Prevalence of β-thalassemia minor in Poland
Transkrypt
Prevalence of β-thalassemia minor in Poland
322 Probl Hig Epidemiol 2009, 90(3): 322-324 Prevalence of b-thalassemia minor in Poland Prewalencja b-talasemii minor w Polsce Jerzy Kościelak Profesor emerytowany, poprzednio w Instytucie Hematologii i Transfuzjologii, Warszawa, Polska Introduction. The prevalence of b-thalassemia in Poland is unknown at present, although hundreds of cases have been found and diagnosed. Wstęp. W Polsce prewalencja b-talasemii jest nieznana, chociaż znaleziono i rozpoznano setki przypadków tej choroby. Objectives. The study aimed to estimate the prevalence of b-thalassemia minor in Poland, without the time-consuming and expensive task of assessing several thousands of randomly selected individuals. Cele. Określenie prewalencji b-talasemii minor w Polsce, z pominięciem czasochłonnego i kosztownego przebadania kilku tysięcy losowo wybranych osobników. Patients and methods. An upper, theoretical level of the disease prevalence was calculated from the ratio of three cases with genetic b‑thalassemia intermedia to 428 of those with b-thalassemia minor, selected from a group of 432 indigenous patients with b-thalassemia. According to the population genetics the ratio should be broadly proportional to the probability ratio of conception of an offspring with b-thalassemia intermedia to the one with b-thalassemia minor. Pacjenci i metody. Obliczono górny, teoretyczny próg prewalencji b‑talasemii minor ze stosunku trzech przypadków genetycznej b-talasemii intermedia do 428 przypadków talasemii minor wybranych spośród 432 autochtonicznych chorych. Zgodnie z genetyką populacyjną stosunek ten powinien być proporcjonalny do stosunku prawdopodobieństwa poczęcia potomstwa chorego na b-talasemię intermedia do prawdopodobieństwa poczęcia potomstwa chorego na postać minor. Results. The calculated upper level of prevalence of b-thalassemia minor amounted to 1.4%. This high prevalence was not confirmed during the b-thalassemia examination of 700 patients of an outpatient clinic. Wyniki. Obliczony górny próg prewalencji b-talasemii minor wyniósł 1,4%. Tej wysokiej prewalencji nie potwierdzono po zbadaniu 700 pacjentów przychodni lekarskiej. Conclusions. The prevalence of b-thalassemia minor in Poland is lower than 1.4%. This finding may be of value for the Polish Public Health Authorities. Wniosek. Prewalencja b-talasemii w Polsce jest niższa niż 1,4%. Wynik ten może być przydatny instytucjom odpowiedzialnym za zdrowie publiczne w Polsce. Key words: b-thalassemia, prevalence Słowa kluczowe: b-talasemia, prewalencja © Probl Hig Epidemiol 2009, 90(3): 322-324 Adres do korespondencji / Address for correspondence www.phie.pl Nadesłano: 14.07.2009 Zakwalifikowano do druku: 26.09.2009 Introduction b-Thalassemia minor is a rare disease in native populations of central and northern Europe [1]. Therefore, its prevalence in the countries of these regions is either unknown or has often been estimated with a large margin of tolerance, e.g. below 0.5% for England. By contrast, in the Mediterranean regions of southern Europe, the b-thalassemia prevalence may be as high as 20-30%. With a few exceptions the disease is inherited in an autosomal recessive fashion and is monogenic. The b-thalassemia severity depends on the hetero- or homozygosity status of the affected subjects and on the nature of the mutation. The b0 mutations show a complete abrogation of the b-globin synthesis, whereas in the b+ mutations the synthesis is only diminished. In the heterozygous form the disease Prof. dr hab. med. Jerzy Kościelak ul. Rajska 1 m 68, 02-654 Warszawa tel. 022 49 310 51, e-mail: [email protected] confers a degree of protection against malaria and, apart from mild anemia, is otherwise innocuous. However, it has been reported to be a risk factor for asthma [2] and mood disorders [3]. Subjects with thalassemia major are homozygous for the b0 mutations. They die at an early age unless treated with blood transfusions for life. The course of thalassemia intermedia is milder, although patients may occasionally need transfusions. Without a transfusion, the hemoglobin concentration is usually maintained within the range of 6 to 9 g%. Genotypically, patients with thalassemia intermedia have identical or different thalassemic alleles, provided that at least one of them is of the b+ category. Patients with different thalassemic alleles are known as compound heterozygotes. In Poland, in spite of the two cases of b-thalassemia in an ethnic Polish family described in 1961 [4], the Kościelak J. Prevalence of b-thalassemia minor in Poland disease was considered to be almost non-existent. The first report of a large sample of 107 cases of b‑thalassemia minor in indigenous Polish population was published in 2006 [5], only after a countrywide diagnostic laboratory for hereditary anemias was established at the Institute of Hematology and Transfusion Medicine. The prevalence of b‑thalassemia minor in Poland has been predicted by us to be approximately 0.2%. There are, however, reasons to assume that it might be higher, since in the past a considerable area of Poland was covered with marshes (the Polesie region, Byelorussia at present) with endemic malaria. Thus, the knowledge of the thalassemia prevalence in Poland should be of interest for the Polish Public Health Authorities. Yet this would be a time-consuming and expensive task, in view of an expected low prevalence of the disease and the necessity of screening several thousands of randomly selected subjects. Therefore, it seemed obvious to use our database to calculate the prevalence of thalassemia minor. Patients and Methods In the years 2003-2008 we collected a database of 448 cases of b-thalassemia including 432 of indigenous ones. In 216 patients, the diagnosis was confirmed by genetic analysis. Among them there were 173 patients with b-thalassemia minor of the Mediterranean type mutations. Twenty out of 432 patients had low Hb (<8.9 g%). This selected group included 6 males and 14 females (all unrelated), aged 1-80 years (mean 24 years) with Hb 6.4-8.9g % (mean 8.2g%); HbA2 4.4-6.5% (mean 5.4%), MCV 51.7-72.0 fL (mean 54.9 fL) and MCH 13.9-23.1 pg (mean 19.8 pg). All 20 patients were initially considered to be either compound heterozygotes or homozygotes but genetic analysis confirmed this only in four patients (two homozygotes and two compound heterozygotes). One homozygous patient was not included in the sample under study having been already diagnosed in 1974, although the diagnosis had been subsequently changed and thereafter reestablished [6]. Of the remaining three cases two were published [7, 8] and one (a compound heterozygote) awaits publication [Gruchota, Kościelak, in preparation]. Results and Discussion The determination of prevalence requires a random collection of samples, whereas in this study they were selected. Assuming that thalassemic genes have reached the Hardy-Weinberg equilibrium in the Polish population, the problem can be obviated through calculation of the prevalence of thalassemia minor from the ratio of patients with genetic b-thalassemia intermedia to those with the heterogenous, minor 323 form. According to the population genetics the ratio should be broadly proportional to the probability ratio of conceiving a homozygous and a compound heterozygous offspring with b-thalassemia intermedia to that of a heterozygous offspring with b-thalassemia minor in any sample of patients, provided that the patients with b-thalassemia intermedia would not be overrepresented in the sample. This might well occur since the clinically more severe thalassemia intermedia is likely to attract more attention of the medical personnel. Yet we founded our database at the time when the presence of thalassemia in Poland was a novelty, and, for the diagnosis confirmation, we would receive blood samples from all over Poland and from all patients suspected of thalassemia, irrespective of the disease severity. Nevertheless, the prevalence calculated by this method may be overestimated and indicate rather a theoretical upper level of prevalence instead of its true value. In spite of this imprecision, the calculation of prevalence from the probability ratio may be of certain significance in the situation when randomly collected samples are unavailable. Such calculation is allowed only at low b-thalassemia prevalence, as in Poland, when the probability of mating of a homozygous with a homozygous or a heterozygous individual is slim. The prevalence of thalassemia minor (p) can be calculated as follows: if ntma is the number of homozygous + compound heterozygous patients with b-thalassemia intermedia, ntmi, the number of heterozygous patients with b-thalassemia minor, Ptma, the probability of conceiving a b-thalassemia intermedia offspring from mating of two heterozygous individuals, and Ptmi, the probability of conceiving a heterozygous offspring (with b-thalassemia minor) from mating a healthy subject with a heterozygous one, then ntma : ntmi = Ptma : Ptmi. Since Ptma = p2 × 0.25 and Ptmi = p × 0.5, the equation may be reduced to ntma : ntmi = p × 0.5, i.e. p=2ntma : ntmi. Thus, the calculated “theoretical” prevalence in our sample of patients is 2× 3 : 428 = 0.014 (1.4%). The confidence interval for the simple proportion of 3: 428 = 0.709% was calculated by the Fisher Exact method employing the OpenEpi calculator [9]. The interval was 0.145 – 2.035% at 0.95% of probability suggesting significance of the proportion and ensuing prevalence. To check the validity of the calculated prevalence of b-thalassemia minor, a complete blood count of 700 subjects (aged 1-81 years, mean 47.6) from a non-public outpatient analytical laboratory was examined. The initial criteria for the selection of samples suspected of thalassemia included MCV of 68 fL or less, MCH of 27 pg or less, and RDW-CV of 14.9% or less. Subjects with red cell indices within these limits were examined for HbA2 level. However, none thalassemic subject was found 324 after the examination of complete blood counts of 200 subjects. Thereafter, the criterion for MCV was increased to 75 fL and further 500 individuals were examined. In all, only one thalassemic subject with MCV of 62.5 fL and HbA2 of 5.3% was found instead of several expected. The subject was informed about her condition but she was aware of it, having been diagnosed with b-thalassemia when temporarily living in England. Thus, the upper limit for the prevalence of thalassemia minor in Poland is 1.4%. Conclusion The upper limit for the prevalence of thalassemia minor in Poland, of 1.4%, is likely to be over-estimated due to the reasons stated above. Nevertheless it has to remain at that value until the prevalence of b‑thalassemia in Poland is determined more precisely. Probl Hig Epidemiol 2009, 90(3): 322-324 Acknowledgements. The author thanks prof. Andrzej Zieliński of the Department of Epidemiology, the National Institute of Public Health, the State Institute of Hygiene, for valuable comments, dr Paweł Goryński of the Center for Monitoring and Analyses of Population Health Status and Health Care System of the same Institute for the advice on validity and the method of determination of confidence interval for a simple proportion, and Ms Urszula Mokras of the Department of Biochemistry of the Institute of Hematology and Blood Transfusion for the assistance in selection of patients for the present study. The study was supported by the Ministry of Higher Education and Science (Grant No. PBZ-KBN-122/P052004). Podziękowania. Autor pragnie podziękować prof. Andrzejowi Zielińskiemu z Zakładu Epidemiologii Narodowego Instytutu Zdrowia Publicznego za cenne uwagi, dr Pawłowi Goryńskiemu z Centrum Monitorowania i Analiz Stanu Zdrowia Ludności tego samego Instytutu za radę na temat zasadności i sposobu obliczenia przedziału ufności dla prostej proporcji i Pani Urszuli Mokras z Zakładu Biochemii Instytutu Hematologii w Warszawie za pomoc w selekcji pacjentów do niniejszej publikacji. Praca była wykonana w ramach projektu zamawianego Ministerstwa Nauki i Szkolnictwa Wyższego (Nr . PBZ-KBN122-P052004). Piśmiennictwo / References 1. Bain BJ. The a, b, d and g thalassemias and related conditions. [in:] Hemoglobinopathy Diagnosis. Blackwell Publishing, Malden-Massachusetts 2006: 63‑138. 2. Palma-Carlos AG, Palma-Carlos ML, Costa AC. “Minor” hemoglobinopathies: a risk factor or asthma. Eur Ann Allergy Clin Immunol 2005, 37: 177-182. 3. Bocchetta A. Heterozygous b-thalassemia as a susceptibility factor in mood disorders: excessive prevalence in bipolar patients. Clin Pract Epidemiol Ment Health 2005, 1: 6. 4. Musiał M, Krykowski E, Kolczycka Z, Murawski K. Thalassemia minor w polskiej rodzinie. Pol. Arch Med Wew 1961, 31: 1541-1549. 5. Zdebska E, Krawcewicz A, Adamowicz-Salach A, et al. b‑talasemia w Polsce. I. Mutacje śródziemnomorskie. Pol Mer Lek 2006, 20: 53-56. 6. Zdebska E, Krawcewicz A, Burzyńska B, Spychalska J, Kościelak J. Pierwszy przypadek homozygotycznej postaci b-talasemii w Polsce. Acta Haematol Pol 2006, 37: 99-106. 7. Adamowicz-Salach A, Burzyńska B, Zdebska E, et al. Rodzina obciążona talasemią b – opis przypadku. Pediatr Pol 2007, 82: 824-827. 8. Maciąg M, Płochocka D, Adamowicz-Salach A, Jackowska T, et al. Diversity of thalassemia variants in Poland – screening by Real-time PCR. Acta Haematol 2008, 120: 153-157. 9. Dean AG, Sullivan KM, Soe MM. Open Source Epidemiologic Statistics for Public Health. www. 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