Summary 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 μg/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.

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Skeletal demineralization and mineral metabolism derangement are well-recognized features of untreated celiac disease (CD). Although treatment with a gluten-free diet appears to prevent bone loss while correcting skeletal demineralization in childhood, there is evidence that bone mineral density does not return to normal in celiacs diagnosed in adulthood. Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor family, and ligand of receptor activator of NFkB (RANKL) are involved in the process of bone turnover and have been implicated in the pathogenesis of osteoporosis and other metabolic bone diseases. We measured OPG, RANKL, bone mineral density (BMD), and biochemical markers of bone turnover in 32 adult female premenopausal celiac patients on a gluten-free diet, and thirty age-matched healthy women. We correlated the OPG/RANKL ratio with the severity of bone loss. Celiac patients had a mean BMD lower than controls in lumbar spine and in the femoral neck. Serum levels of bone alkaline phosphatase (BAP, marker of bone formation), and urinary excretion of telopeptides of type I collagen (a marker of bone resorption) were significantly higher than in controls. Serum OPG and RANKL levels were significantly higher in CD patients than in controls, while the OPG/RANKL ratio was significantly lower in CD patients than in controls and was positively correlated with BMD at the spine. The role of elevated OPG in CD patients is unclear, but it might represent a compensatory mechanism against other factors that promote bone damage. Further studies are required to assess a possible therapeutic potential of osteoprotegerin in optimally treated celiacs with persistent osteopenia.

The present epidemiological study of the molecular characteristics of beta-thalassemia in Sicily was prompted by the disparate phenotypic expression (in clinical status and absolute HbF level) observed in two beta-thalassemic homozygotes who were also homozygous for the beta-like globin gene cluster haplotype III. We suspected that polymorphisms within haplotype III could be the cause for the discrepancy. Based on the association of particular conformations of the (AT)xT(y) motif (-540 5' to the beta gene) with milder forms of thalassemia and sickle cell anemia, 38 homozygous beta-thalassemia patients were studied to define their haplotypes, the -158 site 5' to the G gamma gene (linked to haplotype III) and the structure of the (AT)xT(y) motif. We found that the patient who was phenotypically mild and homozygous for beta-thalassemia, haplotype III, and the -158 C----T mutation was homozygous for the rare (AT)9T5 motif. In contrast, the patient homozygous for beta-thalassemia, haplotype III, and the -158 mutation, but exhibiting a severe clinical course, was homozygous for the (AT)7T7 configuration. Others have suggested that (AT)9T5 is a negative regulatory protein binding sequence, and it is a silent carrier state for beta-thalassemia. The usual configuration (AT)7T7, has considerably less affinity for regulatory protein binding, and it is the most common configuration in Sicilian beta-thalassemics (67 of the 78 chromosomes studied). Within the 38 patients studied, seven were informative because they had various combinations of the (AT)9T5 and (AT)7T7 motif, and the -158 C----T mutation. The results in these patients suggest that only the co-presence of the (AT)9T5 configuration and a C----T change at -158 5' to the G gamma gene is associated with high HbF expression and a mild clinical phenotype. We postulate that these two regions of the beta-like globin gene cluster interact, when endowed with the proper sequences, to enhance the expression of HbF secondary to anemia.

Prognosis of thalassemia major patients has dramatically improved in the past two decades. Previous papers, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was less or completely absent in patients treated with DFP alone or with associated chelation treatment. For this reason, the main aim of this study was to evaluate whether the addition of deferiprone treatment was also associated with a mortality decrease among a large randomised cohort of thalassemia major patients. Survival analysis was performed among 264 thalassemia major patients assessed for eligibility from 09/30/2000 to 01/31/2008, during a long-term multicentre randomised clinical trial. The reported chelation therapies included sequential DFP-DFO, associated DFP and DFO, DFP and DFO interventions. The survival curves were compared by gender and treatment groups using the long-rank test. Cox regression models were used to explore association between risk for death among treatments and survival time. All statistical analyses were performed by STATA 9.2. All these patients performed DFO before the date of randomisation. One death was due to a graft versus host disease (GVHD) in a patient underwent bone marrow transplantation and this patient was censored at the time of transplant. The improved survival for sequential DFP-DFO, DFP-alone, and associated DFP-DFO treated patients versus DFO-treated was statistically significant (log-rank test, χ2= 18.64; p≤0.01). In fact, no deaths were reported during DFP-alone and DFP-DFO associated treatments along a 564.5 person-years period of observation. Only one death was reported during DFP-DFO sequential treatment in a patient who had experienced 1-year before an episode of heart failure. All other ten deaths were among patients under DFO treatment. The hazard ratio for death of DFO treatment versus other treatments was 27.78 (p= 0.002). The main factors correlated with increased hazard ratio for death were cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, hypothyroidism. No correlation between serum ferritin levels and hazard ratio for death was found. These results confirm as deferiprone alone or in addition to deferoxamine intervention is able to reduce mortality in thalassemia major patients probably because of its specific cardioprotective effect occurring independently from body iron overloading