Prediction of cardiac complications for thalassemia major in the widespread cardiac magnetic resonance era: a prospective multicentre study by a multi-parametric approach.

Aims: Cardiovascular magnetic resonance (CMR) has dramatically changed the clinical practice in thalassemia major (TM), lowering cardiac complications. We prospectively reassessed the predictive value of CMR parameters for heart failure (HF) and arrhythmias in TM. Methods and results: We considered 481 white TM patients (29.48 ± 8.93 years, 263 females) enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network. Myocardial and liver iron overload were measured by T2* multiecho technique. Atrial dimensions and biventricular function were quantified by cine images. Late gadolinium enhancement images were acquired to detect myocardial fibrosis. Mean follow-up was 57.91 ± 18.23 months. After the first CMR scan 69.6% of the patients changed chelation regimen. We recorded 18 episodes of HF. In the multivariate analysis the independent predictive factors were myocardial fibrosis (HR = 10.94, 95% CI = 3.28-36.43, P < 0.0001), homogeneous MIO (compared with no MIO) (HR = 5.56, 95% CI = 1.37-22.51, P = 0.016), ventricular dysfunction (HR = 4.33, 95% CI = 1.39-13.43, P = 0.011). Arrhythmias occurred in 16 patients. Among the CMR parameters only the atrial dilation was identified as univariate prognosticator (HR = 4.26 95% CI=1.54-11.75, P = 0.005). Conclusions: CMR guided the change of chelation therapy in nearly 70% of patients, leading to a lower risk of iron-mediated HF and of arrhythmias than previously reported. Homogeneous MIO remained a risk factor for HF but also myocardial fibrosis and ventricular dysfunction identified patients at high risk. Arrhythmias were independent of MIO but increased with atrial dilatation. CMR by a multi-parametric approach dramatically improves cardiac outcomes and provides prognostic information beyond cardiac iron estimation.

How we manage iron overload in sickle cell patients.

Blood transfusion plays a prominent role in the management of patients with sickle cell disease (SCD), but causes significant iron overload. As transfusions are used to treat the severe complications of SCD, it remains difficult to distinguish whether organ damage is a consequence of iron overload or is due to the complications treated by transfusion. Better management has resulted in increased survival, but prolonged exposure to iron puts SCD patients at greater risk for iron-related complications that should be treated. The success of chelation therapy is dominated by patient adherence to prescribed treatment; thus, adjustment of drug regimens to increase adherence to treatment is critical. This review will discuss the current biology of iron homeostasis in patients with SCD and how this informs our clinical approach to treatment. We will present the clinical approach to treatment of iron overload at our centre using serial assessment of organ iron by magnetic resonance imaging.

Management of iron overload in hemoglobinopathies: what is the appropriate target iron level?

Patients with thalassemia become iron overloaded from increased absorption of iron, ineffective erythropoiesis, and chronic transfusion. Before effective iron chelation became available, thalassemia major patients died of iron-related cardiac failure in the second decade of life. Initial treatment goals for chelation therapy were aimed at levels of ferritin and liver iron concentrations associated with prevention of adverse cardiac outcomes and avoidance of chelator toxicity. Cardiac deaths were greatly reduced and survival was much longer. Epidemiological data from the general population draw clear associations between increased transferrin saturation (and, by inference, labile iron) and early death, diabetes, and malignant transformation. The rate of cancers now seems to be significantly higher in thalassemia than in the general population. Reduction in iron can reverse many of these complications and reduce the risk of malignancy. As toxicity can result from prolonged exposure to even low levels of excess iron, and survival in thalassemia patients is now many decades, it would seem prudent to refocus attention on prevention of long-term complications of iron overload and to maintain labile iron and total body iron levels within a normal range, if expertise and resources are available to avoid complications of overtreatment.

Estimating tissue iron burden: current status and future prospects.

Iron overload is becoming an increasing problem as haemoglobinopathy patients gain greater access to good medical care and as therapies for myelodysplastic syndromes improve. Therapeutic options for iron chelation therapy have increased and many patients now receive combination therapies. However, optimal utilization of iron chelation therapy requires knowledge not only of the total body iron burden but the relative iron distribution among the different organs. The physiological basis for extrahepatic iron deposition is presented in order to help identify patients at highest risk for cardiac and endocrine complications. This manuscript reviews the current state of the art for monitoring global iron overload status as well as its compartmentalization. Plasma markers, computerized tomography, liver biopsy, magnetic susceptibility devices and magnetic resonance imaging (MRI) techniques are all discussed but MRI has come to dominate clinical practice. The potential impact of recent pancreatic and pituitary MRI studies on clinical practice are discussed as well as other works-in-progress. Clinical protocols are derived from experience in haemoglobinopathies but may provide useful guiding principles for other iron overload disorders, such as myelodysplastic syndromes.

A significant proportion of thalassemia major patients have adrenal insufficiency detectable on provocative testing.

Advances in chelation therapy and noninvasive monitoring of iron overload have resulted in substantial improvements in the survival of transfusion-dependent patients with thalassemia major. Myocardial decompensation and sepsis remain the major causes of death. Although endocrine abnormalities are a well-recognized problem in these iron-overloaded patients, adrenal insufficiency and its consequences are underappreciated by the hematology community. The aims of this study were to determine the prevalence of adrenal insufficiency in thalassemia major subjects, to identify risk factors for adrenal insufficiency, and to localize the origin of the adrenal insufficiency within the hypothalamic-pituitary-adrenal axis. Eighteen subjects with thalassemia major (18.9±9.3 y old, 7 female) were tested for adrenal insufficiency using a glucagon stimulation test. Those found to have adrenal insufficiency (stimulated cortisol <18 µg/dL) subsequently underwent an ovine corticotropin-releasing hormone (oCRH) stimulation test to define the physiological basis for the adrenal insufficiency. The prevalence of adrenal insufficiency was 61%, with an increased prevalence in males over females (92% vs. 29%, P=0.049). Ten of 11 subjects who failed the glucagon stimulation test subsequently demonstrated normal ACTH and cortisol responses to oCRH, indicating a possible hypothalamic origin to their adrenal insufficiency.

Dose titration of deferasirox iron chelation therapy by magnetic resonance imaging for chronic iron storage disease in three adult red bald-headed uakari (Cacajao calvus rubicundus).

Iron overload is common in lemurs and some New World nonhuman primates raised in captivity, but there is no such documentation in the red bald-headed uakari (Cacajao calvus rubicundus). This study describes postmortem documentation of severe iron storage disease in one red bald-headed uakari and the use of iron chelation with oral deferasirox in the three surviving members of the colony. Magnetic resonance imaging was used to quantify pretreatment iron burden and to follow the response to therapy in two females, 22 and 28 yr of age, and one male 33 yr of age. Baseline liver iron concentrations ranged from 16 to 23 mg/g dry weight. In humans, a liver iron concentration greater than 15 mg/g is considered severe and associated with endocrine and cardiac toxicity. The uakaris were otherwise asymptomatic, generally healthy, nonpregnant, and on a stable, low-iron diet. Quantitative magnetic resonance imaging indicated that dosage escalations up to 100 mg/kg were needed to produce meaningful reductions in iron stores. After 5 yr of therapy, two animals continue at a dosage of 100 mg/kg per day, and the third was transitioned to twice-weekly maintenance dosing because of successful de-ironing. The animals tolerated iron chelation therapy well, having stable hematologic, renal, and hepatic function profiles before, during, and after treatment. Deferasirox monotherapy may represent a therapeutic option in primates with iron storage disease when dietary measures are ineffective and phlebotomy is logistically challenging.

Use of magnetic resonance imaging to monitor iron overload.

Treatment of iron overload requires robust estimates of total-body iron burden and its response to iron chelation therapy. Compliance with chelation therapy varies considerably among patients, and individual reporting is notoriously unreliable. Even with perfect compliance, intersubject variability in chelator effectiveness is extremely high, necessitating reliable iron estimates to guide dose titration. In addition, each chelator has a unique profile with respect to clearing iron stores from different organs. This article presents the tools available to clinicians to monitor their patients, focusing on noninvasive magnetic resonance imaging methods because they have become the de facto standard of care.

R2 and R2* are equally effective in evaluating chronic response to iron chelation.

MRI relaxometry (R2, R2*) has generally replaced liver biopsy for estimation of liver iron stores in response to iron chelation, but there have been no longitudinal studies comparing R2 and R2* techniques. We use R2 and R2* liver iron concentration (LIC) estimates, transfusional iron burdens, and drug compliance data to calculate iron chelation efficiency (ICE) in patients undergoing a Phase II trial of SPD602. Fifty-one patients underwent a baseline examination, 39 patients completed 1 year, and 26 patients completed 2 years. Baseline LICR2 and LICR2* estimates were unbiased, but had limits of agreement exceeding 50%, suggesting that these techniques cannot be interchanged with one another in the same patient. However, ICE estimates across the two techniques compared more favorably, with r(2) values reaching 0.89 at 2 years. 95 confidence intervals for efficiency estimates were 0.0 ± 4.1%. These data indicate that clinical trial and clinical effectiveness data calculated using LICR2 and LICR2* estimates can be compared to one another, even though LIC estimates may be disparate on cross-sectional analysis. While the choice of MRI assessment technique for clinical trials and for clinical management depends on many logistical considerations, one can have confidence comparing conclusions on clinical effectiveness.

Guidelines for quantifying iron overload.

Both primary and secondary iron overload are increasingly prevalent in the United States because of immigration from the Far East, increasing transfusion therapy in sickle cell disease, and improved survivorship of hematologic malignancies. This chapter describes the use of historical data, serological measures, and MRI to estimate somatic iron burden. Before chelation therapy, transfusional volume is an accurate method for estimating liver iron burden, whereas transferrin saturation reflects the risk of extrahepatic iron deposition. In chronically transfused patients, trends in serum ferritin are helpful, inexpensive guides to relative changes in somatic iron stores. However, intersubject variability is quite high and ferritin values may change disparately from trends in total body iron load over periods of several years. Liver biopsy was once used to anchor trends in serum ferritin, but it is invasive and plagued by sampling variability. As a result, we recommend annual liver iron concentration measurements by MRI for all patients on chronic transfusion therapy. Furthermore, it is important to measure cardiac T2* by MRI every 6-24 months depending on the clinical risk of cardiac iron deposition. Recent validation data for pancreas and pituitary iron assessments are also presented, but further confirmatory data are suggested before these techniques can be recommended for routine clinical use.

Ascorbate status modulates reticuloendothelial iron stores and response to deferasirox iron chelation in ascorbate-deficient rats.

Iron chelation is essential to patients on chronic blood transfusions to prevent toxicity from iron overload and remove excess iron. Deferasirox (DFX) is the most commonly used iron chelator in the United States; however, some patients are relatively refractory to DFX therapy. We postulated that vitamin C supplementation would improve the availability of transfusional iron to DFX treatment by promoting iron's redox cycling, increasing its soluble ferrous form and promoting its release from reticuloendothelial cells. Osteogenic dystrophy rats (n = 54) were given iron dextran injections for 10 weeks. Cardiac and liver iron levels were measured after iron loading (n = 18), 12 weeks of sham chelation (n = 18), and 12 weeks of DFX chelation (n = 18) at 75 mg/kg/day. Ascorbate supplementation of 150 ppm, 900 ppm, and 2250 ppm was used in the chow to mimic a broad range of ascorbate status; plasma ascorbate levels were 5.4 ± 1.9, 8.2 ± 1.4, 23.6 ± 9.8 µM, respectively (p < 0.0001). The most severe ascorbate deficiency produced reticuloenthelial retention, lowering total hepatic iron by 29% at the end of iron loading (p < 0.05) and limiting iron redistribution from cardiac and hepatic macrophages during 12 weeks of sham chelation. Most importantly, ascorbate supplementation at 2250 ppm improved DFX efficiency, allowing DFX to remove 21% more hepatic iron than ascorbate supplementation with 900 ppm or 150 ppm (p < 0.05). We conclude that vitamin C status modulates the release of iron from the reticuloendothelial system and correlates positively with DFX chelation efficiency. Our findings suggest that ascorbate status should be probed in patients with unsatisfactory response to DFX.

Iron overload in non-transfusion-dependent thalassemia: a clinical perspective.

Iron overload due to increased intestinal iron absorption represents an important clinical problem in patients with non-transfusion-dependent thalassemia (NTDT), particularly as they advance in age. Current models for iron metabolism in patients with beta (ß)-thalassemia intermedia (TI) suggest that suppression of serum hepcidin results in increased iron absorption and release of iron from the reticuloendothelial system, leading to depletion of macrophage iron, relatively low levels of serum ferritin, and liver iron loading. The clinical consequences of iron overload in patients with NTDT are multifactorial and include endocrinopathy, bone disease, thromboembolism, pulmonary hypertension, cerebrovascular and neuronal damage, liver fibrosis or cirrhosis, and increased risk of hepatocellular carcinoma. Although serum ferritin levels correlate with liver iron concentration (LIC), they underestimate iron load in these patients compared with transfusion-dependent patients with equivalent LIC. Therefore, direct measurement of LIC is recommended with chelation therapy as indicated.

Pituitary iron and volume predict hypogonadism in transfusional iron overload.

Hypogonadism is the most common morbidity in patients with transfusion-dependent anemias such as thalassemia major. We used magnetic resonance imaging (MRI) to measure pituitary R2 (iron) and volume to determine at what age these patients develop pituitary iron overload and volume loss. We recruited 56 patients (47 with thalassemia major, five with chronically transfused thalassemia intermedia and four with Blackfan-Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Hypogonadism was defined clinically based on the timing of secondary sexual characteristics or the need for sex hormone replacement therapy. Patients with transfusional iron overload begin to develop pituitary iron overload in the first decade of life; however, clinically significant volume loss was not observed until the second decade of life. Severe pituitary iron deposition (Z > 5) and volume loss (Z < -2.5) were independently predictive of hypogonadism. Pituitary R2 correlated significantly with serum ferritin as well as liver, pancreatic, and cardiac iron deposition by MRI. Log pancreas R2* was the best single predictor for pituitary iron, with an area under the receiving operator characteristic curve of 0.88, but log cardiac R2* and ferritin were retained on multivariate regression with a combined r(2) of 0.71. Pituitary iron overload and volume loss were independently predictive of hypogonadism. Many patients with moderate-to-severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. The subset of hypogonadal patients having preserved gland volumes may also explain improvements in pituitary function observed following intensive chelation therapy.

Pancreatic iron and glucose dysregulation in thalassemia major.

Pancreatic iron overload and diabetes mellitus (DM) are common in thalassemia major patients. However, the relationship between iron stores and glucose disturbances is not well defined. We used a frequently sampled oral glucose tolerance test (OGTT), coupled with mathematical modeling, and magnetic resonance imaging (MRI) to examine the impact of pancreatic, cardiac, and hepatic iron overload on glucose regulation in 59 patients with thalassemia major. According to OGTT results, 11 patients had DM, 12 had impaired glucose tolerance (IGT), 8 had isolated impaired fasting glucose (IFG), and 28 patients had normal glucose tolerance (NGT). Patients with DM had significantly impaired insulin sensitivity and insulin release. Insulin resistance was most strongly associated with markers of inflammation and somatic iron overload, while disposition index (DI) (a measure of beta cell function) was most strongly correlated with pancreas R2*. Patients with DM and IGT had significantly worse DI than those with NGT or IFG, suggesting significant beta cell toxicity. One-third of patients having elevated pancreas R2* had normal glucose regulation (preclinical iron burden), but these patients were younger and had lower hepatic iron burdens. Our study indicates that pancreatic iron is the strongest predictor of beta cell toxicity, but total body iron burden, age, and body habitus also influence glucose regulation. We also demonstrate that MRI and fasting glucose/insulin are complementary screening tools, reducing the need for oral glucose tolerance testing, and identify high-risk patients before irreversible pancreatic damage.

Impact of iron assessment by MRI.

The use of magnetic resonance imaging (MRI) to estimate tissue iron was conceived in the 1980s, but has only become a practical reality in the last decade. The technique is most often used to estimate hepatic and cardiac iron in patients with transfusional siderosis and has largely replaced liver biopsy for liver iron quantification. However, the ability of MRI to quantify extrahepatic iron has had a greater impact on patient care and on our understanding of iron overload pathophysiology. Iron cardiomyopathy used to be the leading cause of death in thalassemia major, but is now relatively rare in centers with regular MRI screening of cardiac iron, through earlier recognition of cardiac iron loading. Longitudinal MRI studies have demonstrated differential kinetics of uptake and clearance among the difference organs of the body. Although elevated serum ferritin and liver iron concentration (LIC) increase the risk of cardiac and endocrine toxicities, some patients unequivocally develop extrahepatic iron deposition and toxicity despite having low total body iron stores. These observations, coupled with the advent of increasing options for iron chelation therapy, are allowing clinicians to more appropriately tailor chelation therapy to individual patient needs, producing greater efficacy with fewer toxicities. Future frontiers in MRI monitoring include improved prevention of endocrine toxicities, particularly hypogonadotropic hypogonadism and diabetes.

Relaxivity-iron calibration in hepatic iron overload: probing underlying biophysical mechanisms using a Monte Carlo model.

Iron overload is a serious condition for patients with ß-thalassemia, transfusion-dependent sickle cell anemia, and inherited disorders of iron metabolism. MRI is becoming increasingly important in noninvasive quantification of tissue iron, overcoming the drawbacks of traditional techniques (liver biopsy). Effective transverse relaxation rate (1/effective transverse relaxation time) rises linearly with iron while transverse relaxation rate (1/T2) has a curvilinear relationship in human liver. Although recent work has demonstrated clinically valid estimates of human liver iron, the calibration varies with MRI sequence, field strength, iron chelation therapy, and organ imaged, forcing recalibration in patients. To understand and correct these limitations, a thorough understanding of the underlying biophysics is of critical importance. Toward this end, a Monte Carlo-based approach, using human liver as a "model" tissue system, was used to determine the contribution of particle size and distribution on MRI signal relaxation. Relaxivities were determined for hepatic iron concentrations ranging from 0.5 to 40 mg iron per gram dry tissue weight. Model predictions captured the linear and curvilinear relationship of effective transverse relaxation rate and transverse relaxation rate with hepatic iron concentrations, respectively, and were within in vivo confidence bounds; contact or chemical exchange mechanisms were not necessary. A validated and optimized model will aid understanding and quantification of iron-mediated relaxivity in tissues where biopsy is not feasible (heart and spleen).

Cardiovascular MRI in thalassemia major.

MRI assessment of myocardial iron and function has revolutionized the treatment of thalassemia major patients. While knowledge of somatic iron stores is vital for iron chelation management, it does not adequately monitor cardiac risk. MRI monitoring of cardiac T2* allows preclinical recognition of myocardial iron, stratifies prospective cardiac risk, and tracks response to modifications in iron chelation therapy. MRI assessment of cardiac function complements T2* measurements by offering highly accurate and reproducible assessments of ventricular function. This manuscript describes the historical context of cardiac toxicity in thalassemia major, the introduction of cardiac T2* methods in the early 2000s, and the impact of these techniques on patient care as well as our fundamental understanding of iron cardiomyopathy. Technical details regarding T2* image acquisition and postprocessing are also discussed. As barriers to widespread implementation are being overcome, cardiac T2* is rapidly transitioning from a clinical research tool to the standard of care.

Follow-up report on the 2-year cardiac data from a deferasirox monotherapy trial.

The trial CICL670AUS04 was a single-arm, open-label study of the cardiac efficacy of 18 months of deferasirox monotherapy [1]. Cardiac response in this study was related to the degree of liver siderosis. Patients with mild to moderate liver siderosis improved their cardiac T2* while more severely siderotic patients did not, regardless of initial cardiac iron burden. In this letter, we report 2-year data in those patients who completed a 6-month extension phase (N 5 10). Cardiac and liver iron improved steadily during the 24-month period, with final cardiac T2* and LIC improving 37% and 27%, respectively, in this cohort. Serum ferritin and LVEF were not statistically different at anytime-point. When the extension phase (18-24 months) was considered in isolation, serum ferritin, liver iron concentration, and left ventricular ejection fraction were nearly identical to 18 month results. Despite this, cardiac T2* continued to trend higher, increasing 12.7% from 9.5 ms to 10.7 ms (P 5 0.06). Thus defersirox continued to demonstrate cardiac efficacy in patients with mild to moderate hepatic siderosis throughout 2 years of therapy.

Absence of cardiac siderosis despite hepatic iron overload in Italian patients with thalassemia intermedia: an MRI T2* study.

Cardiac involvement in patients with thalassemia intermedia (TI) is characterized by a high-output state and pulmonary hypertension, with systolic left ventricle function usually being preserved. Myocardial iron overload in patients with TI has not been extensively studied. We conducted a cross-sectional study of 49 Italian patients with TI. Patient charts were reviewed and data collected for transfusion and iron chelation history, status of the spleen, and comorbid illnesses or infections. Blood samples were obtained for assessment of hemoglobin, serum ferritin, and liver enzyme levels. Doppler echocardiography was done for all patients. Cardiac and hepatic iron levels were measured by magnetic resonance imaging T2*. The mean age was 40.5 +/- 8.3 years, with a male to female ratio of 29:20. A total of 34 (69.4%) patients were splenectomized, and four patients had evidence of hepatitis C infection. Around 45% of patients were transfusion naïve while the rest received infrequent (47%) or regular (8%) transfusions. A total of 31 (63.3%) patients were maintained on iron chelation therapy. None of the patients had evidence of heart failure. Mean serum ferritin and liver iron concentration were 1,060.2 ng/ml and 8.2 mg Fe per gram dry weight, respectively. None of the patients had evidence of cardiac iron overload (mean cardiac T2* = 38.7 +/- 11.0 ms). There were no statistically significant correlation between cardiac T2* values and liver iron concentration, serum ferritin, or any patient, disease, or treatment-related parameters. Patients with TI show absence of cardiac iron overload even if hepatic iron accumulation is significant.

Pancreatic iron loading predicts cardiac iron loading in thalassemia major.

Diabetes mellitus and cardiomyopathy are common in chronically transfused thalassemia major patients, occurring in the second and third decades of life. We postulated that pancreatic iron deposition would precede cardiac iron loading, representing an environment favorable for extrahepatic iron deposition. To test this hypothesis, we examined pancreatic and cardiac iron in 131 thalassemia major patients over a 4-year period. Cardiac iron (R2* > 50 Hz) was detected in 37.7% of patients and pancreatic iron (R2* > 28 Hz) in 80.4% of patients. Pancreatic and cardiac R2* were correlated (r(2) = 0.52), with significant pancreatic iron occurring nearly a decade earlier than cardiac iron. A pancreatic R2* less than 100 Hz was a powerful negative predictor of cardiac iron, and pancreatic R2* more than 100 Hz had a positive predictive value of more than 60%. In serial analysis, changes in cardiac iron were correlated with changes in pancreatic iron (r(2) = 0.33, P < .001), but not liver iron (r(2) = 0.025, P = .25). As a result, pancreatic R2* measurements offer important early recognition of physiologic conditions suitable for future cardiac iron deposition and complementary information to liver and cardiac iron during chelation therapy. Staging abdominal and cardiac magnetic resonance imaging examinations could significantly reduce costs, magnet time, and need for sedation in young patients.

Cardiac iron across different transfusion-dependent diseases.

Iron overload occurs in patients who require regular blood transfusions to correct genetic and acquired anaemias, such as beta-thalassaemia major, sickle cell disease, and myelodysplastic syndromes. Although iron overload causes damage in many organs, accumulation of cardiac iron is a leading cause of death in transfused patients with beta-thalassaemia major. The symptoms of cardiac iron overload will occur long after the first cardiac iron accumulation, at a point when treatment is more complex than primary prevention would have been. Direct measurement of cardiac iron using T2* magnetic resonance imaging, rather than indirect methods such as measuring serum ferritin levels or liver iron concentration have contributed to earlier recognition of myocardial iron loading and prevention of cardiac toxicity. Cardiac siderosis occurs in all transfusional anaemias, but the relative risk depends upon the underlying disease state, transfusional load, and chelation history. All three available iron chelators can be used to remove cardiac iron, but each has unique physical properties that influence their cardiac efficacy. More prospective trials are needed to assess the effects of single-agent or combination iron chelation therapy on the levels of cardiac iron and cardiac function. Ultimately, iron chelation therapies should be tailored to meet individual patient needs and lifestyle demands.