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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty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 Paraspinal extramcduallry erythropoiesis- a rare cause of spinal cord compression: two case reports(Sri Lanka Medical Association, 2004) Arambepola, M.; Premawardhena, A.P.; de Silva, S.; Olivieri, N.; Weatherall, D.J.INTRODUCTION: Extrameduallry erythropoiesis (EME) is characterized by the appearance of haemopoietic tissue outside the bone marrow. When EME occurs, albeit rarely, outside the liver and spleen problems may occur. We describe two patients with haemoglobin E- [β thalassaemia who had spinal cord compression, due to EME masses which was reversed with treatment with hydroxyurea and hypertransfusion. PATIENT A: Was a 27year old with HbE -(β thalassaemia. His mean pre transfusion haemoglobin level was 5.5 g/dl. He presented with a six-month history of progressive numbness of his legs. On examination he was found to be paraparetic. The magnetic resonance scan (MRI) showed external compression of the spinal cord between the 4th and 8th thoracic vertebrae. Patient was put on a hypertransfusion regimen and hydroxyurea and made a complete recovery within 4 weeks. Patient B: Was a 9 year old boy with a diagnosis of Haemoglobin E [β thalassaemia who presented with paraplegia which had developed over 3 months. His spinal MRI showed two masses one in the upper thoracic vertebrae and the other at the 1st lumbar level. He was commenced on hydroxyurea and hypertransfusiion to maintain pre-transfusion haemoglobin at >9.5g/dl) and his neurological recover was remarkable. Six months later he had no neurological deficit. DISCUSSION: The above cases highlight the potentially dangerous complications of EME when it involves the spinal cord. They also highlight that even lesions which are sufficiently large to cause complete paraplegia are potentially reversible. Hypertransfusion, hydroxyurea, surgery and previously been used with varying success. The problem remains in deciding the optimal method of management.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 Response of jaundice to phenobarbitone in thalassaemic patients co-inheriting Gilbert syndrome(Sri Lanka Medical Association, 2004) Premawardhena, A.P.; Arambepola, M.; Fisher, C.A.; Oliveiri, N.F.; Weatherall, D.J.INTRODUCTION: Genetic mutations causing Gilbert's syndrome are found in up to 20% of Sri Lankans. The co-existence of Gilbert's syndrome together with haemolytic anaemias can lead to significantly higher level of serum bilirubin and also an increased risk of gall stone formation. In such patients persistent jaundice can be a distressing symptom. We used the hepatic enzyme inducer, phenobarbitone in a pilot study to treat symptomatic hyperbilirubinaemia in patients with haemoglobin E- p thalassaemia and Gilbert' syndrome. MATERIAL AND METHODS: Seven haemoglobin E (3 thalassaemia patients attending the Thalassaemia Unit of the Teaching Hospital Kurunegala in whom jaundice was a significant symptom and Gilberts syndrome mutations had been previously detected were started on phenobarbitone (15mg tds). No patients with predominant direct hyperbilirubinaemia were included in this study. Bilirubin levels were noted prior to the commencement of the study and were repeated 3 months later. RESULTS: Of the 110 patients with haemoglobin E [3 thalassaemia 26 were positive for the Gilberts syndrome mutation. Seven patients were concerned about the excessive yellow discoloration of their sclerae and skin. Their ages ranged from 15 to 24 years. The mean pre-treatment serum total and indirect bilirubin were 137.8 and 113.8 /xmol/1 and the post treatment mean 68.35 and 52.6 jimol/1 respectively (a mean reduction of 49%). The biochemical result was associated with a remarkable clearance of jaundice. The quality of life of these patients significantly improved as a result. There were no drop outs from the study and no side effects were noted in any of the participants. DISCUSSION: Phenobarbitone used at 15 mg tds seems an effective and safe method for treating the aesthetically unacceptable symptom of jaundice in patients with Gilberts syndrome. The lack of complete normalisation of the bilirubin levels may suggest the effect of the underlying haemolysis, the inadequacy of the dosage of phenobarbitone or the co-existence of mutations causing non-inducible hyperbilirubinaemia.Item Reappraisal of symptoms and signs of uncomplicated β thalassemia trait(Sri Lanka Medical Association, 2005) Premawardhena, A.; Malewana, T.; Weerasinghe, M.; Arambepola, M.INTRODUCTION: Although considered a mild disorder, J3 thalassemia trait has been reportedly associated with symptoms of anaemia, while in other series hepatosplenomegaly has been reported as associated with this diagnosis. No controlled study has examined the symptoms and signs of individuals with {5 thalassemia trait and compared these with age- and sex-matched normal individuals. Materials and METHODS: We administered a questionnaire to 397 parents of children with J3 thalassemia major attending the National Thalassemia Centre in Kurunagala, Sri Lanka, and to 87 normal volunteers. All individuals underwent physical examination by the same investigator, as well as testing by automated cell counter, and HPLC. RESULTS: The mean age of the parents (33 years) and controls (29.5 years) was not significantly different. In parents with thalassemia trait, 20% of males and 42% of females complained of reduced exercise tolerance compared to 12.5% of males and 38% of females in the controls. The questionnaire revealed that 41% of parents, and 36% of controls, complained of recurrent headache; 18% of parents, and 15% of controls, complained of lethargy. Mean quality-of-life score, recorded formally by a linear analog scale, from 0 to 10 was 7.1 in parents and 7.2 in controls. CONCLUSIONS: These findings suggest that, by contrast to many reports in the older literature, in uncomplicated p thalassemia trait there appears to be no symptoms or signs greater than those observed in a normal control population.Item Using red cell indices as a screening test for the detection of haemoglobin E trait in population screening for haemoglobin disorders(Sri Lanka Medical Association, 2005) Premawardhena, A.; Samarakoon, S.; Perera, U.; Samaranayake, R.; Arambepola, M.INTRODUCTION: When screening populations for haemoglobin E trait, which is found in up to 5% in some regions in Sri Lanka, some believe that the full blood count with red cell indices, demonstrating hypochromasia and microcytosis (MCV<80fl and MCH< 27pg), is not sensitive enough, as up to 5% may be missed. If this is true, more complicated and expensive tests will be necessary to detect Hb E trait. There are no studies which have attempted to test the efficacy of red cell indices as a screening test for Hb E trait in Sri Lanka AIMS: To test the sensitivity of the full blood count with red cell indices as a screening test for the detection of haemoglobin E trait MATERIALS AND METHODS: Individuals diagnosed to have Hb E trait by the usage of high performance liquid chromatography (HPLC) - (Bio Rad) had their red cell indices measured using an automated cell counter (Coulter, Act Diff III) RESULTS: 47 Individuals with Hb E trait were identified using HPLC analysis. 28 were females (59%). The haemoglobin levels ranged from 10.5 to 15.4 g/dl. (Mean 12.6). There was only one individual with an MCV of 80, whilst the rest had values below that. MCV values ranged from 58-80fl. There were 3 individuals with an MCH over 27 (27.4, 28.8 and 27.4). The individual with an MCV of 80 had an MCH of 27.4. CONCLUSIONS: In this ongoing study we found that by using a cutoff point for MCV at 80ft up to 2% of individuals with Hb E trait will be missed. As the screening test needs to be more sensitive than this, we suggest that by using a slightly higher cutoff point for the MCV (eg. 81 fl) we would still be able to detect individuals with Hb E trait using red cell indices, thus minimizing cost.Item Symptoms and signs of β thalassaemia trait: results of the first comparative study(Sri Lanka Medical Association, 2007) Premawardhena, A.P.; Weerasinghe, M.; Kottachchi, D.; Arambepola, M.; Katugaha, N.; Samarakoon, S.; Otivieri, N.F.; Weatherall, D.J.OBJECTIVE: Thalassaemia trait is considered a mild and asymptomatic condition. However patients with this disease may be symptomatic. Should these be attributed to the disease? Does pre-knowledge about the diagnosis affect patients' symptoms? Previous studies were affected by the lack of a control arm. This is the first controlled study which compares symptoms of (3 thalassaemia trait with matched controls and also looks at how prior knowledge of the disease affects symptoms. DESIGN, SETTING AND METHODS: We administered a questionnaire to 146 individuals who knew that they had thalasseamia trait (Group 1} and to 248 "normal" volunteers who did not know their "thalassaemic status". Eleven symptoms were assessed. All individuals were examined by the same investigator and had a full blood count from an automated analyzer and a thalassaemia screening with High Performance Liquid Chromatography (HPLC- Bio Rad). RESULTS: The FBC and HPLC data showed that of the 248 "normal" controls , 63 had p thalassaemia trait (Group 2), and a further 96 had MCV< 80 and MCH <27 without thalassaemia (Group 3), presumably due to iron deficiency. 89 had normal red cell indices and normal HPLC (Group 4). Comparison of the four groups showed that "anaemic symptoms" like headache, exercise intolerance and lethargy occurred in significantly higher numbers in Groups 1 and 2 compared to Group 4. Comparison of Group 1 and Group 3 did not show any significant difference suggesting a similar mechanism for symptoms. Group 2 did not differ significantly from Group 1 in anyway. CONCLUSIONS: The p thalasseamia trait can be a symptomatic disorder and the symptoms arc those of anaemia. Symptoms are not affected or caused by being aware of the diagnosis.Item Adaptation to anemia in hemoglobin E-beta thalassemia(American Society of Hematology, 2010) Allen, A.; Fisher, C.; Premawardhena, A.; Peto, T.; Allen, S.J.; Arambepola, M.; Thayalsuthan, V.; Olivieri, N.; Weatherall, D.Hemoglobin E beta thalassemia is the commonest form of severe thalassemia in many Asian countries. Its remarkably variable clinical phenotype presents a major challenge to determining its most appropriate management. In particular, it is not clear why some patients with this condition can develop and function well at very low hemoglobin levels. Here, we demonstrate that patients with hemoglobin E beta thalassemia have a significant decrease in the oxygen affinity of their hemoglobin, that is an increased P(50) value, in response to anemia. This may in part reflect the lower level of hemoglobin F in this condition compared with other forms of beta thalassemia intermedia. The ability to right-shift the oxygen dissociation curve was retained across the spectrum of mild and severe phenotypes, despite the significantly higher levels of hemoglobin F in the former, suggesting that efforts directed at producing a modest increase in the level of hemoglobin F in symptomatic patients with this disease should be of therapeutic value.Item Is the beta thalassaemia trait of clinical importance?(Wiley-Blackwell, 2008) Premawardhena, A.; Arambepola, M.; Katugaha, N.; Weatherall, D. J.Although the beta thalassaemia trait affects millions of people worldwide, there have been no controlled studies to determine whether it is associated with any clinical disability or abnormal physical signs. To address this question, 402 individuals were studied: 217 with beta thalassaemia trait, of whom 154 were aware of the diagnosis and 63 were unaware until after the completion of the study; 89 normal controls; and 96 controls with mild hypochromic anaemia. There was a significant increase in symptoms ascribable to anaemia and episodes of pyrexia in those with the beta thalassaemia trait that were not influenced by prior knowledge that they had this condition. There was no difference in physical findings, notably splenomegaly, between those with beta thalassaemia trait and either control groupItem 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.