The heterozygote state for β‐thalassemia detrimentally affects health outcomes
Authors: Luciano Graffeo, Angela Vitrano, Antonino Giambona, Salvatore Scondotto, Gabriella Dardanoni, Christian Gluud, Aurelio Maggio
Journal: American Journal of Hematology (2016)

β-Thalassemia is a hereditary blood disorder decreasing hemoglobin synthesis. β-Thalassemia is classified into three phenotypes, depending on the severity of symptoms: (1) thalassemia major (TM); (2) thalassemia intermedia (TI); and (3) thalassemia minor (Tm).1 In TM, signs and symptoms appear within the first two years of life and patients develop life-threatening anemia (hemoglobin (Hb) <7.0 g/dL).1 TM patients are lifetime transfusion-dependent. Over time, chronic blood transfusions can lead to severe body iron accumulation that, in spite of chelation treatments, may result in liver, cardiac, and endocrinological complications. In TI, the signs and symptoms appear after the first two year of life.1 Affected individuals have mild to moderate anemia (Hb 7.0 to 9.0 g/dL) and they may need occasionally blood transfusions. The clinical consequences may include endocrinopathies, bone disease, thromboembolism, pulmonary hypertension, cerebrovascular and neuronal damage, liver fibrosis or cirrhosis, and increased risk of hepatocellular carcinoma. Tm individuals are usually considered healthy and they do not need blood transfusions because of this condition. Here we provide data on complications and mortality in Tm individuals compared to a control group (Ctr). We performed a retrospective review of all subjects voluntarily seeking thalassemia screening2 at the Regional Centre for Thalassemia, Azienda Ospedali Riuniti Villa Sofia-V. Cervello, Palermo (Italy) from January 2000 to July 2014. Our unit is the Hub Centre for Prenatal Diagnosis and Screening of Thalassemias for the whole Sicily. By using data on hospital admissions and mortality provided by Department Health Services and Epidemiological Observatory (DHSEO) of the Sicilian Region, we captured hospital admissions for different complications, as Diagnosis Codes according to the ICD-9-CM,3 from January 2004 until December 2013. Information on hospital admission and mortality before January 2004, for all individuals included in the study, were not available at the DHSEO because data were not computerized. Logistic penalized regression model (LPRM) was used to estimate the risk to develop different complications. The considered model takes into account the effect of group (Tm vs. Ctr), sex (M vs. F), age, and interaction between sex and age on the occurrence of a single complication. The variable relative to a specific complication was set to zero when the complication was not present and 1 when the complication was present at least once regardless of the number of admissions for the specific disease. A Cox regression model, Kaplan–Meier curves, and a log-rank test were used to investigate difference in survival between the two groups of interest. Overall, 26 006 individuals were included in this retrospective review: 4943 subjects had Tm, while 21 063 were normal controls proven negative for the β-thalassemia carrier state. Hematological data showed statistical significant differences between the two groups for all variables considered (Supporting Information Table 1). The risks of hospital admission for cholelithiasis, cirrhosis, mood disorders, and kidney disease were significantly higher in the Tm group vs. control (Table 1). No statistically significant differences were found for arrhythmia, diabetes, and ischemic cardiomyopathy (results not reported). The probability of hospital admission for cholelithiasis, cirrhosis, mood disorders, and kidney disease increased with age and with hospitalization for other causes (Table 1; Supporting Information Figure 1). The probability of hospital admissions for cirrhosis and kidney diseases was greater in males, while that for cholelithiasis was greater in females, with no gender differences identified for mood disorders (Table 1; Supporting Information Figure 1). The risk of death in the Tm group was similar to that of the control group (HR 1·090, 95% CI 0.777 to 1.555, P < .590; log-rank test P = .426; Supporting Information Table 1 and Figure 2), as reported by Gallerani et al.4 These findings in a large cohort of Italian individuals suggest that Tm increases significantly the risk of hospitalization for cirrhosis, kidney disorders, cholelithiasis, and mood disorders when compared with a control group. The statistically significant increased risk of hospitalization for cirrhosis may be related to long-term enhanced iron absorption in the Tm versus control group, probably due to ineffective erythropoiesis and erythroid hyperplasia.5 Different reports suggested the existence of a kidney disorders in Tm.6 The increased risk of hospitalization for kidney diseases shown in our present study further supports the notion that kidney diseases is more common in Tm. Borgna-Pignatti et al. suggested that women with Tm have significantly higher prevalence of cholethiasis.7 They also detected an increased risk of hospitalization for cholelithiasis in females with Tm, which seemed to increase with age perhaps as a consequence of lifetime mild hemolysis and/or ineffective erythropoiesis. The increased risk of hospitalization for mood disorders in the Tm group, shown in the present study, is in accordance with the report by Kes¸kek et al., 2013, which found higher Hamilton Depression Rating scores (HDRS) in Tm individuals vs. healthy controls (P < .001).8 The cause of mood disorders in Tm individuals is not clear. In conclusion, this large retrospective study shows that the β-thalassemia carrier state affects health expectations and outcomes, perhaps as a consequence of mild iron overload and anemia. Large prospective studies should be considered to confirm these findings and identify other relevant risk factors and biomarkers. This study was supported by the Foundation Franco and Piera Cutino. L. G. assisted with data collection, data analyses and statistical interpretation; A.V. assisted with statistical design, data analyses, statistical interpretation, and wrote the manuscript; A. G. reviewed the manuscript for important intellectual content; S. S. and G. D. assisted with data collection; C. G. assisted with statistical analyses and reviewed the manuscript for important intellectual content; A. M. designed research questions, assisted with medical interpretation, and wrote the manuscript. The authors declare no competing financial interests. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.