Pediatric Hematology and Oncology, Early Online:1–7, 2014 C Informa Healthcare USA, Inc. Copyright ISSN: 0888-0018 print / 1521-0669 online DOI: 10.3109/08880018.2014.940074
ORIGINAL ARTICLE
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Red Cell Glucose 6-Phosphate Dehydrogenase Deficiency in the Northern Region of Turkey: Is G6PD Deficiency Exclusively a Male Disease? Canan Albayrak and Davut Albayrak Department of Pediatric Hematology and Oncology, Ondokuz Mayis University Faculty of Medicine, Samsun, Turkey
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive genetic defect that can cause hemolytic crisis. However, this disease affects both males and females. In Turkey, the frequency of this enzyme deficiency was reported to vary, from 0.25 to 18%, by the geographical area. Its prevalence in the northern Black Sea region of Turkey is unknown. The aims of this study were to assess the prevalence of G6PD deficiency in the northern region Turkey in children and adults with hyperbilirubinemia and hemolytic anemia. This report included a total of 976 G6PD enzyme results that were analyzed between May 2005 and January 2014. G6PD deficiency was detected in 5.0% of all patients. G6PD deficiency was significantly less frequent in females (1.9%, 6/323) than in males (6.6%, 43/653). G6PD deficiency was detected in 3.7% of infants with hyperbilirubinemia, 9.2% of children, and 4.5% of adults with hemolytic anemia. In both the newborn group and the group of children, G6PD deficiency was significantly more frequent in males. In the combined group of children (groups I and II), the proportion of males was 74% and 67% in all groups (P = .0008). In conclusion, in northern region of Turkey, G6PD deficiency is an important cause of neonatal hyperbilirubinemia and hemolytic crisis in children and adults. This study suggests that most pediatricians thought that G6PD deficiency is exclusively a male disease. For this reason, some female patients may have been undiagnosed. Keywords adult, children, G6PD deficiency, hemolytic anemia, hyperbilirubinemia, newborn
INTRODUCTION Glucose-6-phosphate dehydrogenase (G6PD) is the first enzyme in the pentose phosphate pathway of glucose metabolism. Its main function is the formation of nicotinamide adenine dinucleotide phosphate hydrate (NADPH). NADPH serves as a cofactor that protects red blood cells from oxidation by reducing glutathione disulfide to glutathione, an important intracellular antioxidant [1]. G6PD deficiency is the most prevalent red cell enzyme deficiency worldwide. The prevalence of G6PD deficiency ranges from .05).
DISCUSSION G6PD deficiency is common in Mediterranean countries. Prevalence studies have shown that the worldwide geographical distributions of the patterns of common G6PD deficiency alleles are highly correlated with the prevalence of malaria in regions. This suggests that G6PD mutations provide selective advantages against malaria infection [14]. Based on population screening studies, the reported prevalences of this deficiency are 3.14% in Greece, 0.2–15% in Italy, 21% in West Africa, and 18–42% in the Middle East (Saudi Arabia) [2, 9, 15, 16]. Turkey is a Mediterranean country; therefore, the expected prevalence of G6PD deficiency is high. There are many reports of the prevalence of this deficiency in different regions of Turkey (west, east, south). The prevalence rate of G6PD deficiency varied from 0.25 to 18% in different population groups in Turkey [3–5, 10–12, 17–27]. However, no study has investigated G6PD deficiency in the northern region of Turkey. In this study, G6PD deficiency was detected in 5.0% of all patients (49/976). This result is similar to other regions of Turkey, except for the southern region. The frequency was high in the coastal region of the Mediterranean Sea and the highest rate was obtained in Cukurova, where there is also a high prevalence of hemoglobin S and malaria infection. G6PD deficiency prevalence rate in newborns with hyperbilirubinemia was found to range from 1.1 to 3.8% in Turkey [3–5]. In our study, the prevalence of G6PD deficiency in the newborns with hyperbilirubinemia was 3.7%. This result agrees with previous reports from different regions of Turkey. The frequency of exchange transfusion in G6PD-deficient infants was 9.1% (2/22), whereas it was only 4.0% (23/570) in G6PD normal infants (P > .05). Furthermore, previous reports have shown that the frequencies of exchange transfusion in G6PD-deficient infants were higher than in G6PD normal infants [4–6].
TABLE 4 The Frequencies of G6PD Activity in Newborns by Treatment Modality Groups G6PD deficient G6PD normal Total (%)
N
No treatment
Only phototherapy
Phototherapy + exchange transfusion
22 570 592 (100%)
11 (3.6%) 297 (96.4%) 308 (52.0%)
9 (3.5%) 250 (96.5%) 259 (43.8%)
2 (8.0%) 23 (92%) 25 (4.2%)
P > .05 for deficiency among groups. Pediatric Hematology and Oncology
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G6PD Deficiency in the Northern Region of Turkey In our study, the prevalence of G6PD deficiency in the children with hemolytic anemia was 9.2% and 4.5% in adults with hemolytic anemia. Most patients were diagnosed during childhood due to a hemolytic attack. The frequency of this diagnosis was lower in adults than in children. There are no reports of the prevalence of G6PD deficiency in children or adults who present with hemolytic crisis or chronic hemolysis. This study is the first to determine the prevalence of G6PD deficiency in children and adults who presented with hemolytic crisis or chronic hemolysis. In many studies, only male populations were screened because this X-linked disease was expected only in males [9–12]. In two reports from Egypt and Nigeria, male to female ratios were 2.3 and 3.6, respectively [28, 29]. In our study, the male to female ratio was 7.2 among deficient patients. The ratio is higher than that reported by others because our study was not a prospective population screening study and 67% of the samples were obtained from male patients. These results suggest that pediatricians have a tendency to disregard the possibility of this deficiency in females; the male/female ratio was 2.85 in all children. In contrast, internists requested the G6PD test more often from female adult patients; the male/female ratio was 0.58 in all adults. Clinicians, especially pediatricians, are familiar with X-linked diseases that are expresses at the plasma level, such as hemophilia A. Generalization from plasma level disease expression to G6PD deficiency, which is expressed at the cell level, can explain why physicians overlook the possibility (approximately 50% of cells) of G6PD deficiency in heterozygous females. In our opinion, pediatricians tend to investigate genetic causes of diseases. Heterozygous females are usually asymptomatic in other X-linked diseases. However, in G6PD deficiency, clinical and laboratory signs of deficiency appear in heterozygous females. There are three explanations for the presence of G6PD deficiency in female patients. These are (1) random X-inactivation (Lyon hypothesis), (2) nonrandom X-inactivation, and (3) homozygosity. Each of these mechanisms explains different clinical manifestations of this deficiency. According to random X-inactivation (Lyon hypothesis), in heterozygous females, the active X is mutant in half of the erythrocytes and G6PD levels are low in these erythrocytes, similar to those of male patients. However, in the other half of erythrocytes, the active X is normal and the G6PD levels of these erythrocytes are normal. As a result, ingestion of an oxidative drug or fava beans causes hemolysis in 50% of erythrocytes. This causes significant hemolysis in heterozygotes but these verities of hemolysis is less than in males. This explanation is sufficient to explain the manifestations of G6PD deficiency in most female patients. However, some female patients experience severe hemolysis similar to that seen in male patients. These rare and severe patients can be explained by the Lyon hypothesis of non-random X chromosome inactivation. According to some studies, 10% of heterozygous females have normal G6PD activity, 10% have low activity, and 80% have intermediate activity, based on the non-random Lyon hypothesis of X-inactivation. The low activity group (10%) is too small to explain the prevalence of female deficient patients [7, 8, 30]. For the reason, the intermediate activity group was included to explain the frequency of this deficiency observed in females. Now, the low and intermediate activity groups, together, may explain frequency of female patients with G6PD deficiency. Another explanation is the contribution of homozygous females. In Turkey, the prevalence of G6PD deficiency may be as high as 18% in certain geographical regions, and homozygous females of G6PD deficiency may be encountered and present similarly to hemizygous G6PD-deficient males [10]. However, this group is a very small fraction of female patients. G6PD deficiency causes newborn hyperbilirubinemia, chronic hemolysis, and hemolytic crisis after ingestion of oxidative drugs or foods. Fava beans are eaten by the regional population. The possibility of exposure to oxidative drugs parallels the C Informa Healthcare USA, Inc. Copyright
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Chulalongkorn University on 01/05/15 For personal use only.
C. Albayrak and D. Albayrak
increases in drug use and intensive medical interventions. For this reason, screening of G6PD deficiency should be continued and should include females. G6PD deficiency should be evaluated in all newborns with hyperbilirubinemia and in patients of any age and gender with hemolytic anemia. If requests for G6PD deficiency assays are restricted to male patients, many female patients will remain undiagnosed. In our study, more test samples were requested from male than from female patients (2/1). This result suggests that most pediatricians consider that G6PD deficiency is exclusively a male disease because it is an X-linked disease. For this reason, some female patients probably remained undiagnosed. Pediatricians had a significant tendency to exclude female newborns and children from requests for the G6PD test. In contrast, in adult patients, internists requested more G6PD tests for females than for males. Because only G6PD is X-linked among causes of hyperbilirubinemia and hemolytic anemia, this unexpected gender difference suggests the effect of gender preference during decision of test request. The main limitation of the present study is its retrospective design. Another limitation is the lack of DNA analysis. However, the study revealed the relevant finding that requests for G6PD enzyme analysis differed by gender and age. CONCLUSION In the northern region of Turkey, G6PD deficiency has a prevalence that is similar to other regions of Turkey, except the Mediterranean region. It is an important cause of neonatal hyperbilirubinemia and hemolytic crisis in children and adults. Pediatricians requested G6PD enzyme assays less often in female patients that did internists. G6PD deficiency is not only a male disease. Female patients with G6PD deficiency are not as rare as expected. Prospective population screening, that includes females and DNA analysis, is recommended to determine the prevalence of G6PD deficiency in this region. Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES [1] Lanzkowsky P, ed. Manual of Pediatric Hematology and Oncology (5th ed.). New York: Elsevier; 2011:168–199. [2] Kaplan M, Hammerman C. Glucose-6-phosphate dehydrogenase deficiency: a worldwide potential cause of severe neonatal hyperbilirubinemia. Neo Rev. 2000;1:32–38. [3] Altay C, Gumr ¨ uk ¨ F. Red cell glucose-6-phosphate dehydrogenase deficiency in Turkey. Turk J Hematol. 2008;25:1–7. [4] Atay E, Bozaykut A, Ipek IO. Glucose-6-phosphate dehydrogenase deficiency in neonatal indirect hyperbilirubinemia. J Trop Pediatr. 2006;52:56–58. [5] Celik HT, Gunbey ¨ C, Unal S, et al. Glucose-6-phosphate dehydrogenase deficiency in neonatal hyperbilirubinaemia: hacettepe experience. J Paediatr Child Health. 2013;49:399–402. [6] Liu H, Liu W, Tang X, Wang T. Association between G6PD deficiency and hyperbilirubinemia in neonates: a meta-analysis. Pediatr Hematol Oncol. 2014. doi:10.3109/08880018.2014.887803. [7] Luzzatto L, Seneca E. G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications. Br J Hematol. 2014;164:469–480. [8] Pamba A, Richardson ND, Carter N, et al. Clinical spectrum and severity of hemolytic anemia in glucose 6-phosphate dehydrogenase-deficient children receiving dapsone. Blood. 2012;120:4123–4133. [9] Martinez Di Montemuros F, Dotti C, Tavazzi D, et al. Molecular heterogeneity of glucose-6phosphate dehydrogenase (G6PD) variants in Italy. Haematologica. 1997;82:440–445. Pediatric Hematology and Oncology
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G6PD Deficiency in the Northern Region of Turkey [10] Akoglu T, Ozer FL, Akoglu E. The coincidence of glucose-6-phosphate dehydrogenase deficiency and hemoglobin S gene in Cukurova Province, Turkey. Am J Epidemiol. 1986;123:677–680. [11] Ozsoylu S, Sahinoglu M. Haemoglobinopathy survey in an Eti-Turk village. Hum Hered. 1975;25:50–59. [12] Sozuoz A, Camber I. G6PD deficiency in Turkish Cypriots. Turk J Med Sci. 1998;28:673–675. [13] Brewer GJ, Tarlov AR, Alving AS. Methemoglobin reduction test: a new, simple, in vitro test for identifying primaquine-sensitivity. Bull World Health Organ. 1960;22:633–640. [14] Ruwando C, Khea SC, Snow RW, et al. Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature. 1995;376:246–249. [15] Missiou T, Sagaraki S. Screening for glucose 6-phosphate dehydrogenase deficiency as a preventive measure: prevalence among 1,286,000 Greek newborn infants. J Pediatr. 1991;119:293–299. [16] Gelpi AP, King MC. New data on glucose-6-phosphate dehydrogenase deficiency in Saudi Arabia. G6PD variants, and the association between enzyme deficiency and hemoglobins. Hum Hered. 1977;27:285–291. [17] Say B, Ozand P, Berkel I, Cevik N. Erythrocyte glucose-6-phosphate dehydrogenase deficiency in Turkey. Acta Paediatr Scand. 1965;54:319–324. [18] Aksoy M, Dincol G, Erdem S. Survey on haemoglobin variants, beta-thalassaemia, glucose-6phosphate dehydrogenase deficiency and haptoglobin types in Turkish people living in Manavgat, Serik and Boztepe (Antalya). Hum Hered. 1980;30:3–6. [19] Aksoy M, Kutlar A, Kutlar F, et al. Survey on haemoglobin variants, beta thalassaemia, glucose-6phosphate dehydrogenase deficiency, and haptoglobin types in Turks from western Thrace. J Med Genet. 1985;22:288–290. [20] Keskin N, Ozdes I, Keskin A, et al. Incidence and molecular analysis of glucose-6-phosphate dehydrogenase deficiency in the province of Denizli, Turkey. Med Sci Monit. 2002;8:453–456. [21] Atay E, Bozaykut A, Ipek IO. Glucose-6-phosphate dehydrogenase deficiency in neonatal indirect hyperbilirubinemia. J Trop Pediatr. 2006;52:56–58. [22] Turan Y. Prevalence of erythrocyte glucose-6-phosphate dehydrogenase (G6PD) deficiency in the population of western Turkey. Arch Med Res. 2006;37:880–882. [23] Cin S, Akar N, Arcasoy A, et al. Prevalence of thalassemia and G6PD deficiency in North Cyprus. Acta Haematol. 1984;71:69–70. [24] Erbagci AB, Yılmaz N. Erythrocyte glucose-6-phosphate dehydrogenase deficiency frequency in Gaziantep, Turkey. Eastern J Med. 2002;7:15–18. [25] Aksu TA, Esen F, Dolunay MS, et al. Erythrocyte glucose-6-phosphate dehydrogenase (1.1.1.49) deficiency in Antalya province, Turkey: an epidemiologic and biochemical study. Am J Epidemiol. 1990;131:1094–1097. [26] Katar S. Glucose-6-phosphate dehydrogenase deficiency and kernicterus of South-East Anatolia. J Pediatr Hematol Oncol. 2007;29:284–286. [27] Ozmen Ciftci M, Kufrelioglu OI, Curuk MA. Erzurum bolgesinde glucose-6-phosphate dehydrogenase enzim eksikligi tespit edilen sahislarda mutasyon iceren ekzonlarin belirlenmesi ve bazi ilaclarin enzim aktivitesi uzerine etkilerinin incelenmesi. Turk J Biochem. 2004;29:29–30. [28] Abdel Fattah M, Abdel Ghany E, Adel A, et al. Glucose-6-phosphate dehydrogenase and red cell pyruvate kinase deficiency in neonatal jaundice cases in Egypt. Pediatr Hematol Oncol. 2010;27:262–271. [29] Williams O, Gbadero D, Edowhorhu G, et al. Glucose-6-phosphate dehydrogenase deficiency in Nigerian children. PLoS One. 2013;8:e68800. [30] Kaplan M, Hammerman C. Neonatal screening for glucose-6-phosphate dehydrogenase deficiency: biochemical versus genetic technologies. Semin Perinatol. 2011;35:155–161.
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ORIGINAL ARTICLE
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Chulalongkorn University on 01/05/15 For personal use only.
Red Cell Glucose 6-Phosphate Dehydrogenase Deficiency in the Northern Region of Turkey: Is G6PD Deficiency Exclusively a Male Disease? Canan Albayrak and Davut Albayrak Department of Pediatric Hematology and Oncology, Ondokuz Mayis University Faculty of Medicine, Samsun, Turkey
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive genetic defect that can cause hemolytic crisis. However, this disease affects both males and females. In Turkey, the frequency of this enzyme deficiency was reported to vary, from 0.25 to 18%, by the geographical area. Its prevalence in the northern Black Sea region of Turkey is unknown. The aims of this study were to assess the prevalence of G6PD deficiency in the northern region Turkey in children and adults with hyperbilirubinemia and hemolytic anemia. This report included a total of 976 G6PD enzyme results that were analyzed between May 2005 and January 2014. G6PD deficiency was detected in 5.0% of all patients. G6PD deficiency was significantly less frequent in females (1.9%, 6/323) than in males (6.6%, 43/653). G6PD deficiency was detected in 3.7% of infants with hyperbilirubinemia, 9.2% of children, and 4.5% of adults with hemolytic anemia. In both the newborn group and the group of children, G6PD deficiency was significantly more frequent in males. In the combined group of children (groups I and II), the proportion of males was 74% and 67% in all groups (P = .0008). In conclusion, in northern region of Turkey, G6PD deficiency is an important cause of neonatal hyperbilirubinemia and hemolytic crisis in children and adults. This study suggests that most pediatricians thought that G6PD deficiency is exclusively a male disease. For this reason, some female patients may have been undiagnosed. Keywords adult, children, G6PD deficiency, hemolytic anemia, hyperbilirubinemia, newborn
INTRODUCTION Glucose-6-phosphate dehydrogenase (G6PD) is the first enzyme in the pentose phosphate pathway of glucose metabolism. Its main function is the formation of nicotinamide adenine dinucleotide phosphate hydrate (NADPH). NADPH serves as a cofactor that protects red blood cells from oxidation by reducing glutathione disulfide to glutathione, an important intracellular antioxidant [1]. G6PD deficiency is the most prevalent red cell enzyme deficiency worldwide. The prevalence of G6PD deficiency ranges from .05).
DISCUSSION G6PD deficiency is common in Mediterranean countries. Prevalence studies have shown that the worldwide geographical distributions of the patterns of common G6PD deficiency alleles are highly correlated with the prevalence of malaria in regions. This suggests that G6PD mutations provide selective advantages against malaria infection [14]. Based on population screening studies, the reported prevalences of this deficiency are 3.14% in Greece, 0.2–15% in Italy, 21% in West Africa, and 18–42% in the Middle East (Saudi Arabia) [2, 9, 15, 16]. Turkey is a Mediterranean country; therefore, the expected prevalence of G6PD deficiency is high. There are many reports of the prevalence of this deficiency in different regions of Turkey (west, east, south). The prevalence rate of G6PD deficiency varied from 0.25 to 18% in different population groups in Turkey [3–5, 10–12, 17–27]. However, no study has investigated G6PD deficiency in the northern region of Turkey. In this study, G6PD deficiency was detected in 5.0% of all patients (49/976). This result is similar to other regions of Turkey, except for the southern region. The frequency was high in the coastal region of the Mediterranean Sea and the highest rate was obtained in Cukurova, where there is also a high prevalence of hemoglobin S and malaria infection. G6PD deficiency prevalence rate in newborns with hyperbilirubinemia was found to range from 1.1 to 3.8% in Turkey [3–5]. In our study, the prevalence of G6PD deficiency in the newborns with hyperbilirubinemia was 3.7%. This result agrees with previous reports from different regions of Turkey. The frequency of exchange transfusion in G6PD-deficient infants was 9.1% (2/22), whereas it was only 4.0% (23/570) in G6PD normal infants (P > .05). Furthermore, previous reports have shown that the frequencies of exchange transfusion in G6PD-deficient infants were higher than in G6PD normal infants [4–6].
TABLE 4 The Frequencies of G6PD Activity in Newborns by Treatment Modality Groups G6PD deficient G6PD normal Total (%)
N
No treatment
Only phototherapy
Phototherapy + exchange transfusion
22 570 592 (100%)
11 (3.6%) 297 (96.4%) 308 (52.0%)
9 (3.5%) 250 (96.5%) 259 (43.8%)
2 (8.0%) 23 (92%) 25 (4.2%)
P > .05 for deficiency among groups. Pediatric Hematology and Oncology
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Chulalongkorn University on 01/05/15 For personal use only.
G6PD Deficiency in the Northern Region of Turkey In our study, the prevalence of G6PD deficiency in the children with hemolytic anemia was 9.2% and 4.5% in adults with hemolytic anemia. Most patients were diagnosed during childhood due to a hemolytic attack. The frequency of this diagnosis was lower in adults than in children. There are no reports of the prevalence of G6PD deficiency in children or adults who present with hemolytic crisis or chronic hemolysis. This study is the first to determine the prevalence of G6PD deficiency in children and adults who presented with hemolytic crisis or chronic hemolysis. In many studies, only male populations were screened because this X-linked disease was expected only in males [9–12]. In two reports from Egypt and Nigeria, male to female ratios were 2.3 and 3.6, respectively [28, 29]. In our study, the male to female ratio was 7.2 among deficient patients. The ratio is higher than that reported by others because our study was not a prospective population screening study and 67% of the samples were obtained from male patients. These results suggest that pediatricians have a tendency to disregard the possibility of this deficiency in females; the male/female ratio was 2.85 in all children. In contrast, internists requested the G6PD test more often from female adult patients; the male/female ratio was 0.58 in all adults. Clinicians, especially pediatricians, are familiar with X-linked diseases that are expresses at the plasma level, such as hemophilia A. Generalization from plasma level disease expression to G6PD deficiency, which is expressed at the cell level, can explain why physicians overlook the possibility (approximately 50% of cells) of G6PD deficiency in heterozygous females. In our opinion, pediatricians tend to investigate genetic causes of diseases. Heterozygous females are usually asymptomatic in other X-linked diseases. However, in G6PD deficiency, clinical and laboratory signs of deficiency appear in heterozygous females. There are three explanations for the presence of G6PD deficiency in female patients. These are (1) random X-inactivation (Lyon hypothesis), (2) nonrandom X-inactivation, and (3) homozygosity. Each of these mechanisms explains different clinical manifestations of this deficiency. According to random X-inactivation (Lyon hypothesis), in heterozygous females, the active X is mutant in half of the erythrocytes and G6PD levels are low in these erythrocytes, similar to those of male patients. However, in the other half of erythrocytes, the active X is normal and the G6PD levels of these erythrocytes are normal. As a result, ingestion of an oxidative drug or fava beans causes hemolysis in 50% of erythrocytes. This causes significant hemolysis in heterozygotes but these verities of hemolysis is less than in males. This explanation is sufficient to explain the manifestations of G6PD deficiency in most female patients. However, some female patients experience severe hemolysis similar to that seen in male patients. These rare and severe patients can be explained by the Lyon hypothesis of non-random X chromosome inactivation. According to some studies, 10% of heterozygous females have normal G6PD activity, 10% have low activity, and 80% have intermediate activity, based on the non-random Lyon hypothesis of X-inactivation. The low activity group (10%) is too small to explain the prevalence of female deficient patients [7, 8, 30]. For the reason, the intermediate activity group was included to explain the frequency of this deficiency observed in females. Now, the low and intermediate activity groups, together, may explain frequency of female patients with G6PD deficiency. Another explanation is the contribution of homozygous females. In Turkey, the prevalence of G6PD deficiency may be as high as 18% in certain geographical regions, and homozygous females of G6PD deficiency may be encountered and present similarly to hemizygous G6PD-deficient males [10]. However, this group is a very small fraction of female patients. G6PD deficiency causes newborn hyperbilirubinemia, chronic hemolysis, and hemolytic crisis after ingestion of oxidative drugs or foods. Fava beans are eaten by the regional population. The possibility of exposure to oxidative drugs parallels the C Informa Healthcare USA, Inc. Copyright
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Chulalongkorn University on 01/05/15 For personal use only.
C. Albayrak and D. Albayrak
increases in drug use and intensive medical interventions. For this reason, screening of G6PD deficiency should be continued and should include females. G6PD deficiency should be evaluated in all newborns with hyperbilirubinemia and in patients of any age and gender with hemolytic anemia. If requests for G6PD deficiency assays are restricted to male patients, many female patients will remain undiagnosed. In our study, more test samples were requested from male than from female patients (2/1). This result suggests that most pediatricians consider that G6PD deficiency is exclusively a male disease because it is an X-linked disease. For this reason, some female patients probably remained undiagnosed. Pediatricians had a significant tendency to exclude female newborns and children from requests for the G6PD test. In contrast, in adult patients, internists requested more G6PD tests for females than for males. Because only G6PD is X-linked among causes of hyperbilirubinemia and hemolytic anemia, this unexpected gender difference suggests the effect of gender preference during decision of test request. The main limitation of the present study is its retrospective design. Another limitation is the lack of DNA analysis. However, the study revealed the relevant finding that requests for G6PD enzyme analysis differed by gender and age. CONCLUSION In the northern region of Turkey, G6PD deficiency has a prevalence that is similar to other regions of Turkey, except the Mediterranean region. It is an important cause of neonatal hyperbilirubinemia and hemolytic crisis in children and adults. Pediatricians requested G6PD enzyme assays less often in female patients that did internists. G6PD deficiency is not only a male disease. Female patients with G6PD deficiency are not as rare as expected. Prospective population screening, that includes females and DNA analysis, is recommended to determine the prevalence of G6PD deficiency in this region. Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES [1] Lanzkowsky P, ed. Manual of Pediatric Hematology and Oncology (5th ed.). New York: Elsevier; 2011:168–199. [2] Kaplan M, Hammerman C. Glucose-6-phosphate dehydrogenase deficiency: a worldwide potential cause of severe neonatal hyperbilirubinemia. Neo Rev. 2000;1:32–38. [3] Altay C, Gumr ¨ uk ¨ F. Red cell glucose-6-phosphate dehydrogenase deficiency in Turkey. Turk J Hematol. 2008;25:1–7. [4] Atay E, Bozaykut A, Ipek IO. Glucose-6-phosphate dehydrogenase deficiency in neonatal indirect hyperbilirubinemia. J Trop Pediatr. 2006;52:56–58. [5] Celik HT, Gunbey ¨ C, Unal S, et al. Glucose-6-phosphate dehydrogenase deficiency in neonatal hyperbilirubinaemia: hacettepe experience. J Paediatr Child Health. 2013;49:399–402. [6] Liu H, Liu W, Tang X, Wang T. Association between G6PD deficiency and hyperbilirubinemia in neonates: a meta-analysis. Pediatr Hematol Oncol. 2014. doi:10.3109/08880018.2014.887803. [7] Luzzatto L, Seneca E. G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications. Br J Hematol. 2014;164:469–480. [8] Pamba A, Richardson ND, Carter N, et al. Clinical spectrum and severity of hemolytic anemia in glucose 6-phosphate dehydrogenase-deficient children receiving dapsone. Blood. 2012;120:4123–4133. [9] Martinez Di Montemuros F, Dotti C, Tavazzi D, et al. Molecular heterogeneity of glucose-6phosphate dehydrogenase (G6PD) variants in Italy. Haematologica. 1997;82:440–445. Pediatric Hematology and Oncology
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