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Thalassemia is a genetic hematologic disease, characterized by a defect in hemoglobin chain synthesis. Because of safe transfusions and effective chelation therapy, survival of affected patients has significantly improved in the last few decades. However new complications are appearing. Among them are hepatocellular carcinoma and other forms of cancer, particularly hematologic malignancies. The present review focuses on the frequency of cancer in thalassemia patients and on possible predisposing factors., (© 2016 New York Academy of Sciences.)

Patients with thalassemia major suffer from many complications, but in the last two decades their lives have improved both in length and quality. We report herein the most common complications and the recent advances that have changed the course of this disease. Also, we report in detail some of the new therapeutic strategies already introduced in practice and briefly some that are still being developed.

Aims: Our aim was to evaluate the correlation between myocardial fibrosis detected using the late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) technique and chronic hepatitis C (CHC) in a large, retrospective, multicentre cohort of thalassemia major patients., Methods: LGE images were acquired in 434 thalassemia major patients (233 men, 31 ± 9 years) enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) study. Hepatitis C virus (HCV)-RNA tests were sensitive to detect more than 50  copies/ml., Results: No patient manifested moderate/severe adverse events associated with the use of Gadobutrol. Myocardial fibrosis was detected in 90 (21%) patients. Among the 312 patients tested for HCV-RNA, there was a significant correlation between the presence of myocardial fibrosis and CHC (P = 0.011). Among the 62 patients with myocardial fibrosis tested for HCV-RNA, we found a significantly higher prevalence of diabetes mellitus in CHC patients versus the no-CHC patients (P = 0.049)., Conclusion: Our findings support the use of the LGE CMR approach well tolerated in the thalassemia major patients with CHC. HCV infection can be involved in the pathogenesis of myocardial fibrosis through both myocarditis directly and the pancreas and liver damage with the development of diabetes indirectly. These patients could therefore benefit from cardioactive drugs and therapeutic interventions directed towards the eradication of virus.

Background: Simian virus 40 (SV40) is a small DNA tumour virus. Footprints of the virus have been detected in different humam lymphoproliferative disorders and in blood specimens of blood from healthy blood donors. This study was carried out to verify whether SV40 antibodies can be detected in serum samples from multiply transfused patients with thalassaemia major., Materials and Methods: An indirect enzyme-linked immunosorbent assay was employed, using SV40 specific synthetic peptides mimicking the antigens of the viral capsid proteins 1-2-3, to test for the presence of antibodies to SV40 in serum samples taken from patients affected by transfusion-dependent thalassaemia major (n=190) and healthy blood donors (n=251)., Results: The prevalence of antibodies against SV40 was higher in patients than in controls (24% vs 17%). The prevalence increased and was significantly higher in the older age group of patients affected by thalassemia major than in controls (38% vs 20%, p<0.04)., Discussion: The higher prevalence of serum antibodies against simian virus 40 in older, multiply transfused patients with thalassamia major than in controls suggests that this virus, or a closely related yet unknown human polyomavirus, could have been transmitted in the past by transfusion with whole blood. At the same time, our data indicate no significant differences in prevalence of SV40 antibodies in patients and controls of younger age thus suggesting that current transfusion methods with leucodepletion and filtered red cells are safe.

The risk of developing hepatocellular carcinoma (HCC) in patients with thalassaemia is increased by transfusion-transmitted infections and haemosiderosis. All Italian Thalassaemia Centres use an ad hoc form to report all diagnoses of HCC to the Italian Registry. Since our last report, in 2002, up to December 2012, 62 new cases were identified, 52% of whom were affected by thalassaemia major (TM) and 45% by thalassaemia intermedia (TI). Two had sickle-thalassaemia (ST). The incidence of the tumour is increasing, possibly because of the longer survival of patients and consequent longer exposure to the noxious effects of the hepatotropic viruses and iron. Three patients were hepatitis B surface antigen-positive, 36 patients showed evidence of past infection with hepatitis B virus (HBV). Fifty-four patients had antibodies against hepatitis C virus (HCV), 43 of whom were HCV RNA positive. Only 4 had no evidence of exposure either to HCV or HBV. The mean liver iron concentration was 8 mg/g dry weight. Therapy included chemoembolization, thermoablation with radiofrequency and surgical excision. Three patients underwent liver transplant, 21 received palliative therapy. As of December 2012, 41 patients had died. The average survival time from HCC detection to death was 11·5 months (1·4-107·2 months). Ultrasonography is recommended every 6 months to enable early diagnosis of HCC, which is crucial to decrease mortality., (© 2014 John Wiley & Sons Ltd.)

Chelation therapy with new drugs prevents cardiac damage and improves the survival of thalassemia patients. Liver diseases have emerged as a critical clinical issue. Chronic liver diseases play an important role in the prognosis of thalassemia patients because of the high frequency of viral infections and important role of the liver in regulating iron metabolism. Accurate assessment of liver iron overload is required to tailor iron chelation therapy. The diagnosis of hepatitis B virus- or hepatitis C virus-related chronic hepatitis is required to detect patients who have a high risk of developing liver complications and who may benefit by antiviral therapy. Moreover, clinical management of chronic liver disease in thalassemia patients is a team management issue requiring a multidisciplinary approach. The purposes of this paper are to summarize the knowledge on the epidemiology and the risks of transmission of viral infections, to analyze invasive and noninvasive methods for the diagnosis of chronic liver disease, to report the knowledge on clinical course of chronic viral hepatitis, and to suggest the management of antiviral therapy in thalassemia patients with chronic hepatitis B or C virus or cirrhosis.

The severity of thalassemia intermedia depends on the degree of imbalance between alpha and non-alpha chains as well as other genetic and environmental factors that modify the natural history of the disease. By definition, the patients spontaneously maintain hemoglobin at or above 7 g/dL, sometimes at the price of intense hyperplasia of the bone marrow that is in turn responsible for bone deformities, osteoporosis, and extramedullary erythropoietic masses that often characterize thalassemia intermedia. Transfusion may become necessary with advancing age, during infection and pregnancy, and when hypersplenism develops. Splenectomy is often needed. Iron overload in nontransfused patients is due to increased gastrointestinal absorption and involves mainly the liver. Complications affecting the lives of patients with thalassemia intermedia include pulmonary hypertension, leg ulcers, pseudoxanthoma elasticum, gallstones, hepatocellular carcinoma, and thromboembolic events.

Pseudoxanthoma Elasticum (PXE) is an autosomal recessive, multisystem disorder affecting connective tissues. We describe three cases of the acquired PXE-like syndrome that often occurs in association with hemolytic anemias, in particular the hemoglobinopathies, and review the literature on the subject. The pathogenesis of the acquired PXE-like lesions is not yet completely understood. None of the mutations observed in the inherited form has been detected in the syndrome accompanying thalassemia. The cardiovascular complications could be life-threatening. Therefore, an close surveillance of these patients is mandatory.

Studies of the standardized, 3D, 16-segments map of the circumferential distribution of T2* values, of cardiovascular magnetic resonance (CMR) in thalassemia major (TM) and thalassemia intermedia (TI) patients and of electrocardiogram (ECG) changes associated with TM, have been carried out. Similarly, the segment-dependent correction map of the T2* values and the artifactual variations in normal subjects and the T2* correction map to correct segmental measurements in patients with different levels of myocardial iron burden have been evaluated. Cardiovascular magnetic resonance can be a suitable guide to cardiac management in TI, as well as in TM; TI patients show lower myocardial iron burden and more pronounced high cardiac output findings than TM patients. Moreover, it is proposed that, due to its good positive predictive value (PPV) and low cost, ECG can be a suitable guide to orient towards CMR examination in TM cases.

A segmental, multislice, multi-echo T2* MRI approach could be useful in heart iron-overloaded patients to account for heterogeneous iron distribution, demonstrated by histological studies. However, segmental T2* assessment in heart can be affected by the presence of geometrical and susceptibility artefacts, which can act on different segments in different ways. The aim of this study was to assess T2* value distribution in the left ventricle and to develop a correction procedure to compensate for artefactual variations in segmental analysis. MRI was performed in four groups of 22 subjects each: healthy subjects (I), controls (II) (thalassemia intermedia patients without iron overload), thalassemia major patients with mild (III) and heavy (IV) iron overload. Three short-axis views (basal, median, and apical) of the left ventricle were obtained and analyzed using custom-written, previously validated software. The myocardium was automatically segmented into a 16-segment standardized heart model, and the mean T2* value for each segment was calculated. Punctual distribution of T2* over the myocardium was assessed, and T2* inhomogeneity maps for the three slices were obtained. In group I, no significant variation in the mean T2* among slices was found. T2* showed a characteristic circumferential variation in all three slices. The effect of susceptibility differences induced by cardiac veins was evident, together with low-scale variations induced by geometrical artefacts. Using the mean segmental deviations as correction factors, an artefact correction map was developed and used to normalize segmental data. The correction procedure was validated on group II. Group IV showed no significant presence of segmental artefacts, confirming the hypothesis that susceptibility artefacts are additive in nature and become negligible for high levels of iron overload. Group III showed a greater variability with respect to normal subjects. The correction map failed to compensate for these variations if both additive and percentage-based corrections were applied. This may reinforce the hypothesis that true inhomogeneity in iron deposition exists., (John Wiley & Sons, Ltd.)

The term thalassaemia intermedia includes a large spectrum of conditions of varying severity. Blood transfusion and chelation are necessary in some patients, especially during childhood, in order to promote growth and prevent bone deformities. Alloimunisation, however, is frequent and can be difficult to control. Splenectomy is usually needed at some time because of hypersplenism and mechanical encumbrance. Reactivation of HbF is possible only in a small proportion of patients: hydroxycarbamide (also known as hydroxyurea) appears to be the most effective drug for this purpose. Antioxidant agents, although theoretically useful, do not improve haemoglobin levels. Stem cell transplantation is an option limited to the severe forms. Gene therapy and other molecular approaches are subjects of intense study. Numerous complications, including pulmonary hypertension, thrombotic events, pseudoxanthoma elasticum and osteoporosis, have been described and all contribute to complicate the treatment of a disease that represents a significant burden for the patients and their families.

Background and Objectives: Seven Italian centers reported data on survival, causes of death and appearance of complications in patients with thalassemia major. The interactions between gender, birth cohort, complications, and ferritin on survival and complications were analyzed., Design and Methods: Survival after the first decade was studied for 977 patients born since 1960 whereas survival since birth and complication appearance was studied for the 720 patients born after 1970. Better survival was demonstrated for patients born in more recent years (p<0.00005) and for females (p=0.0003); 68% of the patients are alive at the age of 35 years. In the entire population 67% of the deaths were due to heart disease., Results: There was a significant association between birth cohort and complication-free survival (p<0.0005). The prevalence of complications was: heart failure 6.8%, arrhythmia 5.7%, hypogonadism 54.7%, hypothyroidism 10.8%, diabetes 6.4%, HIV infection 1.7%, and thrombosis 1.1%. Lower ferritin levels were associated with a lower probability of heart failure (hazard ratio =3.35, p<0.005) and with prolonged survival (hazard ratio = 2.45, p<0.005), using a cut-off as low as 1,000 ng/mL., Interpretation and Conclusions: Survival and complication-free survival of patients with thalassemia major continue to improve, especially for female patients born shortly before or after the availability of iron chelation.

Hepatocellular carcinoma (HCC) frequently complicates hepatic cirrhosis secondary to viral infection or iron overload. Therefore, patients affected by thalassaemia syndromes have a theoretically high risk of developing the tumour. We collected data on patients attending Italian centres for the treatment of thalassaemia. Twenty-two cases of HCC were identified; 15 were male. At diagnosis, the mean age was 45 +/- 11 years and the mean serum ferritin was 1764 +/- 1448 microg/l. Eighty-six percent had been infected by hepatitis C virus. Nineteen of 22 cases were diagnosed after 1993, suggesting that this problem is becoming more frequent with the aging population of thalassaemia patients.

We report a new silent β-globin gene variant found in a family from Angola living in the north eastern Italian city of Ferrara. The probands, two young sisters, presented with hematological parameters compatible with a β-thalassemia (β-thal) minor but with normal Hb A2 levels and normal hemoglobin (Hb) separation on high performance liquid chromatography (HPLC). Molecular analyses revealed a homozygosity for the common -α3.7 (rightward) deletion and heterozygosity for a novel transition ( GCT > ACT) at codon 135 of the β-globin gene, leading to an Ala → Thr single amino acid substitution that was inherited from the healthy father. [ABSTRACT FROM AUTHOR]

Thalassemia major was a rapidly fatal disease in the past, but today, thanks to modern medical care, it is associated with extended survival. Patients transfused with blood screened for viruses and treated with iron chelating agents survive well into the fifth decade. Cardiac siderosis is usually the first cause of death followed by infection. Less frequent are liver disease, thrombotic events, and accidents. Complications are still common and include heart disease, liver fibrosis, endocrine problems (hypothyroidism, diabetes, hypogonadism, and hypoparathyroidism), osteoporosis, thrombophilia, pulmonary hypertension, and pseudoxanthoma elasticum. [ABSTRACT FROM AUTHOR]

Female patients with thalassemia and other hemoglobinopathies enjoy a longer survival when compared to males. We report data from the literature and from our own studies on gender differences in survival of thalassemia patients, and also examine this phenomenon in animals and in the general population. Some of the more widely accepted hypotheses that try to explain the differences in longevity between males and females are reviewed. The oxidative stress hypothesis is commonly accepted by the researchers on ageing, although further support for it is needed. In conclusion, it appears that male and female patients with transfusion-dependent thalassemia major are at the same risk of accumulating iron, but females survive longer and develop less cardiac disease because they tolerate iron toxicity better, possibly as an effect of increased tolerance to chronic oxidative stress. [ABSTRACT FROM AUTHOR]

The article discusses on the prevention of thalassemia major, a most prevailing disease in Italy. According to the author, transfusion and chelation therapy is effective in the treatment of thalassemia. The pathophysiology of the disease, and the direct methods for the measurement of iron accumulation, and the ongoing study on life expectancy is presented. The role of iron overload in decreasing the survival and the prevalence of thalassemia and other hemoglobinopathies is demonstrated.

Iron overload is the main cause of morbidity and mortality in patients with thalassaemia major. In order to establish if the presence of the mutations recently described in the haemochromatosis gene affects the severity of iron overload in thalassaemia patients, we compared the prevalence of mutations C282Y and H63D in 216 young adults regularly transfused and chelated in North-Eastern Italy with the frequency found in a group of blood donors from the same area. For each patient, mean serum ferritin over the last 3 years, liver iron concentration, and the presence of diabetes, hypogonadism and heart disease, were considered. The frequency of the C282Y allele was 1.9% in patients with thalassaemia major and 2.3% in blood donors (P = ns). The frequency of the H63D allele was 16.2% in patients with thalassaemia major and 15.3% in blood donors (P = ns). When age, liver iron concentration and mean yearly serum ferritin levels were compared in patients with and without mutations C282Y and H63D, no significant differences were found. Also, the prevalence of iron-induced complications was not significantly different between patients carrying or not carrying the mutations. The presence of the HH mutations does not seem to influence the degree of iron overload and its consequences in regularly transfused and chelated patients with thalassaemia major. [ABSTRACT FROM AUTHOR]

No abstract available [ABSTRACT FROM AUTHOR]

On May 2012 the city of Ferrara and the surrounding region were hit by several earthquakes. We had the chance to observe the behavior of one thalassemic heart during the shocks, because of a 24-h electrocardiogram recording had been put in place a few hours before the shocks. [ABSTRACT FROM AUTHOR]

An abstract of the paper "A T2* MRI Prospective Survey on Heart Iron in Thalassemia Major Patients Treated with Sequential Deferipron-desferrioxamine Versus Deferasirox," by Alessia Pepe and colleagues from the 2011 SCMR/Euro CMR Joint Scientific Sessions in Nice, France from February 3-6, 2011 is presented.

Aim of this study was to compare plasma levels of the secreted protein Klotho in β-thalassemia major patients and in healthy controls. Also, we examined the existence of correlations between the protein level and osteoporosis, poor muscle strength and fractures. A total of 106 patients with β-thalassemia major and 95 healthy blood donors were enrolled. Klotho level in plasma was measured by mean of an ELISA test and the hand-grip strength using a dynamometer. Intact parathyroid hormone (PTH), 25-hydroxy vitamin D (Vitamin D), serum calcium (Ca), phosphate (P), total alkaline phosphatase (ALP), ferritin, creatinine were measured by standard clinical techniques. DXA was used to measure bone mineral density (BMD) at the lumbar spine (L2–L4), femoral neck and total hip. We found that the Klotho protein concentration was lower in the blood of patients with β-thalassemia major than in healthy controls, and it was directly correlated to the hand-grip strength. In β-thalassemia major patients, the secreted Klotho was lower than in healthy controls. The preliminary investigation into the correlation between markers of osteo- and sarco-penia and Klotho demonstrated a decreased Klotho concentration in β-TM patients and a higher probability of having had fragility fractures. [ABSTRACT FROM AUTHOR]