Beta-thalassemia is a group of hereditary blood disorders, characterized by anomalies in the synthesis of the beta chains of hemoglobin.[1] These anomalies result in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. Beta thalassemia (“β-thal”) is classified into three forms depending on the severity of symptoms: thalassemia trait, thalassemia minor and thalassemia major. Among the three forms of thalassemia, thalassemia major is considered the most severe.[2]
The prevalence of Beta-thalassemia is considered to be one of the highest among autosomal recessive disorders worldwide including the Middle East. The prevalence of β-thal globally is about (1.5 %) [3], and (0.05 %) in Saudi Arabia.[4] looking at β-thal prevalence in Saudi Arabia, there is a noticeable variance by region. Highest rates were observed in the region of Jazan with (3.2 %) for β-thal trait and (0.06 %) for β-thal major. The second highest rate was reported in the Eastern region with (2.37 %) for β-thal trait and (0.04 %) for β-thal major.[5]
Beta thalassemia major (TM) patients are usually presented with complications that include anemia, jaundice, growth retardation, failure to develop secondary sexual characteristics, hypothyroidism, osteoporosis, poor musculature, hepatomegaly, splenomegaly, expansion of the bone marrow, and myocardiopathy. These complications are more common in blood transfused TM patients who don’t receive chelation therapy.[1]
Treatment options include transfusion along with chelation or stem cells transplantation with the latter being the only curative method with a success rate greater than (80.0 %). However, due to its limited availability, transfusion along with chelation therapy becomes the common choice of management in most centers.[6] The standard iron chelation therapy is based on the usage of deferoxamine. Effectiveness of this modality of treatments depends primarily on compliance of the medication.[7] Deferiprone (Ferriprox) is another oral chelator, which was recently approved in many countries including the United States.[8] The most common post-therapeutic complication due to iron chelation is liver fibrosis.[9]
Regularly observed complications include endocrine abnormalities with iron toxicity as the most likely cause of these complications in Thalassemia Major (TM) patients. Delayed puberty and hypogonadism are the most common endocrine complications of iron overload.[8]
The largest study of prevalence of endocrine complications was conducted in 2004, including 3,817 patients with TM in 29 countries. Of the patients, (36.0 %) were over 16 years. In addition, compliance with chelation therapy was poor in (51.0 %) of the patients. Results showed that hypogonadism was the most common complication in thalassemic patients with a prevalence of (40.1 %). The second most common complication was short stature presented in (31.1 %) of males and (30.5 %) of females. In addition, Abnormalities in glucose handling were relatively common in TM patients. The prevalence of Diabetes Mellitus (DM) in TM patients was (3.2 %). The frequency of hypothyroidism in patients with TM has been reported to be (3.2 %) followed by hypoparathyroidism (6.9 %).[10]
Lastly, several studies have suggested the lack of awareness about receiving chelating therapy especially among patients’ parents, and for that reason, the awareness must be increased for a better outcome from the chelation therapy.[11] Blood transfusion in Beta thalassemia patients is mandatory to overcome and eliminate anemia, but iron overload that follows the transfusion process is the primary cause for the endocrine and metabolic complications. These complications are frequently faced by TM patients, and for this reason chelation therapy is a necessity. Despite the existence of several studies that aim to provide better understanding of the prevalence of endocrine and metabolic complications, very few highlighted the efficiency of chelating agents in reducing these complications and the influence of different factors that affect patients’ intake and compliance to the chelation.
The first study, which took place in Tabriz, Iran, was investigating the metabolic and endocrine complications among Beta-thalassemia major patients older than 10 years (July 2008). The study investigated demographic data, medical, surgical and family history of patients presented with endocrine complications along with medications used. Menstruation history was also collected for female subjects from the medical records of 56 patients who have been receiving blood transfusion for 13.16±4.65 years along with desferrioxamine. Other parameters such as luteinizing hormone, follicular stimulating hormone, height, fasting plasma glucose, oral glucose tolerance, thyroid stimulating hormone, free thyroxin and fasting calcium were obtained for all patients included in the study. Serum testosterone for males and serum estradiol for females were also studied. To monitor the effect of chelating therapy on the level of body iron, serum ferritin levels were measured.[12]
The study revealed that Hypogonadism was the most common endocrine abnormality as it occurred in (71.0 %) of TM patients. For females, hypogonadism was diagnosed by the presence of amenorrhea, whereas in males, hypogonadism was considered by the absence of testicular enlargement. Low serum testosterone levels in beta Thalassemia male adults were also observed. The second most common abnormality was short stature (51.8 %) and it was evident by growth failure with a height for age standard deviation score of less than –2. Moreover, short stature was found even in children who receive blood transfusion. Normal stature is thus rarely attained even in well-managed patients. Fasting blood glucose level and oral glucose tolerance tests were used to assess presence of diabetes mellitus by referring to American Diabetes Association and World Health Organization guidelines for the diagnosis of diabetes. The study revealed that the prevalence of impaired fasting glucose was (28.6 %), impaired glucose tolerance was (7.1 %) and diabetes was (8.9 %). The risk factors for diabetes in beta thalassemia patients include age, increased amount of blood transfusion, serum ferritin level, compliance with iron chelating therapy, family history of diabetes, and pubertal status. Overt primary hypothyroidism was present in (16.0 %) of patients (mean age, 17.33±4.22 years). Also, Subclinical hypothyroidism was observed in (10.7 %) of the patients. Hypoparathyroidism is a rare complication that is usually; but not always; accompanied by hypocalcemia (16.6 %). However, hypoparathyroidism may cause various neurological manifestations.[12]
The second study was conducted in 2004 by seven Italian centers and aimed to assess survival and complications in patients with TM treated with transfusion and deferoxamine. About 1073 patients were selected, 501 of whom were females and 527 were males. Of the 1073 patients, 977 were able to survive beyond the first decade of life (91.0 %). One hundred and fifty-seven patients (14.6 %) developed at least one complication.[13]
The results revealed that there was a significant association between birth cohort and complication-free survival (p<.0005). Survival and complication-free survival of patients with thalassemia major continue to improve, especially for female patients born shortly before or after the availability of iron chelation.[13]
The relationship between ferritin and hypogonadism in a subgroup 296 patients was assessed and 94 of them were found to have hypogonadism. Lower ferritin levels were marginally associated with a lower probability of hypogonadism (log scale, hazard ratio 1.31, p=.059). Ferritin level did not appear to be a significant lead predictor to hypothyroidism and diabetes mellitus.[13]
More than half of the patients in the multicenter Italian study had a delayed pubertal maturation. All of them, being born after 1970 or after started chelation therapy at the age of 10 or earlier. There was no difference in frequency of pubertal maturation with increasing year of birth in the cohort born in 1970-1975. Diabetes, however, was reported as the cause of death in 7 patients. Survival and complication-free survival of patients with thalassemia major were found to improve especially for the patients born shortly before or after the availability of iron chelation.[13]
The third study assessed the reasons behind patients missing iron chelation therapy with desferrioxamine. A survey was forwarded to 10 countries: Cyprus, Egypt, Greece, Hong Kong, India, Iran, Italy, Jordan, Taiwan, and the United States. Three hundred questionnaires were sent to each country between October 1999 and January 2000, whereas 200 were sent to Greece. There were 1,888 replies (65.0 %) out of 2,900 questionnaires sent. Only 1,573 of the participants (54.0 %) used desferrioxamine. Patients' reasons for not being on chelator agents were divided according to: (1) access to drug, (2) adverse effects, (3) patient's feelings about the treatment, (4) inadequate support to continue with the treatment and (5) other reasons not listed on the questionnaire. Access to the drug was the most common issue in India (51.0 %, n = 26) and a frequent concern in Iran (25.0 %, n = 15), but in all other countries, it was a reason for less than (17.0 %) of patients. The most frequently reported category in those countries was related to their beliefs about the treatment (58.0 %, n = 387). The second most frequent reason was the adverse effects of infusing desferrioxamine (42.0 %, n = 277).[14]
Although the prevalence of complications related to blood transfusion in TM patients were studied in Saudi Arabia, to the best of our knowledge, there was no study to evaluate the prevalence of endocrine and metabolic complications in specific. Previous studies conducted in Eastern province did not highlight the difference of occurrence of such complications in blood transfused TM patients who receive chelating agent and those who do not receive it. In addition, barriers, or reasons for not being on such treatment were not assessed in previous studies conducted in the region.
Research Aim:
1. To evaluate endocrine complications that might occur in beta thalassemia patients.
2. To compare the onset of endocrine complications among patients who are compliant with chelation therapy and those who are not.
3. To assess the barriers that hinder compliance with chelating therapy.