Medicine
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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty
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Item Survival and complications in patients with haemoglobin E thalassaemia in Sri Lanka: a prospective, longitudinal cohort study.(Elsevier Ltd, 2022) Premawardhena, A.P.; Ediriweera, D.S.; Sabouhanian, A.; Allen, A.; Rees, D.; de Silva, S.; Perera, W.; Katugaha, N.; Arambepola, M.; Yamashita, R.C.; Mettananda, S.; Jiffry, N.; Mehta, V.; Cader, R.; Bandara, D.; St Pierre, T.; Muraca, G.; Fisher, C.; Kirubarajan, A.; Khan, S.; Allen, S.; Lamabadusuriya, S.P.; Weatherall, D.J.; Olivieri, N.F.Background: Worldwide, haemoglobin E β-thalassaemia is the most common genotype of severe β-thalassaemia. The paucity of long-term data for this form of thalassaemia makes evidence-based management challenging. We did a long-term observational study to define factors associated with survival and complications in patients with haemoglobin E thalassaemia. Methods: In this prospective, longitudinal cohort study, we included all patients with haemoglobin E thalassaemia who attended the National Thalassaemia Centre in Kurunegala, Sri Lanka, between Jan 1, 1997, and Dec 31, 2001. Patients were assessed up to three times a year. Approaches to blood transfusions, splenectomy, and chelation therapy shifted during this period. Survival rates between groups were evaluated using Kaplan-Meier survival function estimate curves and Cox proportional hazards models were used to identify risk factors for mortality. Findings: 109 patients (54 [50%] male; 55 [50%] female) were recruited and followed up for a median of 18 years (IQR 14-20). Median age at recruitment was 13 years (range 8-21). 32 (29%) patients died during follow-up. Median survival in all patients was 49 years (95% CI 45-not reached). Median survival was worse among male patients (hazard ratio [HR] 2·51, 95% CI 1·16-5·43), patients with a history of serious infections (adjusted HR 8·49, 2·90-24·84), and those with higher estimated body iron burdens as estimated by serum ferritin concentration (adjusted HR 1·03, 1·01-1·06 per 100 units). Splenectomy, while not associated with statistically significant increases in the risks of death or serious infections, ultimately did not eliminate a requirement for scheduled transfusions in 42 (58%) of 73 patients. Haemoglobin concentration less than or equal to 4·5 g/dL (vs concentration >4·5 g/dL), serum ferritin concentration more than 1300 μg/L (vs concentration ≤1300 μg/L), and liver iron concentration more than 5 mg/g dry weight of liver (vs concentration ≤5 mg/g) were associated with poorer survival. Interpretation: Patients with haemoglobin E thalassaemia often had complications and shortened survival compared with that reported in high-resource countries for thalassaemia major and for thalassaemia intermedia not involving an allele for haemoglobin E. Approaches to management in this disorder remain uncertain and prospective studies should evaluate if altered transfusion regimens, with improved control of body iron, can improve survival.Item Oxidative stress and antioxidant deficiency in the β-thalassaemia in Sri Lanka(Sri Lanka Medical Association, 2021) Perera, S.; Allen, A.; Mettananda, S.; Rodrigo, R.; Perera, L.; Darshana, T.; Moggach, F.; Jackson-Crawford, A.; Heirene, L.; Fisher, C.; Olivieri, N.; Rees, D.; Allen, S.; Premawardhena, A.Introduction In the β thalassaemias oxidative stress is potentially high and this could be further exacerbated in the absence of robust antioxidant defences, such as nutritional vitamin C and E deficiencies. We undertook a comprehensive assessment of oxidant, antioxidant and inflammatory status in patients with subtypes of β-thalassaemia to study these factors in detail. Methods Consenting patients attending the thalassaemia centre in Ragama, (between November 2017 and June 2018) were assessed for the following: methaemoglobin, plasma haemoglobin, heme and ferritin as sources of oxidants, plasma haptoglobin, hemopexin and vitamins C and E as markers of antioxidants, plasma interleukin-6 and C-reactive protein for inflammation. Fruit and vegetable intake was determined by dietary recall. Results 162 patients were recruited. (59 HbE β-thalassaemia, 50 β-thalassaemia major, 40 β-thalassaemia intermedia, 13 HbS β-thalassaemia. Median age was 26.0 years (IQR 15.3-38.8), 101 (62.3%) were female. Oxidants were frequently increased and antioxidants depleted with high levels of oxidant damage, hypoxia and inflammation. Abnormalities were most severe in HbE-β thalassaemia and least severe in β thalassaemia intermedia. Oxidative stress was also more severe in splenectomised patients. Plasma vitamin C concentration was below the lower level of quantitation in 86/160 (53.8%) patients and vitamin E in 130/160 (81.3%) patients. Less than 15% of patients ate fresh fruits or raw vegetables frequently. Conclusion Markedly increased oxidative stress and antioxidant deficiency were observed in this study group, especially in those with HbE β-thalassaemia. Vitamin C & E supplementation may have a role in the long-term management of thalassaemia syndromes.Item Oxidative status in the β-thalassemia syndromes in Sri Lanka; a cross-sectional survey(Elsevier Science-Pergamon Press, 2021) Allen, A.; Perera, S.; Mettananda, S.; Rodrigo, R.; Perera, L.; Darshana, T.; Moggach, F.; Crawford, A.J.; Heirene, L.; Fisher, C.; Olivieri, N.; Rees, D.; Premawardhena, A.; Allen, S.ABSTRACT: In the β-thalassemias, oxidative stress, resulting from chronic hemolysis, globin chain imbalance, iron overload and depleted antioxidant defences, likely contributes to cell death, organ damage, anemia, hypoxia and inflammation. We assessed variations in these parameters in β-thalassemia syndromes in Sri Lanka. Between November 2017 and June 2018, we assessed children and adults attending two thalassemia centres in Sri Lanka: 59 patients with HbE β-thalassemia, 50 β-thalassemia major, 40 β-thalassemia intermedia and 13 HbS β-thalassemia. Median age was 26.0 years (IQR 15.3-38.8), 101 (62.3%) were female and 152 (93.8%) of Sinhalese ethnicity. Methemoglobin, plasma hemoglobin, heme and ferritin were measured as sources of oxidants; plasma total antioxidant capacity, haptoglobin, hemopexin and vitamins C and E assessed antioxidant status; plasma thiobarbituric acid reactive substances and 8-hydroxy-2'-deoxyguanosine assessed oxidative damage; hemoglobin, plasma erythropoietin and transferrin receptor assessed anemia and hypoxia and plasma interleukin-6 and C-reactive protein assessed inflammation. Fruit and vegetable intake was determined by dietary recall. Physical fitness was investigated using the six-minute walk test and measurement of handgrip strength. Oxidant sources were frequently increased and antioxidants depleted, with consequent oxidative damage, anemia, hypoxia and inflammation. Biomarkers were generally most abnormal in HbE β-thalassemia and least abnormal in β-thalassemia intermedia but also varied markedly between individuals with the same thalassemia syndrome. Oxidative stress and damage were also more severe in splenectomized patients and/or those receiving iron chelation therapy. Less than 15% of patients ate fresh fruits or raw vegetables frequently, and plasma vitamins C and E were deficient in 132/160 (82.5%) and 140/160 (87.5%) patients respectively. Overall, physical fitness was poor in all syndromes and was likely due to anemic hypoxia. Studies of antioxidant supplements to improve outcomes in patients with thalassemia should consider individual patient variation in oxidative status both between and within the thalassemia syndromes. KEYWORDS: antioxidants; oxidative damage; oxidative stress; thalassemia; vitamins C and E.Item Identifying haemoglobinopathy traits and iron deficiency in Sri Lanka using the dtchlorophenolindophenol (DCIP) and one- tube osmotic fragility (OF) tests and measurement of red cell zinc protoporphyrin (ZPP)(Sri Lanka Medical Association., 2019) Perera, P. S.; Premawardhena, A.; Mettananda, S.; Rodrigo, R.; Perera, L.; Weatherall, D. J.; Allen, S.; Allen, A.INTRODUCTION & OBJECTIVES: Effective, low-cost, point-of-care tests are needed for haemoglobinopathy traits and iron deficiency throughout Southeast Asia. The objective of this study is to evaluate a combination of simple, low cost, easy-to-interpret and rapid tests as a "one-stop" screening procedure for identifying carriers of haemoglobin variants and iron deficiency in Sri Lanka. METHODS: Between November 2017 and May 2018, the KKU-OF and KKU modified DCIP tests (KKU, Thailand) were compared with High Performance Liquid Chromatography (HPLC) in a cross-sectional survey of 1324/1332 (99.4%) children attending secondary schools in Gampaha district, Sri Lanka. Iron deficiency was indicated in children with a raised red cell ZPP (Helena Biosciences), and confirmed by measurement of low serum ferritin and normal C- reactive protein (CRP). RESULTS: Median age was 17 years (IQR 16-18), all were Sinhalese and 814/1324 (61.5%) were female. HPLC identified 26 students with β-thalassaemia trait and 3 with HbE trait. The KKU-OF test correctly identified all 26 students with β-thalassaemia trait (sensitivity=100%) but was also positive in 288 samples with a normal HPLC result (specificity= 1007/1295; 85.5%). The KKU-DCIP test was positive only in the 3 students with HbE (100% sensitive and 100% specific). Iron deficiency was present in 148/1318 (11.2%) students. CONCLUSION: This one-stop approach may be an effective and affordable procedure in screening for haemoglobinopathy traits and identifying iron deficiency. We are investigating the causes of the false positive OF test results and planning large scale studies to assess cost-effectiveness.Item A Cost-of-illness analysis of β-Thalassaemia major in children in Sri Lanka - experience from a tertiary level teaching hospital.(BioMed Central., 2020) Reed-Embleton, H.; Arambepola, S.; Dixon, S.; Maldonado, B. N.; Premawardhena, A.; Arambepola, M.; Khan, J. A. M.; Allen, S.BACKGROUND: Sri Lanka has a high prevalence of β-thalassaemia major. Clinical management is complex and long-term and includes regular blood transfusion and iron chelation therapy. The economic burden of β-thalassaemia for the Sri Lankan healthcare system and households is currently unknown. METHODS: A prevalence-based, cost-of-illness study was conducted on the Thalassaemia Unit, Department of Paediatrics, Kandy Teaching Hospital, Sri Lanka. Data were collected from clinical records, consultations with the head of the blood bank and a consultant paediatrician directly involved with the care of patients, alongside structured interviews with families to gather data on the personal costs incurred such as those for travel. RESULTS: Thirty-four children aged 2-17 years with transfusion dependent thalassaemia major and their parent/guardian were included in the study. The total average cost per patient year to the hospital was $US 2601 of which $US 2092 were direct costs and $US 509 were overhead costs. Mean household expenditure was $US 206 per year with food and transport per transfusion ($US 7.57 and $US 4.26 respectively) being the highest cost items. Nine (26.5%) families experienced catastrophic levels of healthcare expenditure (> 10% of income) in the care of their affected child. The poorest households were the most likely to experience such levels of expenditure. CONCLUSIONS: β-thalassaemia major poses a significant economic burden on health services and the families of affected children in Sri Lanka. Greater support is needed for the high proportion of families that suffer catastrophic out-of-pocket costs. KEYWORDS: Children; Cost-of-illness; Sri Lanka; Thalassaemia.Item Methemoglobinemia and ascorbate deficiency in hemoglobin E β thalassemia: metabolic and clinical implications.(American Society of Hematology., 2012) Allen, A.; Fisher, C.; Premawardhena, A.; Bandara, D.; Perera, A.; Allen, S.; St Pierre, T.; Olivieri, N.; Weatherall, D.ABSTRACT: During investigations of the phenotypic diversity of hemoglobin (Hb) E β thalassemia, a patient was encountered with persistently high levels of methemoglobin associated with a left-shift in the oxygen dissociation curve, profound ascorbate deficiency, and clinical features of scurvy; these abnormalities were corrected by treatment with vitamin C. Studies of erythropoietin production before and after treatment suggested that, as in an ascorbate-deficient murine model, the human hypoxia induction factor pathway is not totally dependent on ascorbate levels. A follow-up study of 45 patients with HbE β thalassemia showed that methemoglobin levels were significantly increased and that there was also a significant reduction in plasma ascorbate levels. Haptoglobin levels were significantly reduced, and the high frequency of the 2.2 haptoglobin genotype may place an additional pressure on ascorbate as a free-radical scavenger in this population. There was, in addition, a highly significant correlation between methemoglobin levels, splenectomy, and factors that modify the degree of globin-chain imbalance. Because methemoglobin levels are modified by several mechanisms and may play a role in both adaptation to anemia and vascular damage, there is a strong case for its further study in other forms of thalassemia and sickle-cell anemia, particularly when splenic function is defective.Item A "One-Stop" screening protocol for hemoglobinopathy traits and iron deficiency in Sri Lanka(Lausanne : Frontiers Media S.A., 2019) Allen, A.; Perera, S.; Perera, L.; Rodrigo, R.; Mettananda, S.; Matope, A.; Silva, I.; Hameed, N.; Fisher, C. A.; Olivieri, N.; Weatherall, D. J.; Allen, S.; Premawardhena, A.INTRODUCTION: The high frequencies of carriers of severe haemoglobinopathies and of iron deficiency in Southeast Asia require reliable and affordable tests to improve on current screening procedures. OBJECTIVES: We evaluate a "one stop" approach using the THALCON dichlorophenolindophenol (DCIP) and one-tube osmotic fragility (OF) tests and measurement of Zinc Protoporphyrin (ZPP) to detect and distinguish HbE and β-thalassaemia traits from iron deficiency. We compare findings with current screening practice in Sri Lanka that relies on the identification of low mean red cell volume and/or mean red cell hemoglobin for this purpose.METHODS: Between November 2017 and May 2018, we undertook a cross-sectional survey of secondary school students in Gampaha district, Sri Lanka. The THALCON-DCIP and OF tests were compared to capillary electrophoresis (CE), used as a gold standard to detect haemoglobinopathies. ZPP was measured in whole blood. Plasma ferritin and C-reactive protein (CRP) were measured in students with a raised ZPP concentration. RESULTS: We collected venous blood samples from 1,324/1,332 (99.4%) students. The median age of the students was 17 (IQR 16-18) years, all were Sinhalese and 814/1,324 (61.5%) were female. CE identified 3 students with HbE trait and 26 students with β-thalassaemia trait. The THALCON-DCIP test was positive only in the 3 students with HbE (sensitivity 100%, 95% CI 29.2-100.0; specificity 100%, 95% CI 99.7-100.0). The THALCON-OF test identified all 26 students with β-thalassaemia trait (sensitivity = 100%, 95% CI 86.8-100.0) and 287 students with a normal CE result (specificity = 77.9%; 95% CI 75.5-80.1). It was also positive in 2/3 (66.7%) students with HbE trait. Iron deficiency (ZPP > 70 μmol/mol heme) was present in 118/1,240 (9.5%) students with a normal hemoglobin genotype, all of whom had plasma ferritin <15 ng/ml and CRP <5 mg/L. CONCLUSION: This one-stop approach offers reliable and affordable population screening for both haemoglobinopathy traits and iron deficiency in resource-limited settings where these conditions are common and ensures that iron supplements are targeted only to those who require them. Further work is warranted to refine the OF test to reduce the number of false positive resultsItem Genotype-phenotype association analysis identifies the role of α globin genes in modulating disease severity of β thalassaemia intermedia in Sri Lanka(Nature Publishing Group, 2019) Perera, S.; Allen, A.; Silva, I.; Hapugoda, M.; Wickramarathne, M.N.; Wijesiriwardena, I.; Allen, S.; Rees, D.; Efremov, D.G.; Fisher, C.A.; Weatherall, D.J.; Premawardhena, A.β thalassaemia intermedia (βTI) are a heterogeneous group of disorders known to be extremely phenotypically diverse. This group is more complex to manage as no definitive treatment guidelines exist unlike for β thalassaemia major (βTM). There are only a few studies looking at genotype phenotype associations of βTI outside the Mediterranean region. The reasons for the diverse clinical phenotype in βTI are unknown. We categorized fifty Sri Lankan patients diagnosed with βTI as mild, moderate or severe according to published criteria. DNA samples were genotyped for β thalassaemia mutations, α globin genotype and copy number and known genetic modifiers of haemoglobin F production. There were 26/50 (52.0%) in mild group and 12/50 (24.0%) each in moderate and sever categories. 18/26 (69.2%) classified as mild were β heterozygotes and 17/18 (94.4%) had excess α globin genes. 11/12 (91.6%) classified as moderate were β heterozygotes and 8/11 (72.2%) had excess α globin genes. In contrast, 8/12 (66.7%) classified as severe were β homozygotes and 7/8(87.5%) had α globin gene deletions. In Sri Lanka, co-inheritance of either excess α globin genes in β thalassaemia heterozygotes or α globin gene deletions in β thalassaemia homozygotes is a significant factor in modulating disease severityItem The p.H63D allele of the HFE gene protects against low iron stores in Sri Lanka.(Academic Press, 2019) Allen, A.; Premawardhena, A.; Allen, S.; Rodrigo, R.; Manamperi, A.; Perera, L.; Wray, K.; Armitage, A.; Fisher, C.; Drakesmith, A.; Robson, K.; Weatherall, D.In hereditary hemochromatosis, iron overload is associated with homozygosity for the p.C282Y mutation. A second mutation, p.H63D, occurs at significant frequencies in Europe, North Africa, the Middle East and Asia. Early studies in Sri Lanka indicated that the variant had arisen independently, suggesting that it had been the subject of selective pressure. However, its role in iron absorption is unclear. In a survey of 7526 Sri Lankan secondary school students, we determined hemoglobin genotype and measured red cell indices, serum ferritin, transferrin receptor, iron zinc protoporphyrin and hepcidin. These variables were compared according to the presence or absence of the p.H63D variant in a subset of 1313 students for whom DNA samples were available. Students were classified as having low red cell indices if they had an MCV <80 fl and/or MCH <27 pg. Hetero and/or homozygosity for the p.H63D variant was more common in students with normal than low red cell indices (16.4% and 11.9% respectively; p = 0.019). Iron biomarkers and red cell indices were greater in children with the p.H63D variant than in normal and this was statistically significant for MCV (p = 0.046). Our findings suggest that selective pressure by mild iron deficiency contributes to the high frequencies of the p.H63D variant.Item Haemoglobin variants, iron status and anaemia in Sri Lankan adolescents with low red cell indices: A cross sectional survey(Academic Press, 2018) Rodrigo, R.; Allen, A.; Manamperi, A.; Perera, L.; Fisher, C.A.; Allen, S.; Weatherall, D.J.; Premawardhena, A.Iron deficiency complicates the use of red cell indices to screen for carriers of haemoglobin variants in many populations. In a cross sectional survey of 7526 secondary school students from 25 districts of Sri Lanka, 1963 (26.0%) students had low red cell indices. Iron deficiency, identified by low serum ferritin, was the major identifiable cause occurring in 550/1806 (30.5%) students. Low red cell indices occurred in iron-replete students with alpha-thalassaemia including those with single alpha-globin gene deletions. Anaemia and low red cell indices were also common in beta-thalassaemia trait. An unexpected finding was that low red cell indices occurred in 713 iron-replete students with a normal haemoglobin genotype. It is common practice to prescribe iron supplements to individuals with low red cell indices. Since low red cell indices were a feature of all forms of α thalassaemia and also of iron deficiency, in areas where both conditions are common, such as Sri Lanka, it is imperative to differentiate between the two, to allow targeted administration of iron supplements and avoid the possible deleterious effects of increased iron availability in iron replete individuals with low red cell indices due to other causes such as α thalassaemia.