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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty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 Hemoglobin E-beta-thalassemia: Progress report from the international study group(Blackwell Publishing, 2005) Premawardhena, A.; de Silver, S.; Arambepola, M.; Olivieri, N.F.; Vichinsky, E.P.; Merson, L.; Muraco, G.; Allen, A.; Fisher, C.; Peto, T.; Weatherall, D.J.A long-term observational study of Hb E-beta-thalassemia in Sri Lanka is beginning to define some of the genetic and environmental factors that are responsible for its remarkable phenotypic variability. In this population there is a very small difference between the steady-state hemoglobin levels between the mild and severe phenotypes, and it has been possible to stop transfusion in many of those who have been on long-term treatment of this kind. These preliminary observations, made over the last 7 years, provide directions for future research into this increasingly important disease.Item 20 year follow up and survival analysis in a cohort of patients with Haemoglobin E beta Thalassaemia.(Sri Lanka Medical Association., 2019) Olivieri, N.F.; Premawardhena, A.P.; Amir-Arsalan, S.; Ediriweera, D.; Mettananda, S.; Bandara, W.D.; Arambepola, M.; de Silva, S.; Refai, M.A.C.M.; Allen, A.INTRODUCTION & OBJECTIVES: Haemoglobin E beta thalassaemia (EBT) is the commonest beta thalassaemia syndrome in the world and is extremely phenotypically variable. Unlike for transfusion dependent thalassaemia (TDT) there are no clear guidelines for the management of this disease. We have followed up a cohort of 109 patients with EBT for 20 years. Objective of the study was to study the 20-year survival and factors that affect survival. METHODS: Study was conducted at Kurunegala Thalassaemia centre. Transfusions were stopped in 1997 in all 109 patients. Since then they were assessed every three months by the clinical team for the next 20 years. Relevant haematological, biochemical, radiological assessments were done periodically. RESULTS: 32 (30%) of patients were dead at 20 years. Kaplan Meir survival curve identified the median survival to be 51 years. Splenectomy had been done in 73/109 (67%) patients. Splenectomy allowed 66% to be off transfusions even 9.7± 1.3 years post- surgery. However, 33% had to return to transfusions. The commonest cause of death in the cohort was infections (34.3%). Most (72%) infective deaths happened in those who were splenectomised. Transfusions needed to be restarted in 60%, of whom 33% went back to (>8 per year) regular transfusions at a mean 8.4 ±0.8 years after stopping transfusions. CONCLUSION: In this first ever long term follow up study of EBT, significantly shortened survival is observed. Though splenectomy allows prolonged transfusion free phases in many it increases risk of infective deaths. Overall the disease is far less benign than previously thought with a high prevalence of morbidity and mortality.Item Techniques for primary screening for haemoglobinpathies in Sri Lanka: a comparison of single tube osmotic fragility (STOP) and dye test {DCIP) vs full blood count (FBC)(Sri Lanka Medical Association, 2007) Premawardhena, A.P.; Williams, S.; Idirisinghe, A.; Allen, A.; Olivieri, N.F.; Weatherall, D.J.INTRODUCTION: Techniques best suited for haemoglobinopathy screening of the Sri Lankan population need to be determined. Full blood count is used to detect p thalassaemia trait but is affected by iron deficiency. Its ability to detect haemoglobin (Hb) E is less certain. Alternative tests for screening include single tube osmotic fragility (STOP) test (for [5 thalassaemia) and a dye test (DCIP) for HbE. However there is no consensus regarding their usage in population surveys. OBJECTIVES: To decide the validity of STOP and DCIP test as screening tests for haemoglobin disorders in Sri Lanka. DESIGN, SETTING AND METHODS: Blood samples of volunteers attending an educational campaign held at the Faculty of Medicine, Ragama were tested using STOP, DCIP and FBC, and the results compared with the "gold standard" HPLC (high performance liquid chromatography) Results: 1062 individuals participated. HPLC identified 27 p traits and 3 HbE carriers. A total of 508 subjects had either MCV < 80 or MCH <27 on FBC, which included 26 of the p traits and all with HbE. The rest were presumably iron deficient. Only 56 subjects had a positive STOF test including 26 with p trait. 34 had a positive DCIP test including all three HbE carriers. One person with HbA2 of 3.5% had a normal MCV, MCH, negative STOF and negative DCIP. STOF test had a sensitivity and specificity of 96% and 97% for p trait. The DCIP had a sensitivity and specificity of 100% and for the detection of Hb E. CONCLUSIONS: Both STOF and DCIP are excellent tests for primary screening. The STOF is a superior test for screening thalassaemias than FBC in populations with high prevalence of iron deficiency.Item Cardiac functions in older patients with haemoglobin E- β thalassaemia(Sri Lanka Medical Association, 2007) Premawardhena, A.P.; Wanninayake, S.; Dolapihilla, S.N.; Kapuruge, L.; Katugaha, N.; Olivieri, N.F.; Weatherall, D.J.INTRODUCTION: Cardiac disease accounts for most deaths in patients with thalassaemia. Little is known about cardiac functions in ageing patients with thalassaemia OBJECTIVE: To study cardiac functions in older patients with haemoglobin E - p thalassaemia. DESIGN, SETTING AND METHODS: All patients with haemoglobin E - p thaiassaemia over the age of 24 attending the Thalassaemia Centre at Kurunegala were studied. Data were collected on biographs, transfusion load, body iron loads, ischaemic heart disease risk factors and symptoms and signs of heart disease. Serum lipids, 2D-echo and exercise ECG in addition to basic biochemical investigations were assessed in all. Those with a positive exercise ECG underwent stress echocardiography. Data from age-sex matched "healthy" individuals from the same geographic area were used for comparison. RESULTS: Total of 26 patients and 26 controls were studied. The median age was 34.25 years (24-50). Fourteen females were present in either group. 24% of controls, but-none in thalassaemic families had a family history of ischaemic heart disease. Twelve patients with thalassaemia and one control had a positive exercise ECG. All 12 with positive exercise ECG had normal stress echocardiography. Severe hypocholesterolaemia (mean total cholesterol 90.5 vs 376.9mg/dl) was present in all patients with thalassaemia. Pulmonary hypertension was noted in 7 patients with thalassaemia (not in controls). Nine patients with thalassaemia but none of the controls showed diastolic dysfunction. CONCLUSION: The study shows unique cardiac abnormalities that occur in patients with haemoglobin E- β thalassaemia. The marked hypocholesterolaemia may reduce the risk of ischaemic heart disease but significant right heart damage seems to occur in these chronically anaemic patients.Item Age-related changes in adaptation to severe anemia in childhood in developing countries(National Academy of Sciences, 2007) O Donnell, A.; Premawardhena, A.; Arambepola, M.; Allen, S.J.; Peto, T.E.; Fisher, C.A.; Rees, D.C.; Olivieri, N.F.; Weatherall, D.J.Severe forms of anemia in children in the developing countries may be characterized by different clinical manifestations at particular stages of development. Whether this reflects developmental changes in adaptation to anemia or other mechanisms is not clear. The pattern of adaptation to anemia has been assessed in 110 individuals with hemoglobin (Hb) E beta-thalassemia, one of the commonest forms of inherited anemia in Asia. It has been found that age and Hb levels are independent variables with respect to erythropoietin response and that there is a decline in the latter at a similar degree of anemia during development. To determine whether this finding is applicable to anemia due to other causes, a similar study has been carried out on 279 children with severe anemia due to Plasmodium falciparum malaria; the results were similar to those in the patients with thalassemia. These observations may have important implications both for the better understanding of the pathophysiology of profound anemia in early life and for its more logical and cost-effective management.Item A Novel molecular basis for beta thalassemia intermedia poses new questions about its pathophysiology(American Society of Hematology, 2005) Premawardhena, A.; Fisher, C.A.; Olivieri, N.F.; de Silva, S.; Sloane-Stanley, J.; Wood, W.G.; Weatherall, D.J.During a study of the molecular basis for severe forms of beta thalassemia in Sri Lanka, 2 patients were found to be heterozygous for beta thalassemia mutations. Further analysis revealed that one of them has a previously unreported molecular basis for severe thalassemia intermedia, homozygosity for quadruplicated alpha globin genes in combination with heterozygous beta thalassemia. The other is homozygous for a triplicated alpha globin gene arrangement and heterozygous for beta thalassemia. Their differences in clinical phenotype are explainable by the interaction of other genetic factors and, in particular, their early management. The clinical course of the 2 propositi underlines the importance of full genotyping and a long period of observation before treatment is instituted, particularly in patients with beta thalassemia intermedia associated with extended alpha globin gene arrangements. The hemoglobin (Hb) F levels in these patients with severe beta thalassemia intermedia, compared with other forms of this condition in the Sri Lankan population and elsewhere, are unusually low, a consistent finding in extended alpha globin gene interactions and in dominant beta thalassemia, raising the possibility that increased levels of HbF production in beta thalassemia may require mutations at both beta globin gene lociItem Haemoglobin E beta thalassaemia in Sri Lanka(Lancet Publishing Group, 2005) Premawardhena, A.; Fisher, C.A.; Olivieri, N.F.; de Silva, S.; Arambepola, M.; Perera, W.; O Donnell, A.; Peto, T.E.; Viprakasit, V.; Merson, L.; Muraca, G.; Weatherall, D.J.Haemoglobin E beta thalassaemia is the commonest form of severe thalassaemia in many Asian countries, but little is known about its natural history, the reasons for clinical diversity, or its management. We studied 109 Sri Lankan patients with the disorder over 5 years. 25 patients were not receiving transfusion; transfusion was stopped with no deleterious effect in a further 37. We identified several genetic and environmental factors that might contribute to the phenotypic diversity of the disorder, including modifiers of haemoglobin F production, malaria, and age-related changes in adaptive function. Our findings suggest that haemoglobin E beta thalassaemia can be managed without transfusion in many patients, even with low haemoglobin levels. Age-related changes in the pattern of adaptation to anaemia suggest that different and more cost-effective approaches to management should be explored.Item Genetic determinants of jaundice and gallstones in haemoglobin E beta thalassaemia(2001) Premawardhena, A.P.; Fisher, C.A.; Fathihu, F.; de Silva, S.; Perera, W.; Peto, T.E.; Olivieri, N.F.; Weatherall, D.J.Chronic hyperbilirubinaemia, gallstone formation, and gall bladder disease are unusually common in people with haemoglobin E beta thalassaemia in Sri Lanka. To determine whether this has a genetic basis we compared the bilirubin levels and frequency of gallstones in patients with different alleles of the UGT*1 gene. There was a significantly higher bilirubin level in those with the 7/7 genotypes compared with 6/6 and 6/7 genotype (p=0.032 and 0.0015 respectively), who also appeared more prone to gallstone formation. These results suggest that the UGT*1 genotpe is of importance in the genesis of gallstones in this population of patients.Item Iron overload and iron-chelating therapy in haemoglobin E/beta thalassaemia(Lippincott Williams and Wilkins, 2000) Olivieri, N.F.; de Silva, S.; Premawardhena, A.P.; Sharma S.; Viens, A.M.; Taylor, C.M.; Brittenham, G.M.; Weatherall, D.J.Whereas hemoglobin (Hb) E-beta thalassemia is recognized as probably the most common serious hemoglobinopathy worldwide, its natural history remains poorly defined. The interaction of hemoglobin E and beta-thalassemia result in a wide spectrum of clinical disorders, some indistinguishable from thalassemia major and some milder and not transfusion-dependent. Partially as a result of this wide range of phenotypes, clear guidelines for approaches to transfusion and to iron-chelating therapy for patients with Hb E-beta thalassemia have not been developed. By contrast, data that have accumulated during the past 10 years in patients with beta-thalassemia permit a quantitative approach to the management of iron overload and provide guidelines for the control of body iron burden in individual patients treated with iron-chelating therapy. These guidelines may be applicable to patients with Hb E-beta thalassemia. Preliminary evidence from our studies of iron loading in affected patients with Hb E-beta thalassemia in Sri Lanka suggest that this disorder may be associated with variable, but accelerated, gastrointestinal iron absorption, and that the iron loading associated with chronic transfusions in patients with Hb E-beta thalassemia is similar to that observed in patients with beta-thalassemia. These data, in the only cohort of patients with Hb E-beta thalassemia to have undergone quantitative assessment of body iron burden, suggest that the principles that guide assessment of iron loading and initiation of chelating therapy in patients with beta-thalassemia may be generally applicable to those with Hb E-beta thalassemia. Further quantitative studies in both non-transfused and transfused patients will be necessary to permit firm conclusions.Item Thalassaemia in Sri Lanka: implications for the future health burden of asian populations(Lancet Publishing Group, 2000) de Silva, S.; Fisher, C.A.; Premawardhena, A.P.; Lamabadusuriya, S.P.; Peto, T.E.; Perera, G.; Old, J.M.; Clegg, J.B.; Olivieri, N.F.; Weatherall, D.J.; Sri Lanka Thalassaemia Study GroupBACKGROUND: Thalassaemias pose an increasing problem for the Indian subcontinent and many Asian countries. We analysed the different types of thalassaemia in the Sri Lankan population, surveyed gene frequencies in schoolchildren, and estimated the burden of disease and requirements for its control. METHODS: We analysed blood samples from patients attending clinics in nine hospitals and defined the different types of beta thalassaemia by high-performance liquid chromatography (HPLC) and DNA analysis. The range of mutations was obtained by analysis of beta-globin genes. Capillary blood was obtained from schoolchildren from different parts of the island and analysed by HPLC to provide an approximate assessment of the carrier frequency of beta thalassaemia and haemoglobin E (HbE). To estimate the frequency of alpha thalassaemia the alpha-globin genotypes were also analysed when it was possible. FINDINGS: Blood samples were obtained from 703 patients with beta thalassaemia and from 1600 schoolchildren. The thalassaemia mutations were unevenly spread. Although 23 different beta-thalassaemia mutations were found, three accounted for the thalassaemia phenotype in about 70% of the patients, most whom are homozygotes or compound heterozygotes for IVS1-5 (G-->C) or IVS1-1 (G-->A). The third common mutation, codon 26 (G-->A), which produces HbE, interacts with one or other of these mutations to produce HbE/beta thalassaemia; this comprises 13.0-30.9% of cases in the main centres. Samples from 472 patients were analysed to determine the alpha-globin genotype. Overall, 15.5% patients were carriers for deletion forms of alpha+ thalassaemia. Average gene frequencies showed that there will be more than 2000 patients requiring treatment at any one time, in thefuture, of whom those with HbE/beta thalassaemia will account for about 40%. INTERPRETATION: In Sri Lanka, interactions of the two common beta-thalassaemia alleles will nearly always result in a transfusion-dependent disorder. However, about 40% of patients will have HbE/beta thalassaemia, which has a variable course. The management of these disorders could require about 5% of the total health budget. We need to learn more about the natural history and appropriate management of HbE/beta thalassaemia if resources are to be used effectively.