with appropriate adjustment of dose, deferasirox can be clinically effective across different regions, with manageable side effects. © The Japanese Society of Hematology 2011.

Background: Cardiac failure is the leading cause of death in patients with thalassaemia major. However, the introduction of new monitoring techniques, such as cardiac iron Magnetic Resonance Imaging (MRI), may lead to the improvement of patient care and prolong survival. Although the impact of cardiac siderosis in patients with thalassaemia major has been extensively studied, further examination of the effect of specific iron chelators such as deferasirox are important in the development of treatment protocols, while the clinical consequences of cardiac iron accumulation in patients with myelodysplastic syndromes (MDS) is still controversial. Aim(s): The primary objective of this study is to investigate the effect of single agent deferasirox on cardiac iron levels and cardiac function, in a cohort of patients receiving regular red blood cell transfusions. Method(s): Patients with transfusional siderosis were enrolled in this study and received deferasirox for 53 weeks. Doses up to 40 mg/kg/day were allowed according to transfusional requirement, response to chelation therapy and safety markers. Cardiac siderosis (cardiac T2* measured by linear fitting to the decay of logarithmic magnetic resonance signal) and left ventricular ejection fraction (LVEF) were measured at baseline and at 53 weeks. The sample size was originally calculated based on the standard deviation (SD) of the change in log(T2*) (0.47), according to previously published reports. A planned sample size reassessment as per protocol was undertaken when 42 patients had follow-up data. For the sample size reassessment, log(T2*) was calculated for each result and the change in log(T2*) estimated for each patient. Results from the interim sample size reassessment and the analysis of cardiac iron and function are described below. Result(s): Results were available for 36 patients with haemoglobinopathies (mainly represented by thalassaemia major), 5 patients with MDS and one post-bone marrow transplant patien

Beta-thalassaemia major is associated with low bone mass and fractures. We conducted a 2 year randomized controlled trial of zoledronic acid 4 mg administered intravenously every 3 months or placebo in the treatment of beta-thalassaemia-associated osteopenla. We recruited 23 subjects from 2 university hospitals with a T score of less than -1.0 at either the lumbar spine or hip, and 23 subjects completed the study (17 M, 6 F). Treatment groups did not differ significantly with respect to bone mineral density (BMD), age, height, weight and body mass index (BMI) at baseline. BMD was assessed at baseline, 12 months and 24 months by dual-energy X-ray absorptiometry (DXA) at the lumbar spine, femoral reek, total hip and total body. After two years average lumbar spine BMD was 8.9% greater (95%CI 2.3-15.5%, P=0.011) , average femoral neck BMD was 9.1% greater (95%CI 5.5-12.7%, P < 0.0001), average total hip BMD was 9.6% greater (95%CI 6.5-12.6%, P < 0.0001) and average total body BMD was 4.7% greater (95%CI 2.7-6.8%, P < 0.0001) in the treated group compared to placebo. The absolute change in BMD from baseline to 2 years and the annualized rate of change of BMD was significantly greater in treated patients at all four sites. Age, gender, height, weight and BMI did not interact with the effect of treatment and so unadjusted data was used. The serum total ALP decreased 45% by 12 months (P=0.004) and urinary deoxypyridinoline/creatinine ratio decreased 47% by 3 months (NS). We conclude that zoledronic acid (4 mg i.v. 3 monthly) suppresses bone turnover and increases BMD in beta-thalassaemia-associated osteopenia. © 2006 Springer Science+Business Media, Inc.

Since 1996, the identification of the HFE gene has enabled DNA testing for hereditary haemochromatosis (HH). The range of DNA testing available includes: (1) diagnostic, (2) predictive (also called presymptomatic testing) and (3) screening. Access to DNA testing has been facilitated by an Australian Medicare rebate, the first available for genetic disorders. Despite the availability of HFE DNA testing in HH, it remains necessary to interpret results in the context of the clinical picture. Traditional markers based on phenotype (transferrin saturation, ferritin and liver biopsy) are still required in some circumstances. We report our experience with HFE DNA testing using a semi-automated approach, which allows multiplexing for the two common mutations (C282Y and H63D). Screening a cohort of beta-thalassaemia major and sickle cell anaemia patients of predominantly Mediterranean origin showed that these individuals do not have the common C282Y mutation. This excluded C282Y as a factor in the pathogenesis of iron overload in these haemoglobinopathies. It also showed that the C282Y mutation is of limited value when investigating HH in certain ethnic groups. An Australian family studied illustrated the relative contribution of C282Y and H63D in iron overload. A recently reported third mutation (S65C) in the HFE gene was detected in a low frequency in the populations tested.

Extra-medullary haematopoiesis (EMH) occurs in many haematological disorders and is secondary to insufficient bone marrow function or ineffective erythropoiesis. It usually presents as haematopoietic masses in several typical and atypical body locations. This pictorial review briefly discusses the common EMH locations encountered in clinical practice, including the liver, spleen, lymph nodes and paravertebral regions. Unusual presentation as focal hepatic and splenic masses is also discussed. Some atypical EMH locations are then presented together with their pathophysiology and relevant illustrations. These include EMH in the intra-spinal canal, pre-sacral region, nasopharynx and paranasal sinuses. Intra-spinal EMH can cause cord compression and present with neurological symptoms. In these cases, urgent treatment may be required. Haematopoietic masses in the other atypical locations can present with obstructive symptoms or may be diagnosed incidentally on imaging. EMH in unusual locations need to be monitored with follow-up imaging to ensure their stability. In some circumstances, tissue biopsy is appropriate to confirm the diagnosis and exclude other sinister pathology (e.g. malignancy). Treatment is only required where symptoms are present. Management options include blood transfusion, radiotherapy, hydroxyurea or surgical resection in selected cases. © 2012 The Royal Australian and New Zealand College of Radiologists.

Objectives: To adapt a previously published single-tube multiplex polymerase chain reaction (PCR) designed to detect large deletions causing a thalassaemia to include the -alpha 3.7III deletion found in Melanesian and Polynesian populations, and the -alpha 3.5 deletion originally found in the Indian population, which are now found in the multi-ethnic population of Melbourne, Australia. Method(s): The method of Chong SS, Boehm CD, Higgs DR, Cutting GR detects the two most common single-gene deletions: -alpha-3.7 and -alpha4.2, as well as the most common two-gene deletions: -SEA, -FIL, -MED, and - (alpha)20.5. A later modification by Tan A S-C, Quah TC, Low PS, Chong SS incorporated detection of the -THAI deletion. We replaced two primers in this modified PCR leaving all other conditions as previously described. Primer alpha2-R was replaced with alphaC6 - 5' CTC CAG CCG GTT CCA GCT ATT GC 3' and primer alpha2/3.7F was replaced with alphaC8 - 5'GAG CCT GGC CAA ACC ATC AC 3'. The substitution of these two primers allows for continued discrimination between the normal (alpha1 gene) and the three -alpha-3.7 amplicons and enabled detection of the - alpha3.5 deletion. Expected amplicon sizes are 2023 bp for the normal alpha1 gene, 2093/2096/2097 bp respectively for the three -alpha-3.7 deletions and 978 bp for the -alpha3.5 deletion. A separate PCR now needs to be performed to determine zygosity for the -alpha4.2 deletion. Result(s): Our modified PCR was confirmed by testing 100 archival samples of known genotype. However, during routine use over a number of years two novel deletions have also been detected and characterised. Conclusion(s): This multiplex PCR was found to be a reliable and inexpensive way of detecting common alpha-thalassaemia deletions including the -alpha-3.7III and -alpha3.5 deletions.

Iron overload is the most important cause of mortality in patients with thalassaemia major. Iron chelation is therefore a critical issue in the management of these patients and others with transfusion-dependent haemoglobinopathies and congenital anaemias. In recent years, significant developments have been made in the assessment of iron overload, including the use of magnetic resonance imaging for measuring liver and cardiac iron. Advances in the modalities available for iron chelation, with the advent of oral iron chelators including deferiprone and deferasirox in addition to parenteral desferrioxamine, have expanded treatment options. A group of Australian haematologists has convened to formulate guidelines for managing iron overload on the basis of available evidence, and to describe best consensus practice as undertaken in major Australian Haemoglobinopathy units. The results of their discussions are described in this article, with the aim of providing guidance in the management of iron overload in these patients. © 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.

The thalassaemias are the commonest single gene disorders in the world's population and are a common cause of hereditary anaemia. They should be suspected in any individual who has reduced red blood cell indices. A full blood examination and haemoglobin electrophoresis are the tests which should be used first to investigate a suspected carrier of a thalassaemia gene. Iron deficiency can confuse the interpretation of test results, so iron studies are also often required. DNA analysis may be needed to detect the carrier state, particularly in carriers of alpha-thalassaemia.

Background and objective: Growth failure in homozygous beta-thalassaemia has been recognized for many years, and has persisted despite major treatment advances. In this cross-sectional study, sitting and standing height were measured to determine whether growth failure was disproportionate. Design(s): Patient data were analysed in three age groups, 2-10 years, 11-18 years and 19 and over. Sitting height and subischial leg length were also determined in a cohort of parents (n = 19) and normal Greek adolescents (n = 32). Patients and measurements: Of the known 156 patients with homozygous P-thalassaemia in the State of Victoria, 154 (98.7%) attend our institution. Sitting and standing heights were measured, using Harpenden stadiometers, in 57 of 60 (95%) patients aged 2-18 years and in a random selection of 51 of 89 patients aged 19 and over (57%). Measurements are expressed as mean+/-SDS. Other data analysed included serum concentrations of ferritin, zinc, copper, FSH, LH, oestradiol and testosterone, according to standard laboratory assays, together with pubertal status and bone age in patients aged less than 19 years. Result(s): Standing height standard deviation scores in the 2-10 age group were -0.687 +/- 0.861 (n = 9), in the 11-18 age group were -1.838 +/- 1.413 (n = 48) and in the age group 19 and over were -1.175 +/- 1.126. In individuals aged 2-10 years, sitting height standard deviation scores (SDS) were -1.56 +/- 1.02, in individuals 11-18 years were -3.76 +/- 1.51 (n = 48), and in individuals 19 years and over were -2.77 +/- 1.20 (n = 51), compared with subischial leg length SDS which were, in individuals aged 2-10 years 0.214 +/- 0.91; in 11-18 years, -0.063 +/- 1.347, and in individuals 19 and over, 0.37 +/- 1.18. These data show that the reduction in standing height was the result of truncal shortening. Mean sitting height SDS was significantly lower in children with homozygous beta-thalassaemia, compared with their parents (P < 0.001), and in a subgro

Patients with beta-thalassemia major require iron-chelation therapy to avoid the complication of iron overload. Until recently, deferoxamine (DFO) was the major iron chelator used in patients requiring chronic hypertransfusion therapy, but DFO required continuous subcutaneous therapy. The availability of deferasirox (Exjade), an orally active iron chelator, over the past 4 years represented a necessary alternative for patients requiring chelation therapy. However, there have been increasing reports of proximal renal tubular dysfunction and Fanconi Syndrome associated with deferasirox in the literature. We report a case of hypophosphataemic osteomalacia secondary to deferasirox therapy. Copyright © 2012 American Society for Bone and Mineral Research.

Introduction: Iron chelation therapy (ICT) is essential in removing excess iron deposited in body organs, ultimately preventing organ failure and extending the lives of patients (pts) with transfusion-dependent hematological disorders such as beta-thalassemia. Conventional ICT (deferoxamine, Desferal, DFO) requires a burdensome regimen (subcutaneous delivery 5-7 times a week) that has been shown to negatively impact pts' health-related quality of life (HRQL) and adherence to therapy. Adherence to ICT affects survival and therefore a well-tolerated and effective ICT regimen is required. The once-daily oral chelator, deferasirox (Exjade) offers 24-hour ICT, 7 days a week and is potentially less burdensome to pts. Method(s): As part of a larger single-arm, multicenter, open-label trial investigating the efficacy and safety of deferasirox (EPIC study), 217 beta-thalassemia pts >16 years of age were included in this subanalysis. Findings reported here investigate differences in satisfaction, adherence and HRQoL following treatment with deferasirox, in beta-thalassemia patients with prior experience of DFO monotherapy, or DFO in combination with deferiprone (Ferriprox, L1). All pts were asked at baseline and week 52 (end of study [EOS]) to complete the 19-item Satisfaction with ICT questionnaire (SICT) and the 36-item Short Form health survey (SF-36). Mean change scores between baseline and EOS on the four domains of the SICT (Perceived Effectiveness of ICT, Side Effects of ICT, Acceptance of ICT, and Burden of ICT) and the eight domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health) and two summary scores (Physical and Mental Component Scores) of the SF-36 were calculated for patients who completed the respective instruments at both timepoints. Higher scores on the SICT and SF-36 represent greater HRQL, satisfaction with, and adherence to treatment. Adherence to deferasirox was assessed

As sickle cell disease is increasing in Australia, paediatricians and other health care providers need to be aware of the broad range of complications that can occur in this condition. Although the complications of splenic sequestration and chest crises are well recognised, the infrequent but equally dramatic complication of hyperhaemolysis is less well appreciated. Here, we report a case of hyperhaemolysis in a Victorian paediatric patient.

This document considers a number of scenarios involving complex haemoglobinopathies and provides 28 recommendations at both the clinical and laboratory levels on how these should be managed. © 2006 Royal College of Pathologists of Australasia.

HLA class-I and class-II allele frequencies and two-locus haplotypes were examined in 367 unrelated Melanesians living on the islands of Vanuatu and New Caledonia. Diversity at all HLA class-I and class-II loci was relatively limited. In class-I loci, three HLA-A allelic groups (HLA-A*24, HLA-A*34 and HLA-A*11), seven HLA-B alleles or allelic groups (HLA-B*1506, HLA-B*5602, HLA-B*13, HLA-B*5601, HLA-B*4001, HLA-B*4002 and HLA-B*2704) and four HLA-C alleles or allelic groups (HLA-Cw*04, HLA-Cw*01, HLA-Cw*0702 and HLA-Cw*15) constituted more than 90% of the alleles observed. In the class-II loci, four HLA-DRB1 alleles (HLA-DRB1*15, HLA-DRB1*11, HLA-DRB1*04 and HLA-DRB1*16), three HLA-DRB3-5 alleles (HLA-DRB3*02, HLA-DRB4*01 and HLA-DRB5*01/02) and five HLA-DQB1 alleles (HLA-DQB1*0301, HLA-DQB1*04, HLA-DQB1*05, HLA-DQB1*0601 and HLA-DQB1*0602) constituted over 93, 97 and 98% of the alleles observed, respectively. Homozygosity showed significant departures from expected levels for neutrality based on allele frequency (i.e. excess diversity) at the HLA-B, HLA-Cw, HLA-DQB1 and HLA-DRB3/5 loci on some islands. The locus with the strongest departure from neutrality was HLA-DQB1, homozygosity being significantly lower than expected on all islands except New Caledonia. No consistent pattern was demonstrated for any HLA locus in relation to malaria endemicity.