The effect of desferrioxamine chelation versus no therapy in patients with non transfusion-dependent thalassaemia: a multicenter prospective comparison from the MIOT network.

We prospectively assessed by magnetic resonance imaging (MRI) the advantages of desferrioxamine (DFO) with respect to the absence of chelation therapy in non transfusion-dependent thalassaemia (NTDT) patients. We considered 18 patients non-chelated and 33 patients who received DFO alone between the two MRI scans. Iron overload was assessed by the T2* technique. Biventricular function parameters were quantified by cine sequences. No patient treated with DFO had cardiac iron. At baseline, only one non-chelated patient showed a pathological heart T2* value (< 20 ms) and he recovered at the follow-up. The percentage of patients who maintained a normal heart T2* value was 100% in both groups. A significant increase in the right ventricular ejection fraction was detected in DFO patients (3.48 ± 7.22%; P = 0.024). The changes in cardiac T2* values and in the biventricular function were comparable between the two groups. In patients with hepatic iron at baseline (MRI liver iron concentration (LIC) ≥ 3 mg/g/dw), the reduction in MRI LIC values was significant only in the DFO group (- 2.20 ± 4.84 mg/g/dw; P = 0.050). The decrease in MRI LIC was comparable between the groups. In conclusion, in NTDT patients, DFO therapy showed no advantage in terms of cardiac iron but its administration allowed an improvement in right ventricular function. Moreover, DFO reduced hepatic iron in patients with significant iron burden at baseline.

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

BACKGROUND: Little information is available about the kidney's involvement in patients with ß-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 Cox's 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.

Thalassemia intermedia is associated with a proatherogenic biochemical phenotype.

OBJECTIVE: Unlike beta thalassemia major (ß-TM) in which cardiac siderosis represents the leading cause of mortality and morbidity, in beta thalassemia intermedia (ß-TI), pulmonary hypertension (PHT) and thrombosis seems to be the major cardiovascular complications. However, the mechanism underlying these complications in ß-TI is still unclear. Endothelial dysfunction, the key early event in atherogenesis, is now emerging as an important cardiovascular risk determiner in ß-TI patients. Among the factors known to affect endothelial function, iron and cholesterol merit particular consideration in ß-TI patients. Therefore, with the aim to extend our knowledge on the mechanisms connecting atherosclerosis to ß-TI, in this study, we compared lipid and iron metabolism in serum and in peripheral blood mononuclear cells (PBMCs) from ß-TI and ß-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 ß-TI patients were examined, and compared with 70 adult ß-TM, and 50 age-matched controls. Despite the great variability, levels of serum iron and transferrin saturation were significantly higher in ß-TI compared to both controls and ß-TM. By contrast, transferrin and hepcidin levels were lower in ß-TI patients. Changes in serum indicators in ß-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 ß-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 ß-TI patients exhibit a proatherogenic biochemical phenotype which may contribute to enhance cardiovascular risk in these subjects.

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

The purpose of this study was to focus on pathophysiological mechanisms linking ß-thalassemia intermedia (ß-TI) and minor (ß-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 ß-TMI subjects, 22 ß-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 ß-TI and in ß-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 ß-TI- and ß-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 ß-TI and ß-TMI compared to controls. Taken together, these findings provide experimental support for the idea that not only ß-TI patients but also ß-TMI have a proatherogenic biochemical phenotype which may contribute to increase their cardiovascular disease risk.

ß-thalassemia and thyroid failure: is there a role for thyroid autoimmunity?

Autoimmunity is not believed to be involved in tissue damage of Β-Thalassemia (Β-Thal), although nonspecific triggering of autoimmunity by iron overload has been suggested. We recently re-evaluated thyroid function and autoimmunity in 132 Β-Thal patients born and living in Sardinia Island, where a high prevalence of both Β-Thal and autoimmune disease is well documented and in 1002 age and sex-matched euthyroid individuals from the general population. The prevalence of primary hypothyroidism in Β-Thal patients was 28.7% (38/132), without significant difference between males (M) and females (F). Hypothyroidism was associated with smaller and hypoechoic glands, while no difference in the prevalence of anti-thyroid antibodies (ATA) was found between Β-Thal patients with or without thyroid failure. Interestingly, the prevalence of ATA in Β-Thal women (9.2%) was significantly lower than that found in age-matched euthyroid women (20.0%). Our study confirms that thyroid autoimmunity has no role in the pathogenesis of hypothyroidism in b-Thal. Moreover, the lower ATA prevalence in Β-Thal women suggests that iron overload may inhibit rather then trigger thyroid autoimmunity.

Case report: thalassemia intermedia patient with hypertension non-responsive to combined medical treatment.

Pheochromocytoma is a rare disease in the general population and, to the best of our knowledge, only one case has been reported so far in patients with hemoglobinopathies. We describe the occurrence of pheochromocytoma in a patient with thalassemia intermedia associated with Gilbert's disease and Crigler- Najjar Type 2 syndrome.

The planimetric Grothoff's criteria by cardiac magnetic resonance can improve the specificity of left ventricular non-compaction diagnosis in thalassemia intermedia.

We differentiated the left ventricle non-compaction (LVNC) from hypertrabeculated myocardium due to a negative remodeling in thalassemia intermedia (TI) patients applying linear and planimetric criteria and comparing the cardiovascular magnetic resonance (CMR) findings. CMR images were analyzed in 181 TI patients enrolled in the Myocardial Iron Overload in Thalassemia Network and 27 patients with proved LVNC diagnosis. The CMR diagnostic criteria applied in TI patients were: a modified linear CMR Petersen's criterion based on a more restrictive ratio of diastolic NC/C > 2.5 at segmental level and the combination of planimetric Grothoff's criteria (percentage of trabeculated LV myocardial mass LV-MM ≥ 25% of global LV mass and total LV-MMI NC ≥ 15 g/m2). Seventeen TI patients showed at least one positive NC/C segment. Compared to LVNC patients, these patients showed a lower frequency of segments with non-compaction areas (2.41 ± 1.33 vs 5.48 ± 2.26; P < 0.0001), significantly lower LV-MM NC percentage (10.99 ± 4.09 vs 28.20 ± 4.27%; P < 0.0001), LV-MMI (7.58 ± 4.86 vs 19.88 ± 5.02 g/m2; P < 0.0001) and extension of macroscopic fibrosis (0.44 ± 0.18 vs 4.65 ± 2.89; P = 0.004), and significantly higher LV ejection fraction (61.29 ± 5.17 vs 48.50 ± 17.55%; P = 0.016) and cardiac index (4.80 ± 1.49 vs 3.46 ± 1.11 l/min/m2; P = 0.002). No TI patient fulfilled the Grothoff's criteria. All TI patients with an NC/C ratio > 2.5 showed morphological and functional CMR parameters significantly different from the patients with a proved diagnosis of LVNC. Differentiation of LVNC from hypertrabeculated LV in ß-TI patients due to a negative heart remodeling depends on the selected CMR criterion. We suggest using planimetric Grothoff's criteria to improve the specificity of LVNC diagnosis.

Haplotype affinities resolve a major component of goat (Capra hircus) MtDNA D-loop diversity and reveal specific features of the Sardinian stock.

Goat mtDNA haplogroup A is a poorly resolved lineage absorbing most of the overall diversity and is found in locations as distant as Eastern Asia and Southern Africa. Its phylogenetic dissection would cast light on an important portion of the spread of goat breeding. The aims of this work were 1) to provide an operational definition of meaningful mtDNA units within haplogroup A, 2) to investigate the mechanisms underlying the maintenance of diversity by considering the modes of selection operated by breeders and 3) to identify the peculiarities of Sardinian mtDNA types. We sequenced the mtDNA D-loop in a large sample of animals (1,591) which represents a non-trivial quota of the entire goat population of Sardinia. We found that Sardinia mirrors a large quota of mtDNA diversity of Western Eurasia in the number of variable sites, their mutational pattern and allele frequency. By using bayesian analysis, a distance-based tree and a network analysis, we recognized demographically coherent groups of sequences identified by particular subsets of the variable positions. The results showed that this assignment system could be reproduced in other studies, capturing the greatest part of haplotype diversity.We identified haplotype groups overrepresented in Sardinian goats as a result of founder effects. We found that breeders maintain diversity of matrilines most likely through equalization of the reproductive potential. Moreover, the relevant amount of inter-farm mtDNA diversity found does not increase proportionally with distance. Our results illustrate the effects of breeding practices on the composition of maternal gene pool and identify mtDNA types that may be considered in projects aimed at retrieving the maternal component of the oldest breeds of Sardinia.