Left atrial strain in patients with ß-thalassemia major: a cross-sectional CMR study.

OBJECTIVES: The aim of this cross-sectional study was to investigate the association of left atrial (LA) strain parameters with demographics, clinical data, cardiovascular magnetic resonance (CMR) findings, and cardiac complications (heart failure and arrhythmias) in a cohort of patients with ß-thalassemia major (ß-TM). MATERIALS AND METHODS: We considered 264 ß-TM patients (133 females, 36.79 ± 11.95 years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) project. Moreover, we included 35 sex- and age-matched healthy controls (14 females, mean age 37.36 ± 17.52 years). Reservoir, conduit, and booster LA functions were analysed by CMR feature tracking using dedicated software. RESULTS: Compared to the healthy control group, ß-TM patients demonstrated lower LA reservoir strain and booster strains, as well as LA reservoir and booster strain rates. However, no differences were found in LA conduit deformation parameters. In ß-TM patients, ageing, sex, and left ventricle (LV) volume indexes were independent determinants of LA strain parameters. The number of segments with late gadolinium enhancement (LGE) significantly correlated with all LA strain parameters, with the exception of the LA conduit rate. Patients with cardiac complications exhibited significantly impaired strain parameters compared to patients without cardiac complications. CONCLUSION: In patients with ß-TM, LA strain parameters were impaired compared to control subjects, and they exhibited a significant correlation with the number of LV segments with LGE. Furthermore, patients with cardiac complications had impaired left atrial strain parameters. Clinical relevance statement In patients with ß-thalassemia major, left atrial strain parameters were impaired compared to control subjects and emerged as a sensitive marker of cardiac complications, stronger than cardiac iron levels. KEY POINTS: • Compared to healthy subjects, ß-thalassemia major patients demonstrated significantly lower left atrial reservoir strain and booster strains, as well as left atrial reservoir and booster strain rates. • In ß-thalassemia major, ageing, sex, and left ventricular volume indexes were independent determinants of left atrial strain parameters, while left atrial strain parameters were not correlated with myocardial iron overload. • An independent association between reduced left atrial strain parameters and a history of cardiac complications was found in ß-thalassemia major patients.

Pattern and clinical correlates of renal iron deposition in adult beta-thalassemia major patients.

We evaluated pattern and clinical correlates of renal T2* measurements in adult ß-thalassemia major (ß-TM) patients. Ninety ß-TM patients (48 females, 38.15 ± 7.94 years), consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network, underwent T2* magnetic resonance imaging (MRI) for quantification of iron overload (IO) in kidneys, liver, pancreas, and heart. Ten (11.1%) patients showed renal IO (T2* < 31 ms). Global kidney T2* values did not show a correlation with gender, age, splenectomy, regular transfusions or chelation starting age, pre-transfusion hemoglobin, and serum ferritin levels. Global kidney T2* values showed an inverse correlation with MRI liver iron concentration (LIC) values (R = - 0.349; p = 0.001) and a positive correlation with global pancreas T2* values (R = 0.212; p = 0.045). Frequency of renal IO was significantly higher in patients with cardiac IO than in patients without cardiac IO (50.0% vs. 6.3%; p = 0.001). A significant inverse association was detected between global kidneys T2* values and lactate dehydrogenase (LDH) (R = - 0.529; p < 0.0001). In multivariate regression analysis, MRI LIC and LDH were the strongest predictors of global kidney T2* values. A MRI LIC > 4.83 mg/g dw predicted the presence of renal IO (sensitivity = 90.0%; specificity = 61.2%). Global kidney T2* values were inversely correlated with uric acid (R = - 0.269; p = 0.025). In conclusion, in adult ß-TM patients, renal iron deposition is not common and is linked to both hemolysis and total body iron overload.

Bone status and HCV infection in thalassemia major patients.

PURPOSE: Hepatitis C virus (HCV) infection increases the risk for osteoporosis but this relationship has not been investigated among multi-transfused patients with thalassemia major (TM). We cross-sectionally explored the association of HCV infection with bone mineral density (BMD), vitamin D, and bone turnover biomarkers in TM. METHODS: We considered 130 TM patients (41.89 ± 5.49 years, 67 females) enrolled in the E-MIOT (Extension-Myocardial Iron Overload in Thalassemia) Network. BMD measurements taken at the lumbar spine, femoral neck and total hip were expressed as Z-scores, with a BMD Z-score ≤ -2.0 indicating low bone mass. RESULTS: Z-scores were not associated with gender, iron overload indices, vitamin D levels, and biochemical bone turnover markers, but decreased with aging and in presence of hypogonadism and were directly correlated with body mass index (BMI). The prevalence of low bone mass was 70.7 %. Three groups of patients were identified: 78 who never contracted the infection (group 0), 72 who cleared HCV (group 1), and 29 with chronic HCV infection (CHC) (group 2). All Z-scores progressively decreased according to HCV status from group 0 to group 2. Osteocalcin levels were significantly lower in groups 2 and 1 than in group 0. CHC patients were more likely to have low bone mass compared to HCV naive patients, after adjusting for age, BMI, hypogonadism, and pancreatic iron. CONCLUSION: In TM, CHC appears as one additive risk factor for low bone mass and osteocalcin may play a role in this association.

The era of comparable life expectancy between thalassaemia major and intermedia: Is it time to revisit the major-intermedia dichotomy?

In the last few decades, the life expectancy of regularly transfused ß-thalassaemia major (TM) patients has dramatically improved following the introduction of safe transfusion practices, iron chelation therapy, aggressive treatment of infections and improved management of cardiac complications. How such changes, especially those attributed to the introduction of iron chelation therapy, improved the survival of TM patients to approach those with ß-thalassaemia intermedia (TI) remains unknown. Three hundred and seventy-nine patients with TM (n = 284, dead 40) and TI (n = 95, dead 13) were followed retrospectively since birth until 30 June 2015 or death. Kaplan-Meir curves showed statistically significant differences in TM and TI survival (P < 0·0001) before the introduction of iron chelation in 1965, which were no longer apparent after that date (P = 0·086), reducing the Hazard Ratio of death in TM compared to TI from 6·8 [95% confidence interval (CI) 2·6-17·5] before 1965 to 2·8 (95% CI 0·8-9·2). These findings suggest that, in the era of iron chelation therapy and improved survival for TM, the major-intermedia dichotomy needs to be revisited alongside future directions in general management and prevention for both conditions.

Real-life experience with liver iron concentration R2 MRI measurement in patients with hemoglobinopathies: baseline data from LICNET.

BACKGROUND: Real-life data on the use of R2 MRI for the assessment of liver iron concentration (LIC) remain limited. METHODS: We conducted a cross-sectional analysis on 363 patients (mean age 35.6 yr, 44.1% men) with hemoglobinopathies (204 ß-thalassemia major [TM], 102 ß-thalassemia intermedia [TI], and 57 sickle cell disease [SCD]) that were evaluated with R2 MRI as part of LICNET, an MRI network of 13 Italian treatment centers. RESULTS: The mean LIC was 7.8 mg/g (median: 4.0), with high LIC (>7 mg/g) noted in both transfused (TM, TI 37%; SCD 38%) and non-transfused (TI 20%) patients. Ferritin levels correlated with LIC in both transfused (TM, TI, SCD) and non-transfused (TI) patients (P < 0.001), although lower values predicted high LIC in non-transfused patients (1900 vs. 650 ng/mL in TM vs. non-transfused TI). A correlation between LIC and ALT levels was only noted in HCV-negative patients (rs = 0.316, P < 0.001). The proportion of patients with high LIC was significantly different between iron chelators used (P = 0.023), with the lowest proportion in deferasirox (30%) and highest in deferiprone (53%)-treated patients. CONCLUSIONS: High LIC values persist in subgroups of patients with hemoglobinopathy, warranting closer monitoring and management optimization, even for non-transfused patients with relatively low ferritin levels.

Sequential alternating deferiprone and deferoxamine treatment compared to deferiprone monotherapy: main findings and clinical follow-up of a large multicenter randomized clinical trial in -thalassemia major patients.

In ß-thalassemia major (ß-TM) patients, iron chelation therapy is mandatory to reduce iron overload secondary to transfusions. Recommended first line treatment is deferoxamine (DFO) from the age of 2 and second line treatment after the age of 6 is deferiprone (L1). A multicenter randomized open-label trial was designed to assess the effectiveness of long-term alternating sequential L1-DFO vs. L1 alone iron chelation therapy in ß-TM patients. Deferiprone 75 mg/kg 4 days/week and DFO 50 mg/kg/day for 3 days/week was compared with L1 alone 75 mg/kg 7 days/week during a 5-year follow-up. A total of 213 thalassemia patients were randomized and underwent intention-to-treat analysis. Statistically, a decrease of serum ferritin level was significantly higher in alternating sequential L1-DFO patients compared with L1 alone patients (p = 0.005). Kaplan-Meier survival analysis for the two chelation treatments did not show statistically significant differences (log-rank test, p = 0.3145). Adverse events and costs were comparable between the groups. Alternating sequential L1-DFO treatment decreased serum ferritin concentration during a 5-year treatment by comparison to L1 alone, without significant differences of survival, adverse events or costs. These findings were confirmed in a further 21-month follow-up. These data suggest that alternating sequential L1-DFO treatment may be useful for some ß-TM patients who may not be able to receive other forms of chelation treatment.

Long-term sequential deferiprone-deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clinical trial.

A multicentre randomized open-label trial was designed to assess the effectiveness of long-term sequential deferiprone-deferoxamine (DFO-DFP) versus DFP alone to treat thalassaemia major (TM). DFP at 75 mg/kg, divided into three oral daily doses, for 4 d/week and DFO by subcutaneous infusion (8-12 h) at 50 mg/kg per day for the remaining 3 d/week was compared with DFP alone at 75 mg/kg, administered 7 d/week during a 5-year follow-up. The main outcome measures were differences between multiple observations of serum ferritin concentrations. Secondary outcomes were survival analysis, adverse events, and costs. Consecutive thalassaemia patients (275) were assessed for eligibility; 213 of these were randomized and underwent intention-to-treat analysis. The decrease of serum ferritin levels during the treatment period was statistically significant higher in sequential DFP-DFO patients compared with DFP-alone patients (P = 0.005). Kaplan-Meier survival analysis for the two chelation treatments did not show any statistically significant differences (long-rank test, P = 0.3145). Adverse events and costs were comparable between the groups. The trial results show that sequential DFP-DFO treatment compared with DFP alone significantly decreased serum ferritin concentration during treatment for 5 years without significant differences regarding survival, adverse events, or costs.

Improving survival with deferiprone treatment in patients with thalassemia major: a prospective multicenter randomised clinical trial under the auspices of the Italian Society for Thalassemia and Hemoglobinopathies.

The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone-deferoxamine (DFP-DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP-DFO, or combined DFP-DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48.3%) females and 137 (51.7%) males. No deaths occurred with the DFP-alone or the combined DFP-DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP-DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment. The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value<0.013). For each increasing year of age, the hazard ratio for males was 1.03 higher than that for females (p-value<0.013). In conclusion, the results of this study show that the risk factors for predicting mortality in patients with thalassemia major are deferoxamine-treatment, complications, and the interaction effect of sex and age.

Bone demineralization in adult thalassaemic patients: contribution of GH and IGF-I at different skeletal sites.

BACKGROUND AND OBJECTIVE: GH and IGF-I exert an important role in the control of bone formation, as shown by decreased bone mineral density and increased fracture risk in adult hypopituitary patients untreated for GH deficiency (GHD). Different degrees of bone demineralization are frequently reported in patients affected by beta-thalassaemia. Considering the high prevalence of GHD recently observed by our group among adult thalassaemic patients, we elected to study the possible role of GH-IGF-I abnormalities in the pathogenesis of the osteopenia/osteoporosis of this disease. DESIGN: Sixty-four adult thalassaemic patients (49 with thalassaemia major and 15 with thalassaemia intermedia, 23 men and 41 women, aged 31.4 +/- 6.8 years) were studied. METHODS: Bone mineral density was assessed by dual energy X-ray absorptiometry at lumbar spine in 62 patients and at proximal femur in 58. All patients underwent GHRH (1 microg/kg as an i.v. bolus) plus arginine (0.5 g/kg as a 30-min i.v. infusion) testing. Severe GHD was defined by GH peaks < 9 microg/l, whereas partial GHD was defined by GH peaks ranging from 9 to 16.5 microg/l. Blood samples for IGF-I measurement were collected. RESULTS: Lumbar osteoporosis and osteopenia were demonstrated in 46/62 (74.1%) and 14/62 (22.5%) patients, respectively. Femoral osteoporosis and osteopenia were documented in 22/58 (37.9%) and 32/58 (55.1%) patients, respectively. Severe GHD was demonstrated in 16/64 patients (25%), while 11 additional patients (17.1%) displayed partial GHD. IGF-I standard deviation score (SDS) was low, that is, below -1.88, in the majority (54.6%) of patients. Lumbar T-score values were not correlated with either GH peaks or IGF-I SDS values. Femoral T-score values were positively correlated with GH peaks (r = 0.38, P < 0.005) and IGF-I SDS values (r = 0.39, P < 0.005). Multiple regression analysis pointed to both GH peak and IGF-I SDS as predictors of femoral T-score. Furthermore, mean femoral T-score was significantly lower in patients with severe GHD than in those with normal GH secretion (-2.94 +/- 0.25 vs.-2.15 +/- 0.12, P < 0.01). CONCLUSION: This study, while confirming the high prevalence of both osteopenia/osteoporosis and somatotropin-somatomedin deficiency in adult thalassaemic patients, indicates that defective GH secretion and diminished serum IGF-I levels may contribute to femoral demineralization in these patients. Further studies are worth carrying out to evaluate the efficacy of biosynthetic GH administration on bone abnormalities of GH-deficient thalassaemic adults.

Growth hormone deficiency (GHD) in adult thalassaemic patients.

BACKGROUND AND OBJECTIVE: Short stature and growth hormone deficiency (GHD) are frequent occurrences in thalassaemic children, while data on the prevalence of GHD in adult patients are lacking. Therefore, we elected to study the growth hormone and insulin-like growth factor-I (GH-IGF-I) axis in a large group of adult thalassaemic subjects. DESIGN: Cross-sectional study on the prevalence of GHD in 94 adult thalassaemic patients (69 with thalassaemia major and 25 with thalassaemia intermedia, 39 men and 55 women, aged 31.5 +/- 6.8 years, on sex steroid replacement when necessary). METHODS: All patients underwent GHRH (1 microg/kg as an i.v. bolus) plus arginine (0.5 g/kg as a 30 min i.v. infusion) testing. Severe GHD was defined by GH peaks lower than 9 microg/l, whereas partial GHD was defined by GH peaks ranging from 9-16.5 microg/l. Blood samples for IGF-I, ferritin and pseudocholinesterase measurements were collected. Urinary free cortisol (UFC) levels were also assayed. RESULTS: Severe GHD was demonstrated in 21 of the 94 patients (22.3%), while 18 additional patients (19.1%) displayed partial GHD. GH peaks were positively correlated with IGF-I standard deviation score (SDS) (r = 0.22, P < 0.05), although 1 of the 21 patients with severe GHD showed normal IGF-I SDS values, and 44 of the 55 patients with normal GH reserve displayed low IGF-I SDS. A strong positive correlation (r = 0.48, P < 0.0001) between IGF-I SDS and pseudocholinesterase was identified. No correlations were found between ferritin and UFC levels on the one hand and GH peaks and IGF-I SDS on the other. CONCLUSION: Findings from this study demonstrate that GHD, either partial or severe, is not a rare occurrence in adult thalassaemic patients. GHD is associated with a higher prevalence of low serum IGF-I levels, recorded also in patients with normal GH secretion. The lack of correlation between ferritin and both GH peaks and IGF-I SDS suggests that mechanisms additional to iron overload, whose relevance cannot however be definitely ruled out, play a role in the pathophysiology of somatotrophin-somatomedin deficiency in this clinical condition. The positive correlation between IGF-I SDS on the one hand and GH peaks and pseudocholinesterase values on the other hand indicates that reduced liver protidosynthetic activity, in addition to somatotrophin secretory status, is a major determinant of the impaired IGF-I production in thalassaemia. Therefore biosynthetic GH replacement therapy in GH-deficient thalassaemic adults is worth considering.