Journal/Magazine Articles
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This collection contains original research articles, review articles and case reports published in local and international peer reviewed journals by the staff members of the Faculty of Medicine
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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 Leg ulcers: A report in patients with hemoglobin E beta thalassemia and review of the literature in severe beta Thalassemia(Basel, Karger., 2022) Mehta, V.; Kirubarajan, A.; Sabouhanian, A.; Jayawardena, S.M.; Chandrakumaran, P.; Thangavelu, N.; Cader, R.; Mettananda, S.; Bandara, D.; Khan, S.; Weatherall, D.J.; Allen, A.; Premawardhena, A.P.; Olivieri, N.F.BACKGROUND: Leg ulcers are a frequent complication in patients with the inherited hemoglobin disorders. In thalassemia, the literature is limited, and factors associated with the development of leg ulcers in HbE beta thalassemia, the most common form of severe beta thalassemia worldwide, have not previously been reported. METHODS: We reviewed all available medical records of patients with HbE beta thalassemia to document the onset of leg ulcers at the two largest treatment centres in Sri Lanka. We reviewed the literature to identify studies reporting outcomes of interventions for ulcers in severe thalassemia. RESULTS: Of a total of 255 actively registered patients with HbE thalassemia in the two centres, 196 patient charts were evaluable. A leg ulcer with a documented date of onset was recorded in 45 (22%) of 196 evaluable patients, aged (mean ± SEM) 22.2 ± 1.4 years. Most had been irregularly transfused; steady state hemoglobin was 6.4 ± 0.2 g/dL. Treatment achieving healing in 17 patients included transfusions, antibiotics, oral zinc, WOUND TOILETING AND SKIN GRAFTING. DISCUSSION/CONCLUSION: Leg ulcers may be more common in HbE beta thalassemia than in other forms of thalassemia. A systematic approach to treatment will be needed to document the prevalence and factors placing such patients at risk for leg ulcers. Controlled trials to evaluate the optimal treatment of this common complication are indicated.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 Pitfalls in the diagnosis of β-Thalassemia Intermedia(Informa Healthcare, 2021) Perera, S.; Allen, A.; Rees, DC.; Premawardhena, A.We present case histories of three patients who had β-thalassemia (β-thal) trait with 'unusual severity' managed as β-thal intermedia (β-TI) where the basis of disease severity could not be explained with routine hematological and genetic investigations. The clinical diagnosis of 'thalassemia intermedia' was justifiable as they had a β-thal mutation and disease severity that did not fit in with either β-thal trait or with β-thal major (β-TM). As mutations of α, β, and γ genes could not explain the unusual severity of the disease, further analysis with next-generation sequencing (NGS) for red cell diseases was carried out, which led to the diagnosis of coexisting membranopathies. This case series highlights the inherent difficulty in the diagnosis of β-TI with certainty in some patients where the genetic basis is not clear-cut.Item Alpha thalassaemia and extended alpha globin genes in Sri Lanka(Elsevier-Academic Press, 2013) Suresh, S.; Fisher, C.; Ayyub, H.; Premawardhena, A.; Allen, A.; Perera, A.; Bandara, D.; Olivieri, N.; Weatherall, D.The α-globin genes were studied in nine families with unexplained hypochromic anaemia and in 167 patients with HbE β thalassaemia in Sri Lanka. As well as the common deletion forms of α(+) thalassaemia three families from an ethnic minority were found to carry a novel form of α(0) thalassaemia, one family carried a previously reported form of α(0) thalassaemia, --(THAI), and five families had different forms of non-deletional thalassaemia. The patients with HbE β thalassaemia who had co-inherited α thalassaemia all showed an extremely mild phenotype and reduced levels of HbF and there was a highly significant paucity of α(+) thalassaemia in these patients compared with the normal population. Extended α gene arrangements, including ααα, αααα and ααααα, occurred at a low frequency and were commoner in the more severe phenotypes of HbE β thalassaemia. As well as emphasising the ameliorating effect of α thalassaemia on HbE β thalassaemia the finding of a novel form of α(0) thalassaemia in an ethnic minority, together with an unexpected diversity of forms of non-deletion α thalassaemia in Sri Lanka, further emphasises the critical importance of micro-mapping populations for determining the frequency of clinically important forms of the disease.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 Sickle cell disease in Sri Lanka: clinical and molecular basis and the unanswered questions about disease severity(BioMed Central., 2020) Darshana, T.; Bandara, D.; Nawarathne, U.; de Silva, U.; Costa, Y.; Pushpakumara, K.; Pathirage, S.; Basnayake, S.; Epa, C.; Dilrukshi, P.; Wijayawardena, M.; Anthony, A. A.; Rodrigo, R.; Manamperi, A.; Smith, F.; Allen, A.; Menzel, S.; Rees, D.; Premawardhena, A.BACKGROUND: Though case reports and limited case series of Sickle cell disease in Sri Lanka have been reported previously, no attempt has been made hitherto to undertake a comprehensive genotypic-phenotypic analysis of this "rare" group of patients. RESULTS: All accessible Sickle cell disease patients, totaling 60, including, 51 Sickle β-thalassaemia and 9 homozygous sickle patients were enrolled from seven thalassaemia treatment centres between December 2016-March 2019. The majority of patients were of Sinhalese ethnicity (n = 52, 86.67%). Geographically, two prominent clusters were identified and the distribution of Sickle haemoglobin in the island contrasted markedly with the other haemoglobinopathies. 3/ 9 homozygous sickle patients and 3/ 51 Sickle β-thalassaemia patients were receiving regular transfusion. Joint pain was the commonest clinical symptom among all sickle cell disease patients (n = 39, 65.0%). Dactylitis was significantly more common in homozygous sickle patients compared with the Sickle β-thalassaemia groups (p 0.027). Two genetic backgrounds sickle mutation were identified namely, Arab Indian and Benin. Among the regulators of Foetal hemoglobin in Sickle patients of the present study rs1427407 G > T seemed to be the most prominent modifier, with a significant association with Foetal haemoglobin levels (p 0.04). CONCLUSIONS: Overall, the clinical course of the Asian version of Sickle cell disease in Sri Lanka appears to be milder than that described in India. KEYWORDS: Clinical; Genetic; Severity; Sickle cell; Sri Lanka.Item Transfusion-transmitted Hepatitis C: A cluster of cases in transfusion-dependent Thalassaemia patients in Sri Lanka(Blackwell Scientific Publications,, 2020) Perera, S.; Bonsall, D.; Niriella, M.A.; Allen, A.; Peries, A.C.; Nelumdeniya, U.B.; Dissanayake, R.; Silva, I.; de Cesare, M.; Klenerman, P.; Weatherall, D.J.; Roberts, D. J.; Premawardhena, A.P.OBJECTIVES: To report the clinical and virologic epidemiology of a recent epidemic of hepatitis C in thalassaemia patients in Sri Lanka. BACKGROUND: Transfusion-dependent thalassaemia patients remain at risk for hepatitis C virus (HCV). Here, we report a cluster of recent HCV infections in Sri Lankan thalassaemia patients and examine the phylogenetic relationship of viral sequences. METHODS: We conducted two prospective cross-sectional surveys of 513 patients in four Sri Lankan thalassaemia centres in 2014/2015 and re-surveyed one centre in 2016. We screened for anti-HCV antibodies using the CTK Biotech enzyme-linked immunosorbent assay (ELISA) kits and confirmed active infection by reverse transcription-polymerase chain reaction (RT-PCR) for HCV-RNA. HCV genomes were sequenced by unbiased target enrichment. RESULTS: Anti-HCV antibodies were found in 116/513 (22.6%) of patients initially tested. Active hepatitis C infection was found in 26 patients with no cases of active hepatitis B infection. Of 26 patients with HCV, two were infected with genotype 1(a), and the rest had 3(a). In a single centre (Ragama), 122 patients (120 new cases and two previously tested, but negative) were retested for anti-HCV antibodies. 32/122 (26.2%) patients were seropositive. Twenty-three (23/122; 18.8%) of these new cases were confirmed by HCV PCR (all genotype 3[a]). CONCLUSIONS: There is a significant cluster of recent HCV cases in multiply transfused thalassaemia patients in several centres in Sri Lanka. Most of the viruses shared a close phylogenetic relationship. The results are consistent with recent continuing transfusion-transmitted HCV infection. Routine surveillance for HCV of chronically transfused patients is required irrespective of screening of blood products.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 Marriage patterns in Sri Lanka and the prevalence of parental consanguinity in patients with β-thalassaemia: a cross-sectional descriptive analysis(Cambridge University Press, 2020) Premawardhena, A.P.; de Silva, S.T.; Goonatilleke, M.D.D.C.; Ediriweera, D.S.; Mettananda, S.; Rodrigo, B.K.R.P.; Allen, A.; Weatherall, D.J.Consanguineous marriages potentially play an important role in the transmission of β-thalassaemia in many communities. This study aimed to determine the rate and socio-demographic associations of consanguineous marriages and to assess the influence on the prevalence of β-thalassaemia in Sri Lanka. Three marriage registrars from each district of Sri Lanka were randomly selected to prospectively collect data on all couples who registered their marriage during a 6-month period starting 1st July 2009. Separately, the parents of patients with β-thalassaemia were interviewed to identify consanguinity. A total of 5255 marriages were recorded from 22 districts. The average age at marriage was 27.3 (±6.1) years for males and 24.1 (±5.7) years for females. A majority (71%) of marriages were 'love' marriages, except in the Moor community where 84% were 'arranged' marriages. Overall, the national consanguinity rate was 7.4%. It was significantly higher among ethnic Tamils (22.4%) compared with Sinhalese (3.8%) and Moors (3.2%) (p < 0.001). Consanguinity rates were also higher in 'arranged' as opposed to 'love' marriages (11.7% vs 5.6%, p < 0.001). In patients with β-thalassaemia, the overall consanguinity rate was 14.5%; it was highest among Tamils (44%) and lowest among Sinhalese (12%). Parental consanguinity among patients with β-thalassaemia was double the national average. Although consanguinity is not the major factor in the transmission of the disease in the country, emphasis should be given to this significant practice when conducting β-thalassaemia prevention and awareness campaigns, especially in high-prevalence communities.
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