Evaluation of cardiac and hepatic iron overload in thalassemia major patients with T2* magnetic resonance imaging

Objectives: Recent advancements have promoted the use of T2* magnetic resonance imaging (MRI) in the non-invasive detection of iron overload in various organs for thalassemia major patients. This study aims to determine the iron load in the heart and liver of patients with thalassemia major using T2* MRI and to evaluate its correlation with serum ferritin level and iron chelation therapy.

Methods: This cross-sectional study included 162 subjects diagnosed with thalassemia major, who were classified into acceptable, mild, moderate, or severe cardiac and hepatic iron overload following their T2* MRI results, respectively, and these were correlated to their serum ferritin levels and iron chelation therapy.

Results: The study found that 85.2% of the subjects had normal cardiac iron stores. In contrast, 70.4% of the subjects had severe liver iron overload. A significant but weak correlation (r?=??0.28) was found between cardiac T2* MRI and serum ferritin, and a slightly more significant correlation (r?=?0.37) was found between liver iron concentration (LIC) and serum ferritin.

Discussion: The findings of this study are consistent with several other studies, which show that patients generally manifest with liver iron overload prior to cardiac iron overload. Moreover, iron accumulation demonstrated by T2* MRI results also show a significant correlation to serum ferritin levels.

Conclusion: This is the first study of its kind conducted in Indonesia, which supports the fact that T2* MRI is undoubtedly valuable in the early detection of cardiac and hepatic iron overload in thalassemia major patients.     

Elevated serum parathormone levels are associated with myocardial iron overload in patients with β‐thalassaemia major

Objectives: Despite advances in conventional treatment, iron‐induced cardiomyopathy is still the most frequent cause of death among patients with β‐thalassaemia major. Recent studies have correlated increased myocardial iron content to decreased levels of vitamin D in thalassaemic patients. The aim of this study was to measure parathormone (PTH) and metabolites of vitamin D and consequently to investigate whether these parameters predispose to myocardial iron overload in patients with β‐thalassaemia major. Methods: In 62 patients (29 M and 33 F, mean age: 22.79 ± 6.18 yr) with β‐thalassaemia major levels of intact parathormone (iPTH) and vitamin D metabolites [25(ΟH)D₃ and 1,25(ΟH)₂D₃] were measured in serum. Additionally, estimation of myocardial iron content was performed by magnetic resonance imaging, whereas mean serum ferritin concentrations were calculated for 1 yr prior to the study. Results: Results showed markedly decreased levels of serum 25(OH)D₃ in 37 patients (60%), whereas 7 patients (11%) had borderline 25(OH)D₃ levels (between 50 and 75 nmol/L). Serum iPTH levels were significantly higher in patients having increased myocardial iron compared to those having normal myocardial iron (44.04 ± 22.09 pg/mL vs. 31.39 ± 14.30 pg/mL, P = 0.017). Multivariant regression analysis identified PTH levels as the major predictor of increased myocardial iron.     

Combined therapy with desferrioxamine and deferiprone in beta thalassemia major patients with transfusional iron overload

Iron overload is the main cause of morbidity and mortality especially from heart failure in patients with beta thalassemia major (TM). Successful iron chelation is therefore essential for the optimal management of TM. Although desferrioxamine (DFX) has been the major iron-chelating treatment of transfusional iron overload, compliance is a major hindrance in achieving optimal therapeutic results. The availability of oral iron chelation with deferiprone (L₁) since 1987 is useful but showed poor efficacy when used alone as compared to DFX. We therefore decided to compare DFX alone with a prospective combined therapy with DFX and L₁ in beta thalassemia major patients with iron overload. We studied 91 patients with beta thalassemia major (mean age±SD, 15.02±5.8; range 2–30 years) attending the day care unit for regular transfusional support. They received packed red cells every 3–4 weeks to maintain pretransfusion hemoglobin concentration above 9 g/dl. They had been receiving DFX at a daily dose of 40 mg kg⁻¹ day⁻¹ by subcutaneous infusion for 8–10 h on 4–5 nights each week for the past several years. However, due to various reasons, they had developed considerable transfusional iron overload. These patients were allocated to prospectively receive additional therapy with oral iron chelator L₁ at 75 mg kg⁻¹ day⁻¹ body weight in three divided doses with food after informed consent and continued to receive treatment with DFX as per the above dosage. Of the 91 patients, six developed severe gastrointestinal (GI) upset, two agranulocytosis, two arthropathy, one persistently raised liver enzymes, two died owing to sepsis, and two received allogeneic bone marrow transplantation. Amongst the remaining 76 patients, 21 were found noncompliant (not taking DFX regularly, but taking L₁ regularly). Thus, in the 55 evaluable patients {6–48 months on combination therapy; mean [(±SD)22±12 months]}, the mean serum ferritin (±SD) fell dramatically from 3,088 (±1,299) ng/ml (DFX alone) to 2,051 (±935) ng/ml (DFX and L₁; p<0.001). It is interesting to note that there was also a significant improvement in the myocardial function as assessed by the ejection fraction (p<0.004) and fractional shortening (p<0.05) in those patients (n=42) who could be studied after being on combination therapy for a minimum of 1 year. The study emphasizes that beta thalassemia major patients with transfusional iron overload can be successfully treated with a combination of DFX and L₁. Our results also demonstrate a significant statistical improvement after as little as 6 months of combination therapy. Furthermore, these improvements lead to a progressive fall in the mean serum ferritin. Lastly, the study also demonstrates significant improvement in the echocardiographic parameters of myocardial performance in these patients receiving combination therapy.     

History of myocardial iron loading is a strong risk factor for diabetes mellitus and hypogonadism in adults with β thalassemia major

Endocrinopathies are common complications of transfusional hemosiderosis among patients with β thalassemia major (TM). Previous studies had shown associations between some endocrinopathies and iron overload of the myocardium, liver and/or endocrine organs as assessed by MRI techniques. This retrospective analysis of 92 patients with TM (median age 36 yr) from a tertiary adult thalassemia unit in UK aimed to determine independent risk factors associated with endocrinopathies among these patients. Unlike previous studies, longitudinal data on routine measurements of iron load [worst myocardial and liver T2* values since 1999, worst LIC by MRI‐R2 since 2008 and average 10‐yr serum ferritin (SF)] up to April 2010 together with demographic features and age of initiating chelation were analyzed for associations with endocrinopathies. The most common endocrinopathies in this cohort were hypogonadism (67%) and diabetes mellitus (DM) (41%), and these were independently associated with myocardial T2* <20 ms (P < 0.001 and P = 0.008, respectively) and increased age (P = 0.002 and P = 0.016, respectively). DM and hypogonadism were independently associated with average SF >1250 μg/L (P = 0.003) and >2000 μg/L (P = 0.047), respectively. DM was also associated with initial detection of abnormal myocardial T2* at an older age (30 yr vs. 24 yr, P = 0.039). An abnormal myocardial T2* may therefore portend the development of DM and hypogonadism in patients with TM.     

Urine biochemical markers of early renal dysfunction are associated with iron overload in β‐thalassaemia

Summary Renal dysfunction in thalassemia patients can be attributed to chronic anemia, and iron overload as well as to desferioxamine (DFO) toxicity. We analyzed the urine of 91 well‐maintained homozygous β‐thalassemia patients, with no evidence of renal disease, for early evidence of kidney dysfunction by means of electrophoresis and quantitative biochemical tests. Measurement of liver magnetic resonance imaging (MRI) T2 values and serum ferritin concentration was used to estimate iron overload. In 55 of the 91 patients, urine analysis indicated signs of tubular dysfunction. The urine concentration of albumin and beta 2‐microglobulin, as well as the activity of n ‐acetyl‐beta‐d ‐glucosaminidase (NAG), correlated positively with serum ferritin concentration and liver iron deposition, as detected by MRI T2 values. This suggested that the cause of renal dysfunction in homozygous β‐thalassemia is iron overload. On the other hand, the same urine markers did not correlate with age, indicating that chronic anemia or desferrioxamine (DFO) treatment are not related to renal dysfunction in thalassemia.     

No evidence for myocardial iron overload and free iron species in multitransfused patients with sickle/β0‐thalassaemia

Iron overload (IO) in the heart is a life‐threatening complication in transfusion‐dependent patients with thalassaemia major (TM) and to a lesser extent in sickle cell disease (SCD), while no data are available in patients with sickle/β⁰‐thalassaemia. Iron deposition in the heart, liver and pancreas was assessed using T2* MRI sequences, as well as free iron species assays – non‐transferrin bound iron (NTBI) and labile plasma iron (LPI), in addition to serum ferritin, percentage transferrin saturation and serum hepcidin, in 10 multitransfused patients (>30 yr) with sickle/β⁰‐thalassaemia. None of the patients had iron deposition in the heart. Three patients had mild, one had moderate, and two had severe liver IO. Two patients had mild iron deposition in the pancreas. In all the patients, serum hepcidin levels were normal – NTBI and LPI were not detected. Possible explanations of these findings are discussed.     

Assessment and management of iron overload in β‐thalassaemia major patients during the 21st century: a real‐life experience from the Italian Webthal project

We conducted a cross‐sectional study on 924 β‐thalassaemia major patients (mean age 30·1 years) treated at nine Italian centres using the webthal software, to evaluate real‐life application of iron overload assessment and management standards. Serum ferritin <2500 ng/ml was a risk factor for never having liver iron concentration (LIC) measurement, while absence of cardiac disease and siderosis were risk factors for a delay in LIC measurement >2 years. Patients who never had a cardiac MRI (CMR) T2* measurement were <18 years, had iron intake ≤0·4 mg/kg per day, or a serum ferritin <2500 ng/ml. A history of normal CMR T2* was the main risk factor for a delay in subsequent assessment of >2 years. Deferoxamine (22·8%) was more commonly used in patients with Hepatitis C Virus or high serum creatinine. Deferiprone (20·6%) was less commonly prescribed in patients with elevated alanine aminotransferase; while a deferoxamine + deferiprone combination (17·9%) was more commonly used in patients with serum ferritin >2500 ng/ml or CMR T2* <20 ms. Deferasirox (38·3%) was more commonly prescribed in patients <18 years, but less commonly used in those with heart disease or high iron intake. These observations largely echoed guidelines at the time, although some practices are expected to change in light of evolving evidence.     

The impact of two different doses of chelating therapy (deferasirox) on echocardiographic tissue Doppler indices in patients with thalassemia major

Background: Chelating therapy in transfusion‐dependent patients with β‐thalassemia major (β‐TM) is mandatory to reduce the toxic effect of iron on the myocardium. Aim: To evaluate the impact of low and high dose of oral chelating therapy (deferasirox) on pulsed and tissue echocardiographic indices in patients with β‐TM. Methods: This interventional study conducted on patients with transfusion‐dependent β‐TM (n = 38) on deferasirox 20 mg/kg/d medication, group (DFX‐20) for at least 6 months, followed by administration of a higher dose of deferasirox, 40 mg/kg/d, group (DFX‐40) for another 6 months. Pulsed and tissue Doppler echocardiography carried out at the beginning and at the end of treatment interval (6 months) for both groups, with monthly blood analysis of serum ferritin, alanine transaminase, hemoglobin, and creatinine. An age‐matched control group of 38 patients was evaluated for echo Doppler blood analysis. Results: Patients of group DXF‐40 compared with group DFX‐20, the tissue Doppler echocardiogram showed lower E/Em ratio (16.01 ± 2.85 vs. 19.68 ± 2.81, P < 0.05), higher systolic wave velocity (Sm) (5.87 ± 1.40 vs. 4.80 ± 1.20, P < 0.05), and higher early diastolic wave (Em) velocity (4.25 ± 1.70 vs. 3.50 ± 1.80, P < 0.05), respectively. Patients in group DFX‐20, compared with control group, had M‐Mode echo with thicker left ventricle (LV) septal wall (P < 0.001) and posterior wall (P < 0.01), higher left ventricle end diastolic diameter index (P < 0.05). The pulsed Doppler echocardiogram showed a higher LV transmitral E wave velocity (P < 0.05), higher E/A ratio (P < 0.01), and the duration of deceleration time was significantly shorter (P < 0.01). There were no significant changes observed in the left ventricle ejection fraction percentage (LVEF%) or fractional shortening between both treatment groups. Serum ferritin was significantly lower in DFX‐40 group compared with DFX‐20 β‐TM group (338). There was a significant positive correlation between the serum ferritin and the E/Em ratio (r = 0.31, P < 0.001). The tricuspid valve velocity was significantly higher in β‐TM patients compared with the control group (P < 0.05). Conclusion: The increment of oral deferasirox as chelating therapy in β‐TM patients to 40 mg/kg/d over 6 months duration showed a significant increments of systolic and diastolic tissue Doppler velocities with a significant reduction of E/Em ratio in comparison with 20 mg/kg/d. There were no changes of LVEF. A longer duration of follow‐up may be justified in such group of patients.     

Non‐transferrin bound labile plasma iron and iron overload in Sickle Cell Disease: a comparative study between Sickle Cell Disease and β thalassemic patients

Background: Blood transfusions are the standard of care in β thalassemia and transfusions are also indicated in sickle cell disease (SCD) patients with hypersplenism, recurrent vaso‐occlusive crises and for stroke prevention. Iron overload caused by blood transfusions in thalassemia and in SCD may affect morbidity and mortality. Recent studies of iron overload in SCD suggest that the biologic features of SCD and the chronic inflammatory state may protect SCD patients from iron damage. Designs and methods: In view of the controversy regarding the effect of iron overload in patients with SCD we studied the iron status, including non‐transferrin bound iron (NTBI) and labile plasma iron (LPI) levels in a cohort of 36 SCD patients and compare the results with 43 thalassemia patients. Results: Our results indicate that none of the SCD patients had clinical symptoms of iron overload. Only two SCD patients had NTBI values in the gray zone (0.4 units) and none had positive values. By contrast, 14 patients with thalassemia major and three with thalassemia intermedia had NTBI values above 0.6, level that are in the positive pathological range. Similarly, four thalassemia patients, but only one SCD patient had positive LPI levels. Conclusions: The parameters of iron status in SCD patients, even after frequent transfusions are different when compared to patients with thalassemia. The low NTBI and LPI levels found in patients with SCD are in keeping with the absence of clinical signs of iron overload in this disease.     

Observational study of iron overload as assessed by magnetic resonance imaging in an adult population of transfusion‐dependent patients with β thalassaemia: significant association between low cardiac T2* < 10 ms and cardiac events

Background: Thalassaemia major patients usually die from cardiac haemosiderosis. Improved strategies are required to modify this risk. Aims: To assess the significance of cardiac iron overload in patients with β thalassaemia. Method: Observational study of cardiac iron overload as assessed by magnetic resonance imaging (MRI) cardiac T2* relaxometry in 30 adult patients with transfusion‐dependent β thalassaemia. Results: 11/30 patients (37%) had cardiac T2* < 10 ms, 8/30 (27%) in range 10–20 ms and 11/30 (37%) > 20 ms. There was significant inverse correlation between T2* values and values for serum ferritin (SF) and liver iron concentration (LIC) and positive correlation with left ventricular ejection fraction (LVEF). Median LVEF values were 49% in patients with T2* < 10 ms and 58% in patients with T2* > 10 ms (P= 0.02). Very low T2* values <10 ms were strongly associated with the occurrence of cardiac events (congestive heart failure, arrhythmia, cardiac death): occurring in 5/11 patients with T2* < l0 ms and in 0/19 in patients with T2* > 10 ms (P= 0.003 Fisher's exact test; P= 0.002 log rank Kaplan‐Meier time to event analysis). There was no significant association between T2* < 10 ms or cardiac events and traditional measures of iron overload, such as SF levels >2500 µg/L and LIC (evaluated at thresholds of >7 or >15 mg/g dry weight). Conclusion: Very low cardiac T2* values <10 ms are common in adults with β thalassaemia and are significantly associated with risk of cardiac events. This permits the use of individually targeted chelation strategies which are more effective in removing cardiac iron.     

Treatment of chronic hepatitis C with direct‐acting antivirals in patients with β‐thalassaemia major and advanced liver disease

Interferon‐based regimens for chronic hepatitis C (CHC ) were often deferred in patients with β‐thalasaemia major (β‐TM ) due to poor efficacy and tolerance. Current guidelines recommend direct‐acting antivirals (DAA s) for these patients. The aim of this study was to assess the safety and efficacy of DAA s in patients with β‐TM and advanced liver disease due to CHC . Patients were recruited from eight liver units in Greece. The stage of liver disease was assessed using transient elastography and/or liver histology. Five regimens were used: sofosbuvir (SOF ) + ribavirin (RBV ); SOF  + simeprevir ± RBV ; SOF  + daclatasvir ± RBV ; ledipasvir/SOF  ± RBV and ombitasvir/paritaprevir‐ritonavir + dasabuvir ± RBV . Sixty‐one patients (median age 43 years) were included. The majority of patients was previously treated for hepatitis C (75%) and had cirrhosis (79%). Viral genotype distribution was: G1a: n  = 10 (16%); G1b: n  = 22 (36%); G2: n  = 2 (3%); G3: n  = 14 (23%); G4: n  = 13 (22%). The predominant chelation therapy was a combination of deferoxamine and deferiprone (35%). Overall sustained virological response rates were 90%. All treatment regimens were well tolerated and no major adverse events or drug‐drug interactions were observed. Approximately half of the patients who received RBV (7/16, 44%) had increased needs for blood transfusion. Treatment of CHC with DAA s in patients with β‐TM and advanced liver disease was highly effective and safe.