Pulmonary Hypertension Is Uncommon In Well-Transfused Thalassemia Major Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4273-4273
Author(s):  
Jon Detterich ◽  
Leila Noetzli ◽  
Susan Carson ◽  
Paul Harmatz ◽  
Thomas D. Coates ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Pulmonary Artery ◽  
Iron Overload ◽  
Research Funding ◽  
Thalassemia Major ◽  
Left Ventricular ◽  
Cell Disease ◽  
Liver Iron ◽  
Cardiac Iron

Abstract Abstract 4273 Introduction: Pulmonary hypertension is a common and serious cardiovascular complication in patients with thalassemia intermedia and sickle cell disease. Circulating platelet and erythrocyte fragments, as well as cell-free hemoglobin from intravascular hemolysis, may contribute to nitric oxide depletion, intimal proliferation, and pulmonary vascular remodeling. Splenectomy has been also been associated with pulmonary hypertension in some studies. Ineffective erythropoiesis, via release of PLGF and elevation of other proinflammitory cytokines, has also been associated with pulmonary hypertension. However, the risk for pulmonary hypertension in thalassemia major patients remains controversial, with prevalence estimates ranging from 10%-60%. We report echocardiography results from 80 thalassemia major patients enrolled in the Early Detection of Iron Cardiomyopathy Trial (EDICT) at Children's Hospital Los Angeles. Methods: Patients were enrolled from August 2004 until May 2009 in a combined cross-sectional and observational trial probing for early predictors of cardiac dysfunction. Patient visits were scheduled within one week of transfusion. All patients underwent echocardiography and cardiac MRI analysis within 4 months of each other; most were performed during the same clinical visit (median time between scans one day). Comprehensive assessments of pulmonary artery pressure (tricuspid and pulmonary regurgitation velocities), systolic function, and diastolic function were performed using two dimensional imaging, M-mode, and routine and tissue Doppler. All images were collected by experienced echocardiography technicians and analyzed by the principal investigator. Three to five beat averages were used to improve measurement stability. Tricuspid regurgitation (TR) jet was only reported if a full envelope was recognized; at our institution, the upper limit of normal for TR jet is 2.7 m/s. Results: Patient demographics are summarized in Table 1. Patients were gender-balanced and well distributed between 11 and 47 years of age. Patients who had been splenectomized (N=34) tended to be older. Iron overload was severe, with a mean liver iron concentration of 12.4 ± 14.2 mg/g dry weight. Roughly half of the patients had detectable cardiac iron and 9% had overt left ventricular dysfunction (LVEF < 56%). TR jet was detectable in 62/80 patients. Only one patient exhibited pulmonary artery hypertension (TR jet 2.9 m/s), however this patient also had severe cardiac iron overload and overt left ventricular systolic and diastolic dysfunction (LVEF 42.7%, E/E' 10). Two patients had TR jets of 2.6 ms and three had TR jets of 2.5 m/s. Pulmonary insufficiency jets were normal in all patients. TR velocity did not correlate with age, cardiac index, cardiac iron or liver iron, but demonstrated a weak (r=0.29, p=0.02) association with left ventricular diastolic dysfunction (E/E′). Discussion: The EDICT patient cohort suggests a low risk for pulmonary hypertension in well-transfused thalassemia major patients. The single elevated TR jet was explained by iron cardiomyopathy and normalized (2.2 m/s) after two years of aggressive chelation therapy. TR velocities at the upper limits of normal (2.5-2.7 m/s) were observed in five patients; these have been associated with poor outcomes in some sickle cell disease cohorts, but not in thalassemia major. Long-term surveillance remains critical as pulmonary hypertension risk may increase with age. Disclosures: Harmatz: Novartis: Research Funding. Coates:Novartis: Research Funding, Speakers Bureau. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy.

Consequences and management of iron overload in sickle cell disease

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 447-456 ◽  
Author(s):  
John Porter ◽  
Maciej Garbowski
Keyword(s):  
Sickle Cell Disease ◽  
Blood Transfusion ◽  
Iron Overload ◽  
Sickle Cell ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Iron Loading ◽  
Cell Disease ◽  
Liver Iron Concentration ◽  
Liver Iron

Abstract The aims of this review are to highlight the mechanisms and consequences of iron distribution that are most relevant to transfused sickle cell disease (SCD) patients and to address the particular challenges in the monitoring and treatment of iron overload. In contrast to many inherited anemias, in SCD, iron overload does not occur without blood transfusion. The rate of iron loading in SCD depends on the blood transfusion regime: with simple hypertransfusion regimes, rates approximate to thalassemia major, but iron loading can be minimal with automated erythrocyte apheresis. The consequences of transfusional iron overload largely reflect the distribution of storage iron. In SCD, a lower proportion of transfused iron distributes extrahepatically and occurs later than in thalassemia major, so complications of iron overload to the heart and endocrine system are less common. We discuss the mechanisms by which these differences may be mediated. Treatment with iron chelation and monitoring of transfusional iron overload in SCD aim principally at controlling liver iron, thereby reducing the risk of cirrhosis and hepatocellular carcinoma. Monitoring of liver iron concentration pretreatment and in response to chelation can be estimated using serum ferritin, but noninvasive measurement of liver iron concentration using validated and widely available MRI techniques reduces the risk of under- or overtreatment. The optimal use of chelation regimes to achieve these goals is described.

Initial Liver Iron Predicts Cardiac Chelation Efficacy of Deferasirox (Exjade®) Monotherapy in Chronically Transfused β-Thalassemia (β-Thal) Patients: 18- and 24-Month Data.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4069-4069
Author(s):  
John C. Wood ◽  
Alexis A. Thompson ◽  
Carole Paley ◽  
Tara Glynos ◽  
Barinder Kang ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Employment Equity ◽  
Advisory Committees ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Equity Ownership

Abstract Abstract 4069 Poster Board III-1004 Introduction Transfused patients with β-thal major are known to experience clinical consequences of cardiac iron overload despite the widespread use of iron chelation therapy. Approximately 71% of patients will suffer cardiomyopathy, congestive heart failure (CHF) and death. Previous trials have confirmed the efficacy of deferasirox (Exjade®) in removing cardiac iron in patients with β-thal major. This ongoing study evaluates the effects of deferasirox on cardiac iron and left ventricular ejection fraction (LVEF) in patients with β-thal major in a prospective, single-arm, multi-center trial using cardiac MRI T2*. All patients have completed 18 months of therapy and we also report preliminary results from 24 months. Methods 28 patients were enrolled at four US centers. Entry criteria included MRI evidence of cardiac iron (T2* <20 ms) and normal LVEF (≥56%). Deferasirox was administered at 30–40 mg/kg/day for 18 months. Following core study completion (18 months), patients could continue treatment for an additional 6 months if their 18-month cardiac T2* was <20 ms and they demonstrated ≥25% improvement in cardiac T2* or LIC from baseline. Serum ferritin (SF) was assessed monthly. Liver iron concentration (LIC), cardiac T2* and LVEF were assessed by MRI every 6 months. Serum creatinine (SCr), biochemical and hematological status were also monitored. All results are reported as mean ± SE (range) unless otherwise stated. Baseline: All 26 evaluable patients (7 M/19 F; aged 10–44 years) received ≥150 lifetime transfusions. SF was 4307 ± 613 ng/mL (312–12,655), cardiac T2* was 9.5 ± 0.8 ms (1.8–16.1), LIC was 20.6 ± 3.15 mg Fe/g dry weight (dw; 3.6–62.3) and LVEF was 61.8 ± 0.8%. Results At the time of analysis, 22 and 9 patients had 18- and 24-month evaluations, respectively. Six patients discontinued the core trial due to patient decision (n=2), adverse events (AEs; n=2) or abnormal lab tests (n=2). Two of these patients died after discontinuing; the first enrolled with markedly elevated baseline cardiac iron (T2* = 1.8 ms) and died secondary to CHF. The second patient withdrew due to an AE and died 2 months later due to sepsis and multi-organ failure. 18-month results: At 18 months, 10/22 patients were on 40 mg/kg/day. The mean improvement in cardiac T2* from baseline in all patients was 2.2 ms (22%; P=0.016), with 13 patients improving, four remaining stable (T2* change <10%) and five worsening. Baseline LIC was a powerful predictor of response (Figure); cardiac T2* in 14 patients with LIC <18.5 mg Fe/g dw improved 2.2% per month, with 13/14 patients showing large improvements and one patient remaining stable. In contrast, in eight patients with LIC >18.5 mg Fe/g dw, mean T2* worsened 1.4% per month (P<0.0001); three patients remained stable and five worsened significantly. Improvements in cardiac iron were correlated with changes in LIC (r2 = 0.27, P=0.013). In general, initial T2* did not predict therapeutic response, although all three patients with T2* <6 ms increased their cardiac iron. LIC decreased 4.1 mg Fe/g dw over the study interval (P=0.003). LVEF remained stable. 24-month results: At 24 months, 7/9 patients were on 40 mg/kg/day. Relative to the 18-month time-point, 8/9 patients (89%) increased their cardiac T2*, with a mean improvement of 2.7% per month. Mean LIC, SF and LVEF were unchanged over the extension. Safety parameters from patients treated with 30–40 mg/kg/day deferasirox (n=25) were in line with previous studies at 20–30 mg/kg/day. Conclusions Deferasirox monotherapy resulted in statistically significant improvements in cardiac and hepatic iron after 18 months. Baseline LIC <18.5 mg Fe/g dw was a strong predictor of favorable response. LVEF remained stable during the study. Patients in the extension (18–24 months) improved their cardiac T2* without further improvements in LIC or SF. Deferasirox monotherapy at 30–40 mg/kg/day provides good cardiac chelation in patients with moderate cardiac and liver iron burdens. More aggressive therapy is warranted for more severe iron overload. Disclosures: Wood: Novartis: Research Funding. Thompson:Novartis: Research Funding. Paley:Novartis Pharmaceuticals: Employment, Equity Ownership. Glynos:Novartis Pharmaceuticals: Employment. Kang:Novartis Pharmaceuticals: Employment, Equity Ownership. Giardina:Novartis: Research Funding, Speakers Bureau. Harmatz:Ferrokin: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees. Coates:Hope Pharma: Consultancy, Research Funding; Sangart Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Cardiac Iron Overload In Sickle-Cell Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1013-1013
Author(s):  
Antonella Meloni ◽  
Mammen Puliyel ◽  
Alessia Pepe ◽  
Massimo Lombardi ◽  
Vasilios Berdoukas ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Clinical Characteristics ◽  
Transferrin Saturation ◽  
Thalassemia Major ◽  
Cell Disease ◽  
Cardiac Iron ◽  
Cardiac Iron Overload

Abstract Introduction Chronically transfused sickle cell disease (SCD) patients have lower risk of endocrine and cardiac iron overload load than comparably transfused thalassemia major patients. The mechanisms for this protection remain controversial but likely reflects lower transferrin saturation and circulating labile iron pools because of chronic inflammation and regeneration of apotransferrin through erythropoiesis. However, cardioprotection is incomplete; we have identified 6 patients out of the 201 patients (3%) followed at our Institution who have prospectively developed cardiac iron. We present the clinical characteristics of these patients to identify potential risk factors for cardiac iron accumulation. Methods Cardiac, hepatic, and pancreatic iron overload were assessed by R2* Magnetic Resonance Imaging (MRI) techniques as extensively described by our laboratory. The medical records of the selected patients were reviewed for demographic data, for transfusion and chelation history and for hematologic and biochemical parameters. Results Table 1 describes clinical characteristics of the six patients at the time they developed detectable cardiac iron (R2* ≥ 50 ms). Patient 6 was included because he showed a R2* of 49 Hz that was increasing rapidly. Five of the six patients were managed on simple transfusions. Five patients had been on chronic transfusion for more than 11 years. The three patients who developed cardiac iron the earliest (3.7 – 14 years of transfusions) had more efficient suppression of endogenous red cell production (HbS levels 2-5%) compared with patients who required longer transfusional exposure (HbS levels 13.3 – 41%). All patients had qualitatively poor chelation compliance (<50%), based upon their prescription refill rate. All patients had serum ferritin levels exceeding 4600 and liver iron concentration (LIC) greater than 22 mg/g. Pancreatic R2* was greater than 100 Hz in every patient studied (5/6). Figure 1 shows the longitudinal relationship between iron overload in the heart and in the other organs for each patient; initial iron levels are shown in black. Cardiac R2* appears increase dramatically once a critical LIC “threshold” is reached, qualitatively similar to the 18 mg/g threshold observed in thalassemia major patients. Cardiac R2* rose proportionally to pancreas R2*, similar to thalassemia major patients, with all of the patients having pancreas R2* > 100 Hz at the time cardiac iron was detected. Conclusions Cardiac iron overload occurs in a small percentage of chronically transfused SCD patients and is only associated with exceptionally poor control of total body iron stores. Duration of chronic transfusion is clearly important but other factors, such as levels of effective erythropoiesis, may also contribute to cardiac risk. The relationship between cardiac iron and pancreas R2* suggests that pancreas R2* can serve as a valuable screening tool for cardiac iron in SCD patients. Disclosures: Berdoukas: ApoPharma inc: Consultancy. Coates:ApoPharma inc, Novartis, Shire: Consultancy. Wood:Novartis: Consultancy, Honoraria; Shire: Consultancy, Research Funding; ApoPharma: Consultancy, Honoraria, Use of deferiprone in myocardial infarction, Use of deferiprone in myocardial infarction Patents & Royalties.

scholarly journals Pathophysiology and treatment of pulmonary hypertension in sickle cell disease

Blood ◽  
2016 ◽  
Vol 127 (7) ◽  
pp. 820-828 ◽  
Author(s):  
Victor R. Gordeuk ◽  
Oswaldo L. Castro ◽  
Roberto F. Machado
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Sickle Cell Disease ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Sickle Cell ◽  
Left Ventricular ◽  
Cell Disease ◽  
Pulmonary Pressure ◽  
Pulmonary Arterial

Abstract Pulmonary hypertension affects ∼10% of adult patients with sickle cell disease (SCD), particularly those with the homozygous genotype. An increase in pulmonary artery systolic pressure, estimated noninvasively by echocardiography, helps identify SCD patients at risk for pulmonary hypertension, but definitive diagnosis requires right-heart catheterization. About half of SCD-related pulmonary hypertension patients have precapillary pulmonary hypertension with potential etiologies of (1) a nitric oxide deficiency state and vasculopathy consequent to intravascular hemolysis, (2) chronic pulmonary thromboembolism, or (3) upregulated hypoxic responses secondary to anemia, low O2 saturation, and microvascular obstruction. The remainder have postcapillary pulmonary hypertension secondary to left ventricular dysfunction. Although the pulmonary artery pressure in SCD patients with pulmonary hypertension is only moderately elevated, they have a markedly higher risk of death than patients without pulmonary hypertension. Guidelines for diagnosis and management of SCD-related pulmonary hypertension were published recently by the American Thoracic Society. Management of adults with sickle-related pulmonary hypertension is based on anticoagulation for those with thromboembolism; oxygen therapy for those with low oxygen saturation; treatment of left ventricular failure in those with postcapillary pulmonary hypertension; and hydroxyurea or transfusions to raise the hemoglobin concentration, reduce hemolysis, and prevent vaso-occlusive events that cause additional increases in pulmonary pressure. Randomized trials have not identified drugs to lower pulmonary pressure in SCD patients with precapillary pulmonary hypertension. Patients with hemodynamics of pulmonary arterial hypertension should be referred to specialized centers and considered for treatments known to be effective in other forms of pulmonary arterial hypertension. There have been reports that some of these treatments improve SCD-related pulmonary hypertension.

scholarly journals Iron overload parameters and early detection of cardiac disease among Egyptian children and young adults with β-thalassaemia major and sickle cell disease: a cross-sectional study

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1108
Author(s):  
Khaled Salama ◽  
Amina Abdelsalam ◽  
Hadeel Seif Eldin ◽  
Eman Youness ◽  
Yasmeen Selim ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Pulmonary Artery ◽  
Iron Overload ◽  
Sickle Cell ◽  
Systolic Pulmonary Artery Pressure ◽  
Thalassaemia Major ◽  
Cell Disease ◽  
Cardiac Iron ◽  
Diastolic Velocity ◽  
Egyptian Children

Background: Cardiac, hepatic and pancreatic T2* measured by magnetic resonance imaging (MRI) has been proven to be an accurate and non-invasive method for measuring iron overload in iron overload conditions. There is accumulating evidence that pancreatic iron can predict cardiac iron in young children because the pancreas loads earlier than the heart. The aim of our study was to investigate cardiac function and cardiac iron and their relation to pancreatic iron among patients with β-thalassaemia major (βTM) and sickle cell disease (SCD). Methods: 40 βTM and 20 transfusion-dependant SCD patients were included along with 60 healthy age-matched controls. Echocardiography and Tissue Doppler Imaging were performed for all subjects as well as the control group.  Hepatic, cardiac and pancreatic iron overload in cases were assessed by MRI T2*. Results: The study group consisted of 40 βTM and 20 transfusion dependant SCD patients with mean age 13.7 years and mean frequency of transfusion/year 12. Mean cardiac T2* was 32.9 ms and mean myocardial iron concentration was 0.7 mg/g; One patient had cardiac iron overload of moderate severity. Mean pancreatic T2* was 22.3 ms with 20 patients having mild pancreatic iron overload. Pancreatic T2* correlated positively with main pulmonary artery diameter (p=0.046), peak late diastolic velocity at septal mitral annulus (p=0.038), peak early diastolic velocity at tricuspid annulus (p=0.001) and mitral annular plane systolic excursion (p=0.01); and negatively with end systolic pulmonary artery pressure (p=0.007). We couldn’t test the predictability of pancreatic T2* in relation to cardiac T2* as only one patient had cardiac T2*<20 ms. Conclusion: Assessment of pancreatic T2* in multi-transfused patients with βTM and SCD can predict myocardial dysfunction. No direct relation between pancreatic iron and cardiac siderosis was detected.

scholarly journals Iron Overload Is Under-Recognized and Under-Treated in SCD: A Report from the Grndad Registry

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 158-158
Author(s):  
Matthew Sears ◽  
Sophie Lanzkron ◽  
Carolyn Hoppe ◽  
Joshua J. Field ◽  
Payal C Desai ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Research Funding ◽  
Chelation Therapy ◽  
Ferritin Level ◽  
Research Network ◽  
Cell Disease ◽  
Liver Iron ◽  
High Iron

Abstract Background: Chronic transfusion therapy (CTT) is a mainstay of prophylactic management and treatment for adults and children with high risk Sickle Cell Disease (SCD). We estimate that 10-20% of all adults with SCD managed at our centers, especially those with homozygous HbSS disease, are on CTT, for long-term management of cerebral vasculopathy, significant end organ damage, or chronic pain. Iron overload is a common complication of CTT and for patients receiving intermittent transfusion to treat acute complications. Each unit of transfused blood introduces approximately 250 mg of iron into the bloodstream, and with it, increased oxidative stress (A. Remacha, et al., "Guidelines on haemovigilance of post-transfusional iron overload," Blood Transfusion, vol. 11, no. 1, pp. 128-139, 2013). High iron levels in the blood cumulatively lead to systemic iron deposition, particularly in the liver and heart, and untreated may lead to organ dysfunction or death. Patients with high iron levels should be put on iron chelation. Recent NHLBI guidelines suggest that patients on CTT be monitored for iron accumulation with quarterly ferritin levels, and annual or semiannual liver iron scans to assess hepatic iron burden, though the optimal frequency of these scans has not been established (B. P. Yawn, et al., "Management of Sickle Cell Disease: Summary of the 2014 Evidence-Based Report by Expert Panel Members," JAMA, vol. 10, no. 312, pp. 1033-1048, 2014). We examined iron overload, its frequency, severity, and management, in a modern population of adults with SCD enrolled in the multi-center prospective sickle cell registry, Globin Research Network of Data and Discovery (GRNDaD). Methods: GRNDaD is a multi-site registry of both adult and pediatric SCD patients, currently accruing at 5 urban sickle cell centers, in Baltimore MD, Cleveland OH, Milwaukee WI, Columbus OH, and Oakland CA. It currently contains prospective baseline and annual update information on nearly 500 people with SCD. Additionally, approximately 150 more patients have consented, with data entry pending. The dataset comprises demographics as well as baseline and yearly lab values, complications, procedures, treatment, and vaccination history for each patient. Among these data are ferritin levels, liver iron scan results, and chelation therapy information. We analyzed ferritin levels in people with SCD, relative to genotype, age, gender, treatment type, liver iron scan results, and chelation therapy history. Results: There were 402 adults (age≥18 years) in GRNDaD who had a non-crisis ferritin level from a routine follow-up visit. This included people with phenotypic homozygous SCD (HbSS, n=255 and Sβ0 thalassemia, N=13), variant SCD (HbSC, n=80, or Sβ+ thalassemia, n=37), and other or unknown genotypes (n=17, Table 1). Nearly 3 in 10 of all patients with SCD (n=118, 29.3%) had a ferritin level at baseline ≥1500 mg/dL, which is an accepted threshold above which to initiate chelation. Most people with an elevated ferritin had phenotypic SCA (homozygous Hb S) (n=111, or 94%). Over half of all SCD patients with a critically elevated ferritin were on CTT (n=64, 54%), and a similar number of people with SCD and critical ferritin levels were on chelation (n=64, 54%). Less than 1 in 4 had had a liver iron scan within 3 years (n=27, 23%). More than 1 in 3 patients with critical ferritin levels and no chelation therapy remained on CTT (n=21, not shown). Conclusions: Our multi-site registry, GRNDaD, prospectively surveyed a sizable population of adults with SCD, including data about iron overload. Of the adults in the GRNDaD registry with iron overload, we identified an unacceptably high fraction, nearly half, who were not on chelation. Most of these patients were people with phenotypic homozygous SCD. We are systematically addressing this deficiency with educational tools through GRNDaD. Since GRNDaD sites are academic centers across the country which focus on the management of SCD, we speculate that the problem of undertreated iron overload nationally is probably both widespread and under-recognized. We anticipate that, as GRNDaD continues to add additional sites, it will evolve as a robust resource through which to highlight important opportunities for clinical quality improvement in the expanding young adult population with SCD. GRNDaD may be a model for identifying and addressing deficiencies in current clinical practices for management of SCD. Disclosures Lanzkron: selexys: Research Funding; Ironwood: Research Funding; PCORI: Research Funding; HRSA: Research Funding; Pfizer: Research Funding; NHLBI: Research Funding; GBT: Research Funding; Prolong: Research Funding. Field:Incyte: Research Funding; Prolong: Research Funding; Ironwood: Consultancy, Research Funding. Desai:University of Pittsburgh: Research Funding; Selexy/Novartis: Research Funding; NIH: Research Funding; Ironwood: Other: Adjudication Committee; FDA: Research Funding; Pfizer: Research Funding. Little:PCORI: Research Funding; NHLBI: Research Funding; Hemex: Patents & Royalties: Patent, no honoraria; Doris Duke Charitable Foundations: Research Funding.

scholarly journals The relationships between pancreatic T2* values and pancreatic iron loading with cardiac dysfunctions,  hepatic and cardiac iron siderosis among Egyptian children and young adults with β-thalassaemia major and sickle cell disease: a cross-sectional study

F1000Research ◽  
2021 ◽  
Vol 9 ◽  
pp. 1108
Author(s):  
Khaled Salama ◽  
Amina Abdelsalam ◽  
Hadeel Seif Eldin ◽  
Eman Youness ◽  
Yasmeen Selim ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Pulmonary Artery ◽  
Iron Overload ◽  
Sickle Cell ◽  
Systolic Pulmonary Artery Pressure ◽  
Iron Loading ◽  
Thalassaemia Major ◽  
Cell Disease ◽  
Cardiac Iron ◽  
Diastolic Velocity

Background: Cardiac, hepatic and pancreatic T2* measured by magnetic resonance imaging (MRI) has been proven to be an accurate and non-invasive method for measuring iron overload in iron overload conditions. There is accumulating evidence that pancreatic iron can predict cardiac iron in young children because the pancreas loads earlier than the heart. The aim of our study was to assess the relationships between pancreatic T2* values and pancreatic iron loading with cardiac dysfunctions and liver and cardiac iron among patients with β-thalassaemia major (βTM) and sickle cell disease (SCD). Methods: 40 βTM and 20 transfusion-dependant SCD patients were included along with 60 healthy age and sex-matched controls. Echocardiography and Tissue Doppler Imaging were performed for all subjects as well as the control group.  Hepatic, cardiac and pancreatic iron overload in cases were assessed by MRI T2*. Results:  The mean age of our patients was 13.7 years with mean frequency of transfusion/year 12. Mean cardiac T2* was 32.9 ms and mean myocardial iron concentration was 0.7 mg/g; One patient had cardiac iron overload of moderate severity. Mean pancreatic T2* was 22.3 ms with 20 patients having mild pancreatic iron overload. Pancreatic T2* correlated positively peak late diastolic velocity at septal mitral annulus (r=0.269, p=0.038), peak early diastolic velocity at tricuspid annulus (r=0.430, p=0.001) and mitral annular plane systolic excursion (r=0.326, p=0.01); and negatively with end systolic pulmonary artery pressure (r=-0.343, p=0.007) and main pulmonary artery diameter (MPA) (r=-0.259, p=0.046). We couldn’t test the predictability of pancreatic T2* in relation to cardiac T2* as only one patient had cardiac T2*<20 ms. Conclusion: There was a relationship between pancreatic iron siderosis with cardiac dysfunction in multi-transfused patients with βTM and SCD. No direct relation between pancreatic iron and cardiac siderosis was detected.

Pancreatic Iron Deposition Following the Role of Iron Loading Among Transfusion Dependent Sickle Cell Disease Egyptian Children and Young Adults

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4828-4828
Author(s):  
Mohsen Saleh Elalfy ◽  
Khalid Allam ◽  
Ahmed Ibrahim ◽  
Basant Mosaad ◽  
Fatma Soliman Elsayed Ebeid
Keyword(s):  
Young Adults ◽  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Iron Loading ◽  
Cell Disease ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Iron Load

Background: Transfusion in sickle cell disease (SCD) is uncommon but a well-defined practice; either as a replacement in severe anemia or as a prophylactic therapy for its major complications mainly stroke. Differential iron loading in SCD especially the extrahepatic organs is not fully studied. Primary objective is to measure pancreatic iron load among Egyptian transfusion-dependant SCD patients by using MRI T2* relaxometry method. Secondaryobjective is to correlate pancreatic iron load to transfusion iron input, both hepatic and cardiac iron load, trend of serum ferritin. Subjects and Methods: Sixty-six transfusion-dependant SCD child and young adults 8-25 years with more than twenty transfusions before enrollment, non was on regular exchange transfusion; they underwent clinical and laboratory assessments; complete hemogram, serum ferritin and serum amylase. All patients performed MRI examination on a 1.5- Tesla super conductive MR Philips scanner in MRI unit in Ain Shams University Hospital; the study takes about 10 -15 minutes. Radiological quantification of iron overload was performed via simple mathematical models using Microsoft Excel Spread Sheet for heart, pancreas, and kidneys. Results: The mean age of the studied SCD patients were 15.68 ± 7.02 years, they were 35 male (53.0%), 43 of them (65.2%) had positive family history of SCD. All were multiple transfusion; 22 for cardiopulmonary complication and acute chest syndrome (ASC), nine for stroke prevention and 35 for frequent sickling crisis and symptomatic anemia. Most of patients (80.3%) were on chelation therapies that were mainly (92.5%) oral mono-therapy. High frequencies of comorbidities were recorded in the studied cohort; delayed puberty (65.2%), hepatitis C infection (23.1%) and stroke (14.1%). The studied SCD patients had median transfusion index of 120ml/kg/year with mean iron overload per day 0.23 ± 0.15 mg/kg and half of them had serum ferritin > 2500ug/L. Almost two-thirds had moderate to severe liver iron overload with median LIC 11.63 mg/g liver dry weight, none had cardiac iron overload with median cardiac T2* 31 msec and nearly half of them (42.2%) showed marked decrease in signal intensity of renal cortex with relative sparing of the renal medulla and pelvis. Most of them (86%) had normal to mild pancreatic iron overload with median pancreatic R2* 53.8 msec. Pancreatic R2 level was not significantly correlated to either transfused iron, liver iron or serum ferritin and amylase. Patients with moderate to severe pancreatic iron overload had lower pre-transfusion hemoglobin level (p=0.004), higher level of marker of hemolysis (total bilirubin (p=0.012) and indirect bilirubin (p=0.048) than those with normal pancreatic MRI. Radiological quantification of iron overload was performed via a simple cheap and quick method for analysis of data. Conclusion: Moderately heavy transfused patients with SCD had no iron overload in the heart; pancreas follow same pattern as heart with minimal or no pancreatic iron loading, however moderate to severe hepatic iron loading. Whether iron loading might be related only to frequency of transfusion or also to frequency of vaso-occlusive will be discussed. Disclosures No relevant conflicts of interest to declare.

Prolonged QTc in Sickle Cell Disease: A Potential Risk Factor for Early Death?

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2476-2476
Author(s):  
Sean Lindstedt ◽  
Lynne Neumayr ◽  
Gregory Kurio ◽  
Claudia Morris ◽  
Shanda Robertson ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sudden Death ◽  
Iron Overload ◽  
Sickle Cell ◽  
Iron Toxicity ◽  
Control Group ◽  
Cell Disease ◽  
Qtc Prolongation ◽  
Cardiac Iron

Abstract Background: Sudden unexplained death is one of the leading causes of mortality in sickle cell disease (SCD). Prolonged QTc has been associated with sudden death in older patients and in those with cardiac disease. Sudden death due to cardiac arrhythmias occurs in thalassemia (Thal) patients from cardiac iron toxicity, and recently, QTc prolongation has also been identified in this transfusion-dependent population. Chronic transfusion and iron overload have become more frequent in patients with SCD due to treatment regimens aimed at stroke prevention and treatment of stroke, pulmonary hypertension (PH) and recurrent vaso-occlusive crisis. Cardiac iron toxicity is thought to be rare in SCD but other factors such as anemia, PH, and hemolysis-associated nitric oxide dysregulation may predispose SCD to prolongation of the QTc interval. The purpose of this study was to examine the prevalence of QTc prolongation in chronically transfused and iron-overloaded SCD (txSCD) patients compared to a control group of non-transfused SCD patients. Methods: In this study, electrocardiograms (EKGs) were reviewed from SCD patients participating in the MCSIO, a five-year prospective study of the complications of iron toxicity in SCD and Thal. Using Bazett’s formula, a subset of 96 EKGs were analyzed for QTc prolongation, defined as ≥ 0.45 seconds and borderline as 0.44 to 0.449 seconds. Echocardiograms (ECHOs) obtained within an average of seven months were analyzed for left ventricular dysfunction (LVD) --which was defined as an ejection fraction &lt; 55% or shortening fraction &lt; 28% --and the presence of PH, defined as a tricuspid regurgitant jet velocity (TRJV) of ≥ 2.5 m/second. Results: There was no difference in mean age (25.3 ± 13.6) or gender (64% female) between the 65 txSCD and 31 control SCD patients. The txSCD group had been transfused 10 ± 6.2 years and their baseline ferritin was 3107 compared to 116 in the controls. QTc prolongation was present in 32% of the txSCD and 29% of the control group (n.s.); borderline prolongation was seen in an additional 17% and 13%, respectively. Mean QTc in txSCD was also not significantly different from the SCD controls: 0.45±.04 vs. 43±.03 (n.s.). None of the 68 patients with ECHOs had LVD. 36 patients had TRJV measured during the study: 50% of the txSCD had PH compared to 30% of non-transfused SCD (n.s.). The average QTc in PH patients was 0.45 ± .04 compared to 0.43 ± .04 in those without PH (p=.09). However, the frequency of either prolonged or borderline QTc was significantly higher in patients with PH (72% vs. 22%, p= .007). No correlations between QTc and age, gender, or baseline laboratory values (hemoglobin, white blood count, or platelets) were found. In the txSCD, QTc was not correlated to ferritin or years of transfusion. Conclusions: Overall, QTc prolongation was found in 31 % of SCD patients and borderline prolongation in an additional 16%. QTc intervals ≥ 0.44 were more common in patients with PH. Transfusion exposure and iron overload were not associated with QTc prolongation in this group of txSCD patients. The frequency of QTc prolongation is concerning in SCD patients, who often have pulmonary hypertension and are treated with medications known to contribute to QTc prolongation. Routine screening for QTc prolongation appears warranted with treatment of high-risk SCD patients.

MRI-Guided Iron Assessment and Oral Chelator Use Improve Iron Status In Thalassemia Major Patients: a Six-Year Single Center Retrospective Cohort Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 563-563 ◽  
Author(s):  
Diana X Nichols-Vinueza ◽  
Matthew T White ◽  
Andrew J Powell ◽  
Puja Banka ◽  
Ellis J. Neufeld
Keyword(s):  
Side Effects ◽  
Iron Overload ◽  
Research Funding ◽  
Iron Status ◽  
Iron Concentration ◽  
Thalassemia Major ◽  
Target Range ◽  
Single Center ◽  
Liver Iron ◽  
Cardiac Iron

Abstract Background Patients (pts) with thalassemia major (TM) require regular red blood cell transfusions. Adequate iron chelation prevents morbidity and mortality due to transfusional iron overload, and must be guided by accurate assessment of tissue iron levels. Magnetic resonance imaging (MRI) can non-invasively measure liver iron content (LIC) and cardiac iron, and has almost entirely supplanted liver biopsy for LIC at our center. The therapeutic goal is to either (a) maintain iron status within a consensus target range, or (b) decrease the iron burden in pts above the target. Three chelators are FDA approved in the US: deferoxamine (DFO), deferasirox (DFX), and deferiprone (DFP), (approval years 1968, 2005 and 2011 respectively). The aim of this study was to evaluate our ability to improve iron status over time in the MRI and oral chelator era. Methods This IRB-approved, single-center, retrospective observational study covered the period from Jan 2005, when MRI iron assessments became standard at our center, to Dec 2012. The study population included all TM pts followed for chelation at our center who had >2 MRI studies during the study period. LIC was measured by calculating T2* and, starting April 2006, also by measuring T2 using the commercial Ferriscan® technique. Liver T2* was converted to LIC using a regression equation (Wood et al. Blood, 2005; 106:1460). Cardiac iron concentration was measured by calculating cT2*; in this abstract both T2* in msec and its reciprocal R2* (1000/cT2* in Hz, which varies proportionally to iron) are reported. The target for LIC was <7 mg/g dry wt (dw), (mean of T2* and Ferriscan LIC) and for cardiac iron, cR2*<50 Hz (i.e. cT2* >20 msec). Statistical analyses were performed in SAS. Results 42 pts (55% male) met the inclusion criteria and had a median age at first MRI of 17.5y (range 1.9-43). Over a mean follow-up period of 5.2±1.9 y, 190 MRIs were performed with median of 4.5 MRIs per pt, interquartile range 3-6. In 2005, DFO was the predominant chelator (70% vs 26% on research use of chelators, DFX; n=27); DFX predominated after its commercial launch. 29/40 (73%) were on DFX by 2009, but this proportion dropped to 23/36 (64%) by 2012. 13/42 pts (31%) remained within the target ranges for cardiac T2* and LIC throughout the study period. 29/42 pts (69%) had at least one cardiac T2* or LIC out of the target range in a total of 97 MRIs. 38/97 (40%) of these out-of-range MRIs prompted a change in chelation strategy: 61% dose change only, 34% change of monotherapy agent, and 5% change from monotherapy to combination. Two pts died of heart failure due to iron overload during the study period; both had taken DFP before their deaths, but for divergent duration (3 days vs 5 y). The median number of chelation changes was 1.4 per pt/y (IQR 0.9-1.9). 175/229 (76%) dosing changes were for iron status as assessed by MRI or ferritin; 7/229 (3%) were dose decreases for side effects, and 2% were due to weight change only. Change in chelators occurred 82 times during the study. 34% of chelator changes were due to low or high iron status by MRI or Ferritin. 11% of changes were for side effects to a prior chelator and 54% were for other reasons (commercial launch of DFX or clinical trials). From initial to final MRI, both LIC and T2* status of our pts improved significantly (figure). At the initial MRI, 16/41 (40%) of pts were in target range for both LIC and cR2*, 4/41 (10%) were in the highest (undesirable) range of LIC>15 mg/g dw, and/or cardiac T2* <10 msec. From first to last cardiac T2* assessment (n=38), 63% of pts started and ended within the target range, 13% improved from abnormal to target range, 24% remained out of the target range. The two pts who died were among the persistent abnormal cardiac T2* group. For LIC (n=42), 45% remained in the target range throughout, 33% started out of target range and ended within, 12% improved but not to the target, 7% worsened, and one outlier remained severe. Conclusions The introduction of routine MRI assessments of LIC and cardiac R2* (T2*), together with the introduction of oral chelators, has improved the fraction of TM pts with liver and cardiac iron within the target range at our center. Annual MRIs facilitate chelation changes when necessary. Legend: A: Cardiac iron status from first to last MRI for each subject. Reciprocal cR2* and cT2* are on left and right Y-axes. B: Liver iron status. P-values are by Wilcoxon signed-rank test. Disclosures: Neufeld: Shire: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Apopharma: Consultancy.

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