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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty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 A randomised double-blind placebo-controlled clinical trial of oral hydroxyurea for transfusion-dependent β-thalassaemia(Nature Publishing Group, 2022) Yasara, N.; Wickramarathne, N.; Mettananda, C.; Silva, I.; Hameed, N.; Attanayaka, K.; Rodrigo, R.; Wickramasinghe, N.; Perera, L.; Manamperi, A.; Premawardhena, A.; Mettananda, S.Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. However, its clinical usefulness in β-thalassaemia is unproven. We conducted a randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of hydroxyurea in transfusion-dependent β-thalassaemia. Sixty patients were assigned 1:1 to oral hydroxyurea 10-20 mg/kg/day or placebo for 6 months by stratified block randomisation. Hydroxyurea treatment did not alter the blood transfusion volume overall. However, a significantly higher proportion of patients on hydroxyurea showed increases in fetal haemoglobin percentage (89% vs. 59%; p < 0.05) and reductions in erythropoietic stress as measured by soluble transferrin receptor concentration (79% vs. 40%; p < 0.05). Based on fetal haemoglobin induction (> 1.5%), 44% of patients were identified as hydroxyurea-responders. Hydroxyurea-responders, required significantly lower blood volume (77 ± SD27ml/kg) compared to hydroxyurea-non-responders (108 ± SD24ml/kg; p < 0.01) and placebo-receivers (102 ± 28ml/kg; p < 0.05). Response to hydroxyurea was significantly higher in patients with HbE β-thalassaemia genotype (50% vs. 0%; p < 0.01) and Xmn1 polymorphism of the γ-globin gene (67% vs. 27%; p < 0.05). We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent β-thalassaemia. Hydroxyurea reduced the transfusion burden in approximately 40% of patients. Response to hydroxyurea was higher in patients with HbE β-thalassaemia genotype and Xmn1 polymorphism of the γ-globin gene.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 Efficacy and Safety of Oral Hydroxyurea in Patients with Transfusion Dependent β Thalassaemia: a Randomized Double-Blind Placebo-Controlled Clinical Trial(Sri Lanka Medical Association, 2020) Yasara, N.; Wickramarathne, N.; Silva, I.; Hameed, N.; Attanayaka, A.M.K.R.; Jayasinghe, V.L.; Wickramasinghe, N.; Rodrigo, R.; Perera, L.; Mettananda, K.C.D.; Manamperi, A.; Premawardhena, A.; Mettananda, S.INTRODUCTION AND OBJECTIVES: Patients with β- thalassaemia require blood transfusions and iron chelation for life. Hydroxyurea is a licenced medication for sickle cell disease but its usefulness in transfusion dependent β-thalassaemia is unclear. Here, we aim to assess the efficacy and safety of oral hydroxyurea in patients with transfusion dependent β-thalassaemia. METHODS: A phase III randomized double-blind placebo-controlled clinical trial was conducted at Thalassaemia Unit of Colombo North Teaching Hospital in 2019. Forty-one patients with transfusion dependent β-thalassaemia were randomized into hydroxyurea (10-20mg/kg/day) or placebo (pharmaceutically inert capsule identical to hydroxyurea) groups. Transfused blood volume, pre-transfusion haemoglobin, haemoglobin F level and side effects were monitored monthly during 6- month treatment and 6-month follow-up periods. Adverse events were assessed by trained medical officers. The study was approved by ethics committee of University of Kelaniya and registered in Sri Lanka Clinical Trials Registry (SLCTR/ 2018/024). RESULTS: Of the 41 (hydroxyurea-20; placebo-21) patients, three discontinued treatment due to thrombocytopenia (hydroxyurea-2) and rash (placebo-1). Baseline characteristics of two groups were similar. Mean pre-transfusion haemoglobin (8.52+0.57 vs 8.38+0.55, p=0.45) and haemoglobin F levels (4.3+7.1% vs 3.1+1.9%, p=0.48) were higher in hydroxyurea group compared to placebo. Also, transfused blood volume was lower in hydroxyurea group (102+24ml/kg vs 111+27ml/kg, p=0.3). However, none were statistically significant. Based on elevation of haemoglobin F (>1.5% from baseline), we identified 6/18 patients as hydroxyurea responders. Hydroxyurea responders required significantly lower blood volume (87+13ml/kg) compared to non-responders (110+25ml/kg, p=0.05) and placebo group (111+27ml/kg, p<0.05) while maintaining higher pre-transfusion haemoglobin level (8.6+0.5 vs 8.4+0.5 and 8.3+0.5). No serious side effects were reported. CONCLUSIONS: One-third of patients with transfusion dependent β-thalassaemia responded to hydroxyurea treatment requiring 20% less blood compared to controls. No serious side effects were reported following hydroxyurea treatment.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 Microcytic anemia in children: Parallel screening for iron deficiency and Thalassemia provides a useful opportunity for Thalassemia prevention in low- and middle-income countries(Hemisphere Pub. Corp., 2020) Mettananda, S.; Paranamana, S.; Fernando, R.; Suranjan, M.; Rodrigo, R.; Perera, L.; Vipulaguna, T.; Fernando, P.; Fernando, M.; Dayanath, B.K.T.P.; Costa, Y.; Premawardhena, A.ABSTRACT:Microcytic anemia in children is commonly attributed to iron deficiency without attempting to find the cause. Inadequate investigations to exclude hemoglobinopathies lead to missed opportunities for identification of thalassemia carriers. Here we aim to describe the relative contribution of iron deficiency and thalassemia to microcytic anemia in children. This hospital-based prospective study was conducted at the Colombo North Teaching Hospital, Ragama, Sri Lanka. All newly diagnosed patients with microcytic anemia were recruited and data were collected using an interviewer-administered questionnaire. Full blood count, blood film, serum ferritin, c-reactive protein, quantification of hemoglobin sub-types and α-globin genotype were performed using 4 ml of venous blood. A total of 104 children (Male- 60.5%) were recruited. Iron deficiency was the cause for anemia in 49% whilst 16% and 10% had α- and β-thalassemia trait respectively. Seven (6.7%) children had co-existing iron deficiency and thalassemia trait while two coinherited α- and β-thalassemia trait. Children with β-thalassemia trait had significantly higher red cell count and lower mean corpuscular volume compared to children with iron deficiency. However, none of the red cell parameters were significantly different between children with α-thalassemia trait and iron deficiency. Iron deficiency contributes only to half of children with microcytic anemia; one-fourth had thalassemia trait. Co-existence of iron deficiency and thalassemia trait or co-inheritance of α- and β-thalassemia trait were found in 9%. Parallel investigation of children with microcytic anemia to diagnose iron deficiency and thalassemia provides an opportunity to identify thalassemia carriers which is beneficial for thalassemia prevention.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 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 Microcytic anaemia in children: Do we really know the cause?(Sri Lanka Medical Association, 2018) Paranamanna, S.; Fernando, V. R.; Suranjan, P. D. M.; Rodrigo, R.; Perera, L.; Vipulanayake, U. K. T.; Fernando, A. G. L. N. P.; Fernando, A.M.; Costa, Y.; Dayanath, D.K.T.P.; Premawardhena, A.; Mettananda, S.INTRODUCTION & OBJECTIVES: Microcytic anaemia is common among children and is often attributed to iron deficiency. Other causes are given less priority. We aimed to describe the aetiology of microcytic anaemia among children aged between 6-59 months.METHODS: A descriptive study was conducted at Teaching Hospital, Ragama from March 2016 to February 2017. All newly diagnosed patients with microcytic anaemia (haemoglobin <11 g/dL and mean corpuscular volume <80 Fl) were recruited. Data was collected using an interviewer-administered questionnaire and 5ml of venous blood was obtained for full blood count, serum ferritin, capillary electrophoresis and alpha-globin genotype during a period free from any acute illness. A therapeutic trial with oral iron (6mg/kg/day) was given to all children and response was assessed after one month. Ethical approval was obtained from Ethics Committee of University of Kelaniya and data were analysed using SPSS. RESULTS: Sixty-six children (male-54.5%; mean age-20.5±13.9 months) were recruited. Severity of anaemia was mild-38%, moderate-61% and severe- I%. Reported clinical features were: irritability (26%), loss of appetite (6%), fatigue (5%), pica (3%), brittle hair (26%), dry skin (23%), angular stomatitis (2%) and glossitis (2%). Aetiologically, 28 (42.4%) had iron deficiency (ferritinlg/dl after 1 month) was observed in 27 (40 9%).CONCLUSION: Less than half of children with microcytic anaemia had low serum ferritin and only 41 % of children demonstrated a response to a trial of oral iron Thalassaemia trait, especially alpha-thalassaemia is an important cause for microcytic anaemia in asymptomatic children.Item Anaemia among women of child-bearing age: Contributions of alpha and beta-thalassaemia(Sri Lanka Medical Association, 2018) Mettananda, S.; Suranjan, P.D.M.; Fernando, V.R.; Dias, T.D.; Rodrigo, R.; Perera, L.; Mettananda, K.C.D.; Gibbons, R. J.; Premawardhena, A.; Higgs, D. R.INTRODUCTION AND OBJECTIVES: Anaemia during pregnancy is attributed to iron deficiency and pregnant women prescribed iron supplements without investigating for a cause. However, aetiology can be diverse and iron efficiency may contribute only partly. We aimed to describe the aetiology of anaemia among women of child bearing age. METHODS: This descriptive study was conducted at Teaching Hospital, Ragama from June-December 2017. Patient database of deliveries between January 2015 and September 2016 at University Obstetrics Unit was screened (n=3636) to identify women with anaemia (haemoglobin