Beta thalassemia ranks first amongst the genetic disorders associated with haemoglobin synthesis in terms of prevalence and it is the result of an inherited defect in the synthesis of the beta chain of the adult haemoglobin. Consequently the erythropoiesis is defective and anemia is produced [¹]. Considering the 5 to 7% carrier rate in Pakistan, the number of carriers is expected to approach 10 million [²]. This grades thalassemia as one of the most common inherited disorders in Pakistan [³]. Due to lack of appropriate documentation, precise data pertaining to the incidence and prevalence of the disease are lacking. However, different studies statistically estimate that the number of thalassemia major patients born each year is in the order of 4000 to 9000 [⁴,⁵]. Due to repeated blood transfusions, all thalassemic patients require Iron Chelation Therapy (ICT) in order to reduce the increased iron load that if not eliminated properly can result in life threatening complications, including severe cardiac toxicity in the second decade of life, producing a significant decrease in the total life expectancy of these patients [⁶]. However, the practice of repeated parenteral ICT therapy imposes various economic burdens in those who cannot afford such a therapy. Oral chelators such as Deferasirox are much more expensive than the traditional ICT's which makes access difficult for the majority of socio-economically under-privileged patients [⁷]. Desferoxamine (DFE), a parenteral drug used widely as ICT has been employed in the treatment of beta thalassemia for nearly four decades and has shown to be effective in reducing the hepatic and extra-hepatic adverse affects, particularly myocardial toxicity [⁸]. However, despite the protracted method of 8- to 10- hours of infusion at least five times a week, the patients suffering from beta thalassemia are often not able to achieve the desired threshold of Ferritin levels in their blood [⁹]. This study also highlighted the dismal situation of ICT having a negative impact on health related quality of life (HRQOL), and that in most of the cases compliance with ICT being suboptimal, signifying non-satisfactory provision of chelation therapy with respect to economic, clinical and quality of life related outcome.

The aim of the present study is to assess the socio-demographic factors, serum Ferritin levels and adherence to iron chelation therapy in multi-transfused Thalassemia major patients. The series is composed mainly of Thalassemics children and young patients.

A total of 79 patients were enrolled in the study duration. The mean age was 10.8 ± 4.5 years. As shown in Table 1, 46 (58.2%) were males where as the rest i.e. 33 (41.8%) were females. Half of the patients were between ages 9 and 15 years.

Blood group "O" was found to be the predominant. The results highlight the education status of the patients showing that 78.8% of the care takers of the patients had education less than the Matric (39.4% stating that they "never went to school", and an equal number responding that they left the school during the primary education). Most of the patients belonged to a poor socio-economic background reflected from the monthly house hold income with all the care takers having income below 20,000 Pakistani Rupees PKR (Approximately 245 US dollars) per month. The preponderance (36.4%) lies between 5000-10,000 PKR (61 US dollars-122 US dollars) per month. Approximately three fourths (75.8%) stated that they owned a house. The vaccination history revealed that less than half (45.5%) care takers stated that they vaccinated their children for Hepatitis B while 12.1% not even knew whether they have carried out the procedure or not.

The mean serum Ferritin levels were found to be 4236.5 (± 2378.3) ng/ml. The values in males were similar (4075.2 ± 2440.7) ng/ml compared to females (4461 ± 2306.6) ng/ml. The figure was less than 1000 ng/ml in just 2 cases, whereas the values were between two to three thousand ng/ml in 19 cases. Figure 1 displays the serum Ferritin ranges and the number of patients who fall within a specified range. 11 cases had serum Ferritin values exceeding 7000 ng/ml. The values increased progressively with age above 9 years as suggested in Figure 2.

Desferrioxamine therapy was used by three fifth of the patients. As expected, serum Ferritin values were much lower (3319.6 ± 1925.8) ng/ml in the group who received the therapy compared to those who did not use the medication (5514.8 ± 2383.0) ng/ml. Monthly house hold income was associated with use of Desferrioxamine therapy, with just one third of patients below income of 3000 Rupees per month taking the medication compared to over two thirds above that income.

Iron overload is an unavoidable complication suffered by thalassemia major patients as a consequence of excessive number of blood transfusions. It is so common that it has been referred to a "second disease" during treatment of first [¹¹]. Serum Ferritin is an easy and in-expensive indirect measurement of iron burden, however, a single measure may not provide reliable indication of iron levels. The new non-invasive methods of measuring iron storage in the body such as MRI or SQUID have greater sensitivity, but they have limited use in developing countries such as Pakistan because of cost and complexity. As excessive iron can lead to organ complications, chelation therapy is employed to lower its levels. Borgna-Pignatti et al reported that a lower Ferritin concentration predicted longer survival, and reduced risk of various complications [¹²]. Many studies concluded that cirrhosis of liver is associated with increase in serum Ferritin level [^13-16].

Patients with lower socio-economic strata visit the government tertiary care hospitals as depicted in our results. All the patient's care takers had a monthly income below 20,000 rupees per month. Considering the average 500 mg vial price of desferrioxamine to be 150-180 rupees (Approximately 5000 rupees per month), it's exceedingly difficult for the care takers to cope with the therapy. These prices do not include infusion devices, the cost of which is covered by the hospital through governmental funding. Table 2 depicts the effect of gender and monthly household income on the use of Desferrioxamine therapy.

When not provided with desferrioxamine therapy the patients suffer grave consequences of iron over load, the spectrum of which lies from generalized weakness, weight loss, joint pain, abdominal pain to critical illness such as cirrhosis, hepatoma, diabetes, cardiomyopathy, arthritis, arthropathy, hypopituitarism with hypogonadism and death[¹⁷]. The organ most sensitive to chronic iron overload is heart. Chronic iron over load in liver increases chances of cirrhosis and hepatic carcinoma, hepatoma. The death occurs mostly due to liver disease, hepatocellular carcinoma, diabetes or cardiomyopathy[¹⁸]. However, T2 weighted Magnetic Resonance Imaging (MRI) studies show that Desferrioxamine is not as cardio-protective as the oral chelator deferiprone as oral deferiprone is more effective than desferrioxamine in removal of myocardial iron [¹⁹]. Furthermore, Desferrioxamine therapy is associated with adverse effects and demands associated with administration regimen rendering the compliance sub-optimal. A combination regimen of Desferrioxamine with Deferiprone is shown to be the most rapid way of reducing iron-overload in both liver and heart.

The mean serum Ferritin level in our study was 4236.5 ng/ml, which is markedly higher when compared to normal serum Ferritin levels in children in which the mean serum Ferritin level is considered to be in range of 12-122 ng/ml [²⁰]. The values in our study are higher compared with similar regional and international studies. A study conducted in Islamabad, the federal capital of our country showed the mean serum Ferritin level in patients of beta thalassemia was 3390 ng/ml [²¹]. Cunningham et al in 2004 reported mean serum Ferritin levels in beta thalassemia patients of North America to be 1696 ng/ml [²²]. The difference is largely attributable to the difference in the standards of healthcare between the 2 regions. For instance, the dosage was not adjusted with weight in our group of patients, which could contribute to high Ferritin levels. However, Choudhry VP et al in India reported mean serum Ferritin levels to be 6723 ng/ml [²³], even higher than in our study.

Age and chelation therapy are significantly linked with Ferritin levels in our study. This is depicted in the graph (Figure 2) below, which outlines that there is a directly proportional relationship between age inyears and the serum Ferritin levels. Approximately four-fifths of the patients in our study had serum Ferritin values exceeding 2000 ng/ml, which is almost ten times higher than the upper limit of normal. As expected, serum Ferritin values were much lower (3319.6 ± 1925.8) in the group who received the therapy compared to those who did not use the medication (5514.8 ± 2383.0). Monthly house hold income was associated with use of Desferrioxamine therapy, with just one third of patients below income of 3000 Rupees per month taking the medication compared to over two thirds above that income. Interestingly, female gender was associated with increased use of Desferrioxamine therapy.

The importance of chelation therapy can be appreciated from the fact that levels of Ferritin are inversely linked to the survival in Thalassemia major patients. A study reported that the 15 year cardiac disease free survival in patients on iron chelation therapy with Ferritin levels below 2500 ng/ml was 91% compared to under 20% with levels in excess of this value [²⁴].

The height and weight (and consequently the body mass index) of the patients was not obtained. The dose and frequency of Desferrioxamine infusions is not ascertained and is also a limitation.

The problems of poverty, low education level and inadequate provision of health care are the main stumbling blocks in effective treatment of thalassemic patients of iron over load, the complications of which are the main cause of morbidity and mortality in thalassemia major.

Use of Depefirone, routine measurements of serum Ferritin levels, adherence to guidelines, awareness amongst the public for prevention of the disease and antenatal diagnosis are some of the methods which can decrease the sufferings of not only the patients, but also of their families.

The authors declare that they have no competing interests.

HR and TR conceived the study. HR, MUK and TR wrote the manuscript under supervision of SA. FU, QZ, ANK and AR contributed in the study design and data analysis. All the authors read and approved the final manuscript.

The authors are grateful to Areeba Ejaz and Muhammad Hasan, House Officers, Civil Hospital Karachi, Pakistan for their help in data collection.