IntroductionIn the last 4 decades, regular blood transfusions and chelation therapy have improved the survival of patients with thalassemia major. 1-3 Despite the progress on chelation therapy, cardiac complications remain the main cause of death among transfusiondependent thalassemia patients related to the susceptibility of cardiac cells to iron overload toxicity. 4,5 The interest in the clinical management of chronic liver diseases has been increasing, however, because of the high prevalence of viral infections in adult transfusion-dependent thalassemia patients and the central role of the liver in regulating the iron metabolism. 5,6 The assessment of heart and liver iron overload is required to tailor iron chelation therapy. Furthermore, the diagnosis of hepatitis B virus (HBV)-or hepatitis C virus (HCV)-related chronic hepatitis is required to identify patients who have a high risk of developing liver complications and who may obtain a benefit by antiviral therapy.The goals of this paper are to summarize 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. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From An expert hepatologist prepared an initial draft based on systematic review of published literature by Medline search on viral hepatitis in thalassemia patients, examined recently published guidelines on the diagnosis, management, and treatment of chronic hepatitis B and chronic hepatitis C edited by the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian-Pacific Association for the Study of the Liver 7-10 and the Consensus Development Conference sponsored by the National Institutes of Health. 11 Recommendations of the panel of experts were based insofar as possible on evidence from publications that reported data on thalassemia patients. If evidence from thalassemia patients was unavailable, the panel selected recommendations from published guidelines that were suitable for thalassemia patients. Recommendations were evaluated according to the Grading of Recommendations Assessment Development and Evaluation system and classified into 3 levels: high, moderate, or low 12 (Table 1). For each recommendation, the level of evidence (high, moderate, or low) and population studied (general population of patients with viral chronic hepatitis or thalassemia patients) was specified. The panel of experts discussed the draft issue by issue, and 3 experts on blood transfusion, iron metabolism, and viral hepatitis management reviewed the recommendations. Finally, 8 international external experts in pediatrics, hematology, and viral hepatitis reviewed and criticized the recommendations. Methods Results What proportion of thalassemia patients have chronic viral infections?Worldwide, from 0.3% to 5.7% of thala...

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SummaryIn the last few decades, the life expectancy of regularly transfused b-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 b-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 < 0Á0001) before the introduction of iron chelation in 1965, which were no longer apparent after that date (P = 0Á086), reducing the Hazard Ratio of death in TM compared to TI from 6Á8 [95% confidence interval (CI) 2Á6-17Á5] before 1965 to 2Á8 (95% CI 0Á8-9Á2). 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.

SummaryA 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 = 0AE005). KaplanMeier survival analysis for the two chelation treatments did not show any statistically significant differences (long-rank test, P = 0AE3145). 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. This trial was registered at http://www.clinicaltrials.gov as # NCT00733811.

SummaryThe correlation between liver stiffness, measured by transient elastography, liver fibrosis, using the histological METAVIR score, and iron overload, measured by atomic absorption spectrometry was evaluated in 56 homozygous-b-thalassaemics. Liver stiffness increased proportionally to liver fibrosis staging (r = 0AE70; P > 0AE001) independently of liver iron concentration (r = 0AE01; P = 0AE932). The area under the receiver-operating characteristic curve for prediction of cirrhosis was 0AE997 (95% confidence interval [CI]: 0AE925-1AE000) with cut-off of 13 kPa with 100% sensitivity (95% CI: 69AE0-100AE0) and 95% specificity (95% CI: 84AE2-99AE3). Transient elastography is a reliable non-invasive tool for diagnosing advanced liver fibrosis in homozygous-b-thalassaemics, regardless of the degree of iron overload.

Iron overload and hepatitis virus C infection cause liver fibrosis in thalassemics. In a monocentric retrospective analysis of liver disease in a cohort of 191 transfusion-dependent thalassemics, in 126 patients who had undergone liver biopsy (mean age 17.2 years; 58 hepatitis virus C-RNA positive and 68 hepatitis virus C-RNA negative) the liver iron concentration (median 2.4 mg/gr dry liver weight) was closely related to serum ferritin levels (R = 0.58; p<0.0001). Male gender (OR 4.12) and serum hepatitis virus C-RNA positivity (OR 11.04) were independent risk factors for advanced liver fibrosis. The majority of hepatitis virus C-RNA negative patients with low iron load did not develop liver fibrosis, while hepatitis virus C-RNA positive patients infected with genotype 1 or 4 and iron overload more frequently developed advanced fibrosis. Hepatitis virus C infection is the main risk factor for liver fibrosis in transfusion-dependent thalassemics. Adequate chelation therapy usually prevents the development of liver fibrosis in thalassemics free of hepatitis virus C-infection and reduces the risk of developing severe fibrosis in thalassemics with chronic hepatitis C.

A multicenter randomized open-label long-term sequential deferiprone-deferoxamine (DFP-DFO) versus DFP alone trial (sequential DFP-DFO) performed in patients with thalassemia major (TM) was retrospectively reanalyzed to assess the variation in the left ventricular ejection fraction (LVEF) [1].Serial observations of LVEF over 3 years, in the same patient, were retrospectively assessed in 99 patients with TM during the sequential DFP-DFO multicenter randomized open-label trial [1]. A generalized estimating equation (GEE) model was used to demonstrate changes in mean LVEF over time [2].The regression coefficient of treatment suggested that the DFP-alone group showed a statistically significant increase in mean LVEF over time (coefficient 0.97, 95% CI (0.51; 1.44), P-value <0.0001).These findings suggest that long-term treatment with DFP-alone can significantly enhance LVEF over time. These findings agree with a survival analysis reporting a substantial decline in cardiac deaths during recent years, related to the switching of high-risk patients from DFO to chelation regimens that include the oral chelator DFP [3][4][5].Oral chelation treatment has improved greatly adherence and management of patients with TM [6,7].The improvement of the LVEF after 1-year DFP treatment has been reported [8][9][10][11].However, the effects of DFP on LVEF after long-term treatment have not been fully investigated.This letter reports a retrospective survey performed on patients with TM, previously enrolled in a long-term randomized open-label trial carrying ahead in Italy on the behalf of the Italian Society for the Study of Thalassaemia and Haemoglobinopathies (SoSTE) [1]. Ninety-nine out of 213 patients enrolled in the sequential DFP-DFO trial underwent longterm echocardiographic study of LVEF measured at baseline and every 12 months over three consecutive years (Fig. 1). Among these, 39 and 60 received sequential DFP (75 mg/kg for 4 days/week)-DFO (50 mg/kg for 3 days/week) or DFP-alone (75 mg/kg for 7 days/week) treatment, respectively (Table I).The hematological and clinical findings at enrollment are shown in Table I. No differences were observed at baseline between the two randomized groups. Particularly, the main findings of body iron overloading, expressed as serum ferritin at baseline, liver iron concentration (LIC), baseline LVEF <55%, and total number of blood transfusions were not statistically significantly different (Table I). Moreover, although baseline LVEF appears unlike between the two groups ( Fig. 1), this was not statistically significantly different (P-value 5 0.10, Table I).The DFP-alone group showed statistically significant increase over time in mean LVEF in comparison with sequential DFO-FP treatment (coefficient 0.97, 95% CI (0.51; 1.44), P-value <0.0001).Furthermore, the regression coefficient of treatment suggested that there was a statistically significant difference in mean LVEF between the two treated groups favoring the sequential group (coefficient 2.36, 95% CI (0.02; 4.71), P-value 5 0.047, but this ...

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.