Abstract
Objectives
Patients with beta-thalassemia intermedia tend to present later in life with milder anemia than beta-thalassemia major patients. The incidence of mortality and its causes in this patient population remains unknown. We aim to reveal the incidence and most common causes of death in this population.
Methods and results
We reviewed the charts of all of the beta-thalassemia intermedia patients who had been followed at the Chronic Care Center in Hazmieh, Lebanon during a 10-year period. A total of 18 patients out of 127 had died during the follow-up period giving a cumulative 10-year mortality incidence of 14%. The most common causes of cardiac deaths were due to renal and cardiac causes.
Discussion
Most causes of death have been linked to the high levels of iron coupled with anemia present in this patient population. Many of deaths could be prevented by adequate treatment.
Conclusion
Larger studies with more comprehensive data capture on risk factors of mortality in this patient population are called for.
Introduction
The beta-thalassemias are a group of inherited disorders of hemoglobin synthesis in which patients have variable degrees of defective beta-globin chain synthesis, alpha/beta-globin chain imbalance, ineffective erythropoiesis, and premature red cell death. Patients with beta-thalassemia intermedia (TI) tend to present later in life and have milder anemia than beta-thalassemia major (TM) patients, which allows them to remain largely transfusion-independent. However, the imbalance in ineffective erythropoiesis and hemolysis lead to a variety of pathophysiologic sequelae including hypercoagulability and iron overload, which translate into high rates of clinical morbidities almost involving every organ system.Citation1 The incidence of mortality and its causes in this patient population remain unknown.
Methods and results
This is a descriptive cross-sectional study were we reviewed the medical charts of all of the TI patients who had been followed at the Chronic Care Center in Hazmieh, Lebanon during the period between 1 January 2003 and 31 December 2012. A total of 18 patients out of 127 had died during the follow-up period giving a cumulative 10-year mortality incidence of 14%. The average age of death was 34.6 years and 16 out of 18 patients were splenectomized (). The majority of deaths were due to cardiovascular disease (n = 6, 33.3%). Four patients died of heart failure (22%): two had progressive disease, one suddenly collapsed from acute heart failure, while the other decompensated when he had severe dehydration from a diarrhea he had developed. Two patients (11%) died of pulmonary hypertension (PHT): one patient died from an exacerbation post-cholecystectomy while the other had this condition secondary to recurrent pulmonary emboli from a deep vein thrombosis as shown in . The second most common cause of death was renal failure (n = 4, 22%): three patients succumbed to renal complications while the fourth died from sepsis post-renal transplant. Available abnormal echocardiography results are summarized in . The third most common cause of death was liver disease occurring in two patients (11%). Cirrhosis had developed in one patient secondary to hepatitis C infection. One other hepatitis negative patient died from hepatocellular carcinoma. Other causes of death each occurring in one patient (5.75%) were non-Hodgkin's lymphoma, a skeletal myopathy that was not further evaluated for economic reasons, pancreatic cancer, and infection after bone marrow transplant. In two patients, we were not able to retrieve the cause of death due to lack of detailed records.
Figure 1. Percentage distribution of causes of deaths in beta-thalassemia intermedia patients over 10 years. NHL, non-Hodgkins lymphoma; BMT, bone marrow transplant.
Table 1. Patient characteristics
Table 2. Abnormalities on echocardiography
Discussion
It has been classically thought that cardiomyopathy rarely affects TI patients as compared with TM, since such patients are speared of cardiac iron overload.Citation2 However, it may be proposed that even in the absence of cardiac siderosis on magnetic resonance imaging, cardiac muscle injury may occur in TI patients on continued exposure to high levels of non-transferrin-bound iron.Citation3 Chronic anemia and PHT could also be playing a role in heart failure in this patient population.Citation1 PHT, which is more common in TI than TM,Citation4 seems to be an important contributing factor to mortality by itself in our series. Although PHT in hemoglobinopathies is often associated with vascular and hemodynamic dysregulation, the contribution of hypercoagulability and chronic thromboembolic disease in TI patients cannot be excluded as was the case in one of our patients.
Renal failure was the cause of death in around one-quarter of our patients, and this issue warrants special attention. Renal damage in TI patients may be attributed to chronic anemia and iron overload among other factors.Citation5 Anemia, by reducing the systemic vascular resistance would lead to a hyperdynamic circulation that damages the kidneys. Moreover, chronic hypoxia by itself was shown to cause renal damage through oxidative stress and lipid peroxidation leading to glomerulosclerosis and fibrosis.Citation6 Iron overload has also been found to contribute to this process through the production of reactive oxygen species in the proximal tubular fluid.Citation6
Iron overload in TI patients occurs due to reduced serum hepcidin levels and increased intestinal iron absorption. It is a cumulative process that can eventually lead to considerably elevated liver iron concentration, hepatic fibrosis, and damage.Citation7,Citation8 This is thought to be a risk factor for the development of liver cirrhosis, setting the ground for the development of hepatocellular carnioma.Citation9 Both of these conditions were causes of mortality in our series. Moreover, improvements in care and survival in beta-thalassemia patients allow for common causes of death in non-thalassemic populations to manifest, including cancers.Citation10
Conclusion
We have identified that morbidities often encountered in patients with TI can potentially lead to a fatal course, further emphasizing the need for prompt diagnosis and optimal management. Larger studies with more comprehensive data capture on risk factors of mortality in this patient population are called for.
Author disclosures and funding sources
A.T.T. and K.M.M. have received honoraria and research support from Novartis. The study did not receive external funding.
References
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