Early Detection Of Iron Overload Research Articles

Optimized serum ferritin prediction of iron overload in transfusion-dependent thalassemia: likelihood ratio and age-adjustment approach.

Early detection of iron overload in transfusion-dependent thalassemia (TDT) patients is critical to prevent complications and improve survival. Evaluate the utility of serum ferritin (SF) in the prediction of hepatic and myocardial iron overload (HIO and MIO) compared to T2*-MRI. Retrospective SETTINGS: Governmental hospitals. Patients with TDT who had T2*-MRI examinations between January 2016 to October 2019 were included. The predictive value of SF for detection of HIO and MIO was assessed by measuring area under the curve (AUC). A sample size of 123 cases was calculated to detect a correlation of 0.25 with 90% power and a two-sided type I error of 0.05. The correlation between SF and estimated hepatic iron concentration. 137 TDT patients who required regular blood transfusions. The predictive value of SF was excellent for detection of HIO (AUC=0.83-0.87) but fair for detection of MIO (AUC=0.67). The two independent predictors of MIO were age and SF. The log of (age × SF) enhanced the SF predictive value for MIO (AUC=0.78). SF values of 700 and 1250 mg/L effectively excluded mild and moderate HIO with a sensitivity of 97.8% and 94.2%, respectively (LR-=0.1). While SF values of 1640 and 2150 mg/L accurately diagnosed mild and moderate HIO with a specificity of 95.55% and 96.4%, respectively (LR+>10). A log of (age × SF) cut-off value of 4.15 effectively excluded MIO (LR-=0.1), while a value of 4.65 moderately confirmed MIO (LR+=3.2). SF is an excellent predictor of hepatic IO in TDT. Age adjustment enhanced its myocardial IO predictive accuracy. Likelihood ratio-based SF cut-off values may help clinicians in risk stratification and treatment decision-making. The laboratory data were gathered retrospectively and although the risk of selection bias for T2*-MRI examination is thought to be low, it cannot be ignored. None.

The Dysregulation of Hepcidin-Ferroportin Axis in Childhood Acute Lymphoblastic Leukemia Survivors after Completion of Chemotherapy

Background The hepcidin-ferroportin axis is known to play the essential role on iron homeostasis in human. The binding of hepcidin to ferroportin (FPN) on the membranes of iron-exporting cells induces the ubiquitination of FPN and thereby decreases the delivery of iron to plasma. Low hepcidin with high FPN was well established in patients with ineffective erythropoiesis, e.g. beta-thalassemia major and myelodysplastic syndrome. On the other hand, studies showed increased hepcidin accompanied with decreased FPN in patients with some cancers. Further, anemia in multiple myeloma and Hodgkin's lymphoma were reported to be associated with high hepcidin levels (Blood 2008;112:4292). Here, we investigated the function of the hepcidin-ferroportin axis in childhood acute lymphoblastic leukemia (ALL) survivors who completed chemotherapy. Methods Thirty-three children, aged ≤18 years with ALL and completing TPOG-ALL-2013 protocol before June 30, 2020, were enrolled (ALL-off Gr). According to the treatment protocol, they had been classified as standard-risk (SR) in 20, high-risk (HR) in 12 and very-high-risk (VHR) in 1, respectively. Thirty-eight healthy siblings were assigned as the normal controls (normal Gr) after exclusion of acute illness and iron deficiency. Twenty newly-diagnosed ALL children (ALL-Dx Gr) who did not have sepsis at diagnosis (Dx), and 13 patients with beta-thalassemia major (TM Gr) who received regular transfusion were also enrolled. Serum iron, total iron-binding capacity, ferritin, hepcidin and FPN were collected at Dx in ALL-Dx Gr and at 6-month follow-up after completion of chemotherapy in ALL-off Gr. Selected biochemical assays were checked in normal Gr and TM Gr on the day of routine RBC transfusion. Hepcidin and FPN levels of peripheral blood were measured using ELISA kits (DRG, EIA-5782 for hepcidin & Elabscience, E-EL-H2355 for FPN, respectively). Results The clinical features and biochemical data of all patients are shown in Table 1. The hepcidin and FPN of normal Gr were comparable with those of reference papers. The low hepcidin, high FPN and relatively low hepcidin/ferritin of TM Gr were in consistent with those of published reports. There were no significant differences of age (P =.243) and gender (P =.899) between ALL-off Gr and normal Gr. The ferritin and transferrin saturation between ALL-Dx and ALL-off Grs showed statistical difference (P <.001 and P =.02, respectively). In figure 1, the hepcidin and FPN levels of ALL-Dx Gr were significantly higher than those of the normal Gr (P <.001). The trends remained but did not reach statistical significances between ALL-off and normal Grs. None of ALL-off Gr had mutation of HFE C282Y/H63D, HJV C119F or SLC40A1 C326S. Further, in ALL-off Gr, 6 patients had abnormal ferritin levels (>300 ng/mL; median, 871.55; range, 351.6-959.0)(high-ferritin). MRI scans of liver and heart from the 6 high-ferritin patients did not show any evidence of iron overload. In Figure 2, hepcidin levels were significantly higher in ALL-off patients with high-ferritin or receiving cumulative RBC transfusions >10 units. And ALL-off patients with high-ferritin, RBC transfusions >10 units or receiving HR/VHR treatment regimens had significantly higher FPN levels. Multivariate analysis demonstrated only high-ferritin predicted significantly higher hepcidin (P =.02) and FPN (P <.001) levels in ALL-off Gr. Conclusions The dysregulation of hepcidin-ferroportin axis showed high hepcidin and uncontrolled FPN hyperactivity at Dx of childhood ALL which may point to the impaired down-regulation of FPN by hepcidin. Our findings imply the impaired mechanism may not be fully recovered in ALL survivors after completing chemotherapy, especially those with ferritin >300 ng/mL, HR/VHR groups or receiving higher RBC transfusions. The routine monitoring of the axis function could facilitates the early detection of iron overload in liver and heart. Disclosures No relevant conflicts of interest to declare.

Global longitudinal strain as an Indicator of cardiac Iron overload in thalassemia patients

Background and objectiveCardiac involvement due to iron overload is the most common cause of morbidity and mortality in patients with thalassemia, and many patients remain asymptomatic until the late stages. Therefore, early detection of heart problems in such patients at subclinical stages can improve the prognosis of these patients. We investigated the role of speckled tracking (SI) and tissue Doppler echocardiography (TDI) in early detection of iron overload in these patients.Methods52 thalassemic patients who were receiving regular blood transfusion with normal global LV function were examined by two- and three-dimensional echocardiography. Cardiac MRI was done and T2* images were considered as the non-invasive gold standard for evaluating cardiac iron deposition. Serum ferritin level was assessed and the relationships between serum ferritin levels and echo finding with cardiac MRI T2* was investigated.ResultsNo significant relationship was seen between serum ferritin levels and cardiac MRI T2*. Among the echocardiographic findings, septal systolic myocardial velocity (P = 0.002 and r = 0.43) and global strain (GLS) (P = 0.000 and r = 0.60) were significantly associated with T2*. A GLS < 19.5 could predict a T2* level below 20 by 82.14% sensitivity and 86.36% specificity (area under the curve = 0.87; p < 0.0001).ConclusionWhile serum ferritin level and ejection fraction are not useful candidates, GLS may be used as a valuable marker to screen thalassemia patients for myocardial iron deposition, using a cut off value below − 19.5. This approach may facilitate the cardiac follow up, reduce the costs, and contribute to preventing deterioration of cardiac function in countries with limited availability of cardiac MRI.

Hepatocellular Carcinoma in β-Thalassemia Patients: Review of the Literature with Molecular Insight into Liver Carcinogenesis.

With the continuing progress in managing patients with thalassemia, especially in the setting of iron overload and iron chelation, the life span of these patients is increasing, while concomitantly increasing incidences of many diseases that were less likely to show when survival was rather limited. Hepatocellular carcinoma (HCC) is a major life-threatening cancer that is becoming more frequently identified in this population of patients. The two established risk factors for the development of HCC in thalassemia include iron overload and viral hepatitis with or without cirrhosis. Increased iron burden is becoming a major HCC risk factor in this patient population, especially in those in the older age group. As such, screening thalassemia patients using liver iron concentration (LIC) measurement by means of magnetic resonance imaging (MRI) and liver ultrasound is strongly recommended for the early detection of iron overload and for implementation of early iron chelation in an attempt to prevent organ-damaging iron overload and possibly HCC. There remain lacking data on HCC treatment outcomes in patients who have thalassemia. However, a personalized approach tailored to each patient’s comorbidities is essential to treatment success. Multicenter studies investigating the long-term outcomes of currently available therapeutic options in the thalassemia realm, in addition to novel HCC therapeutic targets, are needed to further improve the prognosis of these patients.

Hepatocellular Carcinoma in a β-Thalassemia Intermedia Patient: Yet Another Case in the Expanding Epidemic

The incidence of hepatocellular carcinoma (HCC) in patients with thalassemia is increasing, the two well recognized HCC risk factors in thalassemia being iron overload and chronic hepatitis C. The carcinogenicity of iron is related to its induction of oxidative damage, whereas chronic hepatitis leads to necroinflammation that can accelerate progression to HCC. We hereby report the case of a non transfused, hepatitis C-negative, β-thalassemia intermedia (β-TI) patient from our practice who had evidence of significant iron overload, suggesting the importance of increased iron burden as a HCC risk factor in this patient population. As such, screening thalassemia patients using magnetic resonance imaging (MRI)-based liver iron concentration (LIC) measurement and liver ultrasound is strongly recommended for early detection of iron overload and HCC, respectively. Data appears to be lacking on HCC treatment outcomes in patients who have thalassemia, but an approach tailored to each patient’s comorbidities is key to treatment success. The prognosis of these patients can be improved by multicenter studies investigating novel HCC therapeutic targets in the thalassemia realm.

Hepatocellular carcinoma as an emerging morbidity in the thalassemia syndromes: A comprehensive review.

The incidence of hepatocellular carcinoma (HCC) in patients with thalassemia is on the rise. The 2 well recognized HCC risk factors in thalassemia are iron overload and chronic viral infection with hepatitis C. The carcinogenicity of iron is related to its induction of oxidative damage, which results in genotoxicity, and to immunologic dysregulation, which attenuates cancer immune surveillance. Chronic hepatitis B and C infections lead to necroinflammation, which can prompt progression to HCC, but an independent role of hepatitis B virus in hepatic carcinogenesis among patients with thalassemia has not been demonstrated. Screening patients who have thalassemia using magnetic resonance imaging-based liver iron concentration measurement and liver ultrasound is recommended for early detection of iron overload and HCC, respectively. Prevention primarily resides in hepatitis B vaccination, donor blood screening, hepatitis treatment, and iron chelation. Although solid data is lacking on the outcomes of HCC treatment in patients with thalassemia, a personalized approach tailored to the individual patient's comorbidities remains necessary for treatment success. Treatment modalities for HCC include surgical resection, chemoembolization, and liver transplantation, among others. Multicenter studies are needed to better explore therapeutic targets that can improve the prognosis of these patients. Cancer 2017;123:751-58. © 2016 American Cancer Society.

Study of Male Sex Hormone Levels in Male Egyptian Children with Beta-Thalassemia: Correlation with Iron load

Beta thalassemia is an inherited hemoglobin disorder resulting in chronic hemolytic anemia. RBCs hemolysis and repeated blood transfusions are the major causes of secondary iron overload which leads to deposition of iron in different endocrine glands. Delayed puberty and hypogonadism are the most obvious clinical consequences of iron overload. The aim of this study was to evaluate male sex hormone levels in male children with β- thalassemia major in correlation with iron overload. The present study was conducted on 60 male children with β- thalassemia major with serum ferritin of more than 1000 ng/ml with their age ranging from 11-18 years and mean age value of 14.16±2.48 (Group I) and 60 male children with β- thalassemia major of matched age with no iron overload (Group II). For all children in both groups the following were done: Complete blood count, Hb electrophoresis, serum ferritin, serum iron, TIBC, serum testosterone levels and assessment of testicular volume by ultrasound and Orchidometer. Serum iron and ferritin were significantly higher while TIBC, serum testosterone levels and testicular volume were significantly lower in Group I than Group II (Mean serum iron was 221.70 ± 46.76 in group I versus 122.45 ± 14.32 in group II with p value of 0.001, mean serum ferritin was 2595.06 ± 903.43 in group I versus 373.75 ± 6.82 in group II with p value of 0.001, mean serum TIBC was 210.93 ± 18.17 in group I versus 311.40 ± 13.57 in group II with p value of 0.001, mean serum testosterone was 1.01±1.61 in group I versus 2.73±2.66 in group II with p value of 0.006, mean testicular volume was 4.45± 4.92 in group I versus 8.66±7.08 in group II with p value of 0.016). There was significant negative correlation between serum ferritin and serum testosterone and between serum ferritin and testicular volume in studied patients in group I (r = -0.457 and p value = 0.011 for correlation between ferritin and testosterone and r = -0.908 and p value = 0.001 for correlation between ferritin and testicular volume). Male sex hormone and testicular volume were significantly lower in thalassemic patients with iron overload, significant negative correlation and serum ferritin. Regular follow up for thalassemia patients for early detection of iron overload with regular assessment of puberty as thalassemic patients are vulnerable to develop hypogonadism and may require sex hormone replacement therapy.

Central Role of LIC-R2 (Ferriscan®) Determination in Patients with Hemoglobinopathies: Licnet Experience

▪The main cause of mortality in the thalassemia population remains iron-induced cardiac failure (Borga-Pignatti et al Ann N Y Acad Sci 2005); in addition iron overload in the liver, pancreas and other organs causes progressive damage . Iron overload in human tissues can be treated by chelation therapy. Thus, early detection of iron overload is crucial. Nowdays liver iron overload in human tissues can be monitored noninvasively by magnetic resonance imaging (MRI) by two techniques, T2* and R2 MRI (Ferriscan®). There is not too much literature that compares the two methods in hemoglobinopathies. Our center instituted a network, LICNET (Liver Iron Cutino Network), promoted from Piera Cutino partnership and addressed to the diagnostics of iron overload in liver by R2 MRI in patients with hemoglobinopathies.Patients with thalassemia Major (TM), thalassemia intermedia (TI) and Sickle-Cell/b-thalassemia (S/b-T)), were retrospectively considered for this study. Primary endpoint was to evaluate agreement between T2* and R2 MRI measures of liver iron concentration (LIC) using a Bland-Altman (B-A) method that compares differences between observations on the same patient made with the two methods (Bland & Altman Lancet 1986). Secondary endpoints were to evaluate: 1) hepatic iron overload in our population; 2) difference in R2 LIC in patients with different chelation regimen; 3) relation between hepatic iron overload versus transfusion requirements. LIC was measured by calculating T2* and by measuring R2 using commercial Ferriscan® technique (St Pierre TG et al Blood 2005). To convert liver T2* to LIC a regression equation was used: LIC T2*=0.0254×R2*+0.202 (where R2*=1000/T2*) (Wood JC et al Blood 2005).LICNET involves 14 Italian thalassemia and radiology centers. Overall 301 adult patients with hemoglobinopathies (TM (177), TI (74) and S/b-T (50)) underwent to iron evaluation from 2012 to 2014. The mean age at R2 MRI evaluation was 33.2±10.7, 41.2±13.8 and 38.7±13.9, respectively in TM, TI and S/b-T. Iron overload was assessed in patients where most of the patients have been treated with deferasirox (DFX) therapy (TM (28.8%), TI (25.7%) and S/b-T (26.0%)), the remaining cohorts were treated with deferoxamine (DFO), deferiprone (DFP) chelation both alone and in combination or sequential administration.One hundred and twelve observations were measured both for T2* and R2. Concerning the primary endpoint, in the B-A plot it was observed that T2* method yielded a higher LIC than Ferriscan (differences>0), the estimated bias (estimated mean difference) was 2.6 (95% LoA – 17.8; 22.9), and this difference increased at high levels of iron content (Estim. Diff= -1.18+0.32Average mg/g/dw, p=0.0001) (Fig. 1). Secondary endpoints showed that hepatic iron overload determined by T2* was not statistically different among 3 cohorts of patients while it was border line by LIC-R2 (p=0.2608 and p=0.0672). Furthermore, DFX treated patients showed lower LIC-R2 determination in comparison with other treatment (Table 1). Finally, the increase of transfusion requirements was not associated with more severe iron overload in patients with TI and S/b-T. This may be in relation with compliance and type of chelation treatment. These findings show that LIC-R2 (Ferriscan®) is crucial to have accurate and reliable measures for iron body burden control in hemoglobinopathies.Table 1Liver iron concentration determined by Ferriscan (R2) in patients with hemoglobinopathies treated by different chelation regimens.TMTIS/ b -TChelation TherapyLIC R2 (mean±sd)LIC R2 (mean±sd)LIC R2 (mean±sd)DFO5.3±5.78.5±7.720.9±19.9DFP12.9±12.312.5±8.112.7±20.2DFX7.6±9.26.1±7.13.7±3.2Combined DFO+DFP10.1±12.117.8 (n=1)---Sequential DFO-DFP4.3±3.1------Combined DFO+DFX---9.7 (n=1)--- [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Magnetic Resonance Imaging (MRI) Detection of Iron Overload In Patients with Myelodysplastic Syndrome (MDS),

Abstract 3827 Introduction:Transfusion dependent anemia and iron overload (IO) are associated with reduced survival in MDS. Serum ferritin is the most common method of assessing body iron content, but is also an inflammatory marker, and may not correlate with IO in specific organs. T2* magnetic resonance imaging (MRI) is a non-invasive method for detecting IO. The prevalence of IO in patients with MDS, as detected by T2* MRI, is currently unknown. Purpose: We designed a single center trial to evaluate the efficacy of T2* MRI in detection of IO in patients with MDS, determine the prevalence of iron overload in this disease and correlate MRI findings with iron indexes (ferritin, transferrin and labile plasma iron [LPI]). Material and methods: Patients with WHO-2008 defined MDS or chronic myelomonocytic leukemia (CMML), independent of transfusion requirements, were eligible. Patients receiving iron chelation therapy were excluded. Iron indexes were measured at the time of T2* MRI evaluation. Hepatic iron overload (HIO) was considered in patients with a hepatic iron concentration (HIC) ≥ 2 g/mg. Cardiac iron overload (CIO) was considered in patients with a T2* value < 20 milliseconds. Results: A total of 58 patients with MDS and two patients with CMML have been recruited. Three patients were not evaluated by MRI due to claustrophobia, so 57 patients remain for the analysis. Median age was 66 years (range 18–89). MDS subtypes by WHO included: refractory anemia (N=5), refractory anemia with ring sideroblasts (RARS; N=7), 5q- syndrome (N=4), refractory cytopenias with multilineage dysplasia (N=21), refractory anemia with excess blasts-I (N=7) and –II (N=7), unclassifiable MDS (N=3), CMML (N=2) and therapy-related MDS (N=1). Clinical features at time of MRI are presented in table 1. Median cardiac T2* value was 42 ms (range 19.7–70.1 ms), and only one patient had a T2* value indicative of CIO. Median HIC value was 3.9 g/mg (range 0.9–16 g/mg), and 68% of patients had HIO. Patients with HIO had higher ferritin levels (1182 ng/mL vs. 185 ng/mL, p<0.0001) and transferrin saturation (76% vs. 34%, p<0.0001), but no difference in LPI (0.13 vs. 0.12 mM, p=0.49). HIO was found in 76% of transfusion dependent patients, but in also 59% of patients without history of transfusions. Among patients with HIO but without a history of transfusions, 50% had RARS. Considering MRI as a gold standard for detecting HIO, a ferritin value ≥ 1.000 ng/ml had a positive predictive value (PPV) for HIO of 98% and a NPV of 48%; for transferrin saturation ≥ 50%, PPV was 91% and NPV was 55%. Conclusions: This is one of the largest studies evaluating IO in MDS by T2* MRI. The prevalence of iron overload in MDS is underestimated by using conventional iron indexes and T2* MRI can help in the early detection of IO. In some subtypes of MDS, such as RARS, mechanisms other than transfusion dependency lead to IO.Table 1Clinical Features at Time of MRIFeatureMedian [Range] or No. (%)Age, years66 [18–89]Male Sex31 (54)Hb, g/dL8.8 [5–12.6]WBC, x 109/L4.1 [0.45–17.6]Platelets, x 109/L104 [8–546]BM Blasts, %1.2 [0–20]Transfusion Dependency•Yes29 (50)•No17 (21)•Unknown11 (19)No. of Transfusions8 (0–84)Iron Saturation, %63 [5–100%]Ferritin, ng/ml968 [21.8–12738]Labile Plasma Iron, microM0.12 [−0.21–12.3]History of Fungal Infections4 [7] Disclosures:Santos:Janssen-Cilag: Consultancy, Speakers Bureau; United Medical: Consultancy, Speakers Bureau; Novartis: Research Funding. Hamerschlak:Novartis: Research Funding.

Iron overload measurements by CMR in patients with suspected hemochromatosis - comparison of methods for T2* calculation in myocardium and liver

Introduction Iron tissue overload can be detected non-invasively by CMR using T2* measurements techniques. Hemochromatosis is a disorder of iron metabolism that results in excess iron accumulation in tissues and organs. If left undiagnosed and untreated, iron overload can cause serious, sometimes fatal health problems. Early detection of iron overload and hemochromatosis treatment can prevent complications and prolong life.

Early detection of iron overload in the heart: a key role for MRI!

Hereditary haemochromatosis is autosomal recessive disorder associated with the HLA-A locus on the short arm of chromosome 6 [1]. It is the most common genetic disorder worldwide [2]. About 56,000 babies are born each year with thalassaemia major, of whom 30,000 require lifelong transfusions to survive [3]. The disease is very prevalent in European countries along the Mediterranean Sea and in South East Asia. In other countries it becomes a problem because of immigration from these areas. Excessive iron deposition occurs mostly in the pancreas, pituitary, but also in the heart. In normal subjects, absorption of iron from the gut is inversely correlated with iron stores. In homozygous hereditary haemochromatosis there is increased absorption of iron, which is not regulated by iron stores [4]. This leads to progressive iron accumulation because there is no normal mechanism for excretion of excess iron once it has been absorbed into the body. The clinical manifestations of iron overload include liver disease in 75% of cases, weakness and lethargy in 74%, skin hyperpigmentation in 70%, diabetes mellitus in 48%, arthralgia in 44%, impotence in 45%, electrocardiographic abnormalities in 31% and heart failure and conduction disturbances in 15% [5, 6]. Heart failure remains a major cause of death in these patients, frequently people younger than 35 years [7]. In the majority of patients iron induced cardiomyopathy can be reversed by intense chelation therapy with desferrioxamine and deferiprone [3, 8]. At this moment T2* magnetic resonance imaging is the best way for early detection of iron overload in patients with haemochromatosis [9–11]. T2* is an unique magnetic resonance parameter measured in milliseconds and shortened in relation to the level iron in the heart. The parameter can be used for screening haemochromatosis patients and to guide chelation therapy in those with established cardiac haemochromatosis [8]. The paper of Mavrogeni et al. [12] in this issue of the International Journal of Cardiac Imaging shows, that heart failure patients with severe iron overload indicated by a T2* value less than 10 ms had a lower exercise capacity than patients with a T2* value higher than 10 ms. The authors also show, that there was a excellent relation of the extent of iron overload measured by T2* and exercise tolerance in thalassemia patients. As shown by others, thalassemia patients present prolonged phase II on-transient oxygen kinetics during submaximal, constant workload exercise, compared with healthy controls, possibly suggesting a slower rate of high energy phosphate production and utilization and reduced oxidative capacity of myocytes [13]. This could also account for their significantly limited exercise tolerance. Reduction of exercise tolerance is also s highly associated with the limited functional status of peripheral muscles in these patients [14]. This study shows again that T2* MRI plays a crucial role in screening cardiac haemochromatosis and guidance of chelation therapy. Early detection of cardiac iron load and early initiation of treatment are crucial for survival of these patients. Recently the chelator deferasirox has been shown to be more effective in better at improving myocardial iron [15]. This could improve outcome in thalassemia patients. As shown, early effects of therapy can only be detected with dedicated MRI sequences. Unfortunately these MRI scanners are not always available in those areas, where the prevalence of haemachromatosis patients is extremely high.

Patient screening for cardiac hemochromatosis, echocardiography or MRI?

Hereditary hemochromatosis is autosomal recessive disorder associated with the HLA-A locus on the short arm of chromosome 6 [1]. Excessive iron deposition occurs mostly in the heart, pancreas and pituitary. In normal subjects, absorption of iron from the gut is inversely correlated with iron stores. In homozygous hereditary hemochromatosis there is increased absorption of iron, which is not regulated by iron stores [2]. This leads to progressive iron accumulation because there is no normal mechanism for excretion of excess iron once it has been absorbed into the body. The clinical manifestations of iron overload include liver disease in 75% of cases, weakness and lethargy in 74%, skin hyperpigmentation in 70%, diabetes mellitus in 48%, arthralgia in 44%, impotence in 45%, electrocardiographic abnormalities in 31% and heart failure and conduction disturbances in 15% [3, 4]. Repeated phlebotomy can prevent iron accumulation in the heart. At this moment T2* magnetic resonance imaging is the best way for early detection of iron overload in patients with hemochromatosis [5, 6]. However, magnetic resonance imaging is time consuming and expensive. If echocardiography would be able to detect cardiac iron overload in the same way as T2* magnetic resonance imaging, this would be more cost effective and could be used to screen patients with hemochromatosis on the presence or abscense of cardiac involvement. The study of Davidsen et al. in the current issue of the International Journal of Cardiac Imaging shows, that tissue Doppler imaging was able to detect hemochromatosis determination of S0[7]. A cut-off value of S0 = 10.88 cm/s achieved a 56% sensitivity and 74% specificity for separating haemochromatosis from controls (Communication from the authors). This gives a positive predictive value of 68% and a negative predictive value of 57%. Although the discriminating value of S0 is not extremely high, echocardiography with tissue Doppler imaging could be used as a screening tool to detect cardiac involvement in patients with haemochromatosis. One has to be aware that the negative predictive value is slightly higher than 50%. This means, that if no abnormalities can be found, additional imaging with T2* MRI is still needed. At this moment echocardiography and tissue Doppler imaging is not able to replace T2* magnetic resonsance imaging. Even if echocardiographic abnormalities are found it will be prudent to perform additional imaging with T2* MRI. However, because echocardiography and tissue Doppler imaging is a cheap, non-invasive and easy technique initial screening in patients with haemochromatosis can be done using this technique followed Editorial comment to the paper entitled ‘‘Left ventricular longaxis function in treated haemochromatosis’’ by Davidsen et al. Doi: 10.1007/s10554-008-9383-4.

Left ventricular diastolic function compared with T2* cardiovascular magnetic resonance for early detection of myocardial iron overload in thalassemia major

To compare left ventricular (LV) diastolic function with myocardial iron levels in beta thalassemia major (TM) patients, using cardiovascular magnetic resonance (CMR). We studied 67 regularly transfused patients with TM and 22 controls matched for age, gender, and body surface area. The early peak filling rate (EPFR) and atrial peak filling rate (APFR) were determined from high-temporal-resolution ventricular volume-time curves. Myocardial iron estimation was achieved using myocardial T2* measurements. Myocardial iron loading was found in 46 TM patients (69%), in whom the EPFR correlated poorly with T2* (r = -0.20, P = 0.19). The APFR (r = 0.49, P < 0.001) and EPFR/APFR ratio (r = -0.62, P < 0.001) correlated better with T2*. The sensitivity of the diastolic parameters for detecting myocardial iron loading ranged from 4% (EPFR and APFR) to 17% (EPFR/APFR ratio). Myocardial iron overload results in diastolic myocardial dysfunction, but low sensitivity limits the use of a single estimation for early detection of iron overload, for which T2* has a superior categorical limit of normality.

Qualitative and quantitative magnetic resonance imaging in haemoglobin H disease: Screening for iron overload

OBJECTIVES: To evaluate the clinical utility of magnetic resonance imaging (MRI) in screening for iron overload in non-transfusion dependent Haemoglobin (Hb) H disease. PATIENTS AND METHODS: Thirty-six non-transfusion dependent HbH patients were evaluated with axial spin echo TI and gradient echo T2 MRI of the abdomen and heart. The ratios of signal intensities (SIR) of the liver, spleen, pancreas and heart to paraspinous muscles were calculated. SIR <1 was taken as indicative of iron overload. Qualitative grading (0–4 scale) of iron overload was also performed. The relationship between TI and T2 SIR and serum ferritin, and that between qualitative grading and serum ferritin were examined using standard statistical methods. Comparisons were also made between qualitative grading and quantitative T1 and T2 SIR data in diagnosing iron overload. Six patients underwent liver biopsies. RESULTS: T2 SIR was more sensitive in detecting iron overload than TI SIR. Thirty-three livers, 13 spleens, six pancreas and one heart were diagnosed as having iron overload with T2 SIR, including three patients with normal serum ferritin. A positive diagnosis by T2 SIR was more closely related to that of qualitative grading than TI SIR. Serum ferritin was negatively correlated with hepatic SIR (T1 and T2), and with T2 SIR of the spleen and pancreas, even after adjustment for age. Liver haemosiderosis was confirmed in all six patients who underwent liver biopsies. Liver iron concentration of only one and a half times the normal was found in one patient with positive MR findings. CONCLUSION: MR is a non-invasive, effective method for early detection of iron overload particularly in the liver and spleen. Qualitative grading and quantitative T2 SIR data are equivalent in diagnosing iron overload. Routine screening of non-transfusion dependent HbH patients will identify high risk patients in whom early therapeutic intervention may prevent further complications and morbidity.