Maria Paola Carta

Increased survival and reversion of iron-induced cardiac disease in patients with thalassemia major receiving intensive combined chelation therapy as compared to desferoxamine alone.

Myocardial iron overload is the leading cause of death in patients with beta-thalassemia major. An intensification monotherapy with deferoxamine (DFO) as well as a combination therapy with DFO and deferiprone (DFP) reduces myocardial iron and improves cardiac function. However, the prognosis for thalassemia major patients with established cardiac disease switched from DFO monotherapy to combined DFP/DFO chelation is unknown. Twenty-eight thalassemia major patients with cardiac disease were enrolled in a prospective study lasting 42+/-6 months. Fifteen (9 high-ferritin and 6 low-ferritin) were placed on DFP/DFO (DFP, 75 mg/kg t.i.d.; DFO, 40-50mg/kg over 8-12h at night 5-7 days/week), while 13 (5 high- and 8 low-ferritin) received DFO alone. No cardiac events were observed among high-ferritin patients on combination therapy, whereas 4 cardiac events (p=0.0049), including three deaths, occurred in high-ferritin patients on DFO monotherapy. These findings demonstrate that in thalassemia major patients with well-established cardiac disease combined iron-chelation therapy with DFP/DFO is superior to DFO monotherapy.

Hepatocellular carcinoma in thalassaemia: an update of the Italian Registry.

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.

Thalassemia intermedia is associated with a proatherogenic biochemical phenotype

OBJECTIVE Unlike beta thalassemia major (β-TM) in which cardiac siderosis represents the leading cause of mortality and morbidity, in beta thalassemia intermedia (β-TI), pulmonary hypertension (PHT) and thrombosis seems to be the major cardiovascular complications. However, the mechanism underlying these complications in β-TI is still unclear. Endothelial dysfunction, the key early event in atherogenesis, is now emerging as an important cardiovascular risk determiner in β-TI patients. Among the factors known to affect endothelial function, iron and cholesterol merit particular consideration in β-TI patients. Therefore, with the aim to extend our knowledge on the mechanisms connecting atherosclerosis to β-TI, in this study, we compared lipid and iron metabolism in serum and in peripheral blood mononuclear cells (PBMCs) from β-TI and β-TM patients and controls. METHODS AND RESULTS In this study the iron status and the lipid profile in serum and in peripheral blood mononuclear cells (PBMCs) of 22 adult β-TI patients were examined, and compared with 70 adult β-TM, and 50 age-matched controls. Despite the great variability, levels of serum iron and transferrin saturation were significantly higher in β-TI compared to both controls and β-TM. By contrast, transferrin and hepcidin levels were lower in β-TI patients. Changes in serum indicators in β-TI patients were associated with altered expressions in PBMCs of hepcidin and IL-1α, involved in some way in the regulation of iron homeostasis. In addition β-TI exhibited a reduction of total and high density lipoprotein cholesterol in serum and of neutral cholesterol ester hydrolase in PBMCs, and an increase of cytoplasmic neutral lipids and mRNA levels of acetyl-coenzymeA:cholesterol acyltransferase. CONCLUSIONS Taken together, these findings provide experimental support for the idea that β-TI patients exhibit a proatherogenic biochemical phenotype which may contribute to enhance cardiovascular risk in these subjects.

Renal function in patients with β-thalassaemia major: a long-term follow-up study

BACKGROUND Little information is available about the kidneys involvement in patients with β-thalassaemia major (TM). In particular, there are no studies reporting the outcome of renal function over time. METHODS In this retrospective study, we evaluated the changes in estimated glomerular filtration rate (eGFR) in 81 adult patients with TM followed for 10 years. Only patients who had an eGFR of >90 mL/min/1.73 m(2) at presentation were admitted to the study. All patients were regularly followed for at least 10 years. RESULTS At 10 years, 66 patients showed a mild decline in eGFR that remained, however, within a normal range (from 119.9 to 113.6 mL/min/1.73 m(2), P = 0.636). In the remaining 15 patients (18.5%), eGFR decreased to <90 mL/min (from 98.1 to 78.2 mL/min/1.73 m(2); P = 0.004). The repeated-measures models showed that the decline in eGFR over time was significantly higher (P = 0.0068) in patients with baseline phosphaturia >1000 mg/24 h (P = 0.0068), while eGFR tended to decline more rapidly in patients with baseline uricuria >700 mg/24 h than in those with lower uricuria (P = 0.0783). Univariate Coxs proportional regression models showed that abnormal levels of calcaemia were associated with the risk of kidney damage [hazard ratio (HR) 0.30, 95% confidence interval 0.09-0.97 for calcaemia 8.4-10.2 mg/dL versus HR not estimable for calcaemia <8.4 or >10.2 mg/dL]. CONCLUSIONS In most adults with TM, the eGFR tends to remain within a normal range after 10 years. However, patients with elevated phosphaturia, elevated uricuria and/or abnormal levels of calcaemia show a significant decline in eGFR over time, suggesting that tubular damage acquired in childhood caused by either TM or its treatment may eventually result in abnormal eGFR. Further studies in a larger cohort of TM patients are needed to further elucidate the long-term impact of TM on renal function.

Evidence for a proatherogenic biochemical phenotype in beta thalassemia minor and intermedia.

The purpose of this study was to focus on pathophysiological mechanisms linking β-thalassemia intermedia (β-TI) and minor (β-TMI) with cardiovascular risk. Iron status, prooxidant-antioxidant balance and lipid profiles in serum, and lipid content in peripheral blood mononuclear cells (PBMCs) were evaluated in 20 β-TMI subjects, 22 β-TI patients and in 30 nonthalassemic blood donors. The mRNA levels of some genes involved in the regulation of iron and cholesterol metabolism were also determined. In β-TI and in β-TMI, serum iron, prooxidant-antioxidant ratio, transferrin saturation and erythropoietin levels were higher, while transferrin and hepcidin were lower compared to controls. Hepcidin and interleukin-1α mRNA levels were found to be reduced in β-TI- and β-TMI-PBMCs, while those of tumor necrosis factor alpha were increased. A reduction in high-density lipoprotein cholesterol in serum and an accumulation of neutral lipids coupled with increased mRNA levels of acetyl-coenzyme A:cholesterol acyltransferase and decreased neutral cholesterol ester hydrolase in PBMCs were also observed in β-TI and β-TMI compared to controls. Taken together, these findings provide experimental support for the idea that not only β-TI patients but also β-TMI have a proatherogenic biochemical phenotype which may contribute to increase their cardiovascular disease risk.

Human Immunodeficiency Virus and β-thalassemia Major: A “Competition of Guilt” for Pulmonary Arterial Hypertension. Report of A Case and A Review of the Literature

We report a case of a 43-year-old woman, affected by human immunodeficiency virus (HIV) and β-thalassemia major (β-TM), adequately treated with antiretroviral and transfusion-chelation therapy, that develops progressive right ventricular dysfunction due to severe pulmonary arterial hypertension (PAH), in absence of symptoms. The existence of both HIV and β-TM cardiomiopathy has recently been reported, but how these two diseases have a “competition of guilt” for creating PAH is still to be understood. The main physiopathological principles regarding HIV and β-TM associated PAH are reviewed. The possible interplay between these two different pathologies is discussed.