G-6-PD Deficiency-Induced Hemolysis in Diabetic Twins
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《交互式心脏血管和胸部手术医学期刊》
the Department of Biotechnology, IGSR, Alexandria University, Alexandria, Egypt.
Abstract:
We report hemolysis due to glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in two Egyptian monozygotic brothers, at the onset of diabetes type 1. Hemolysis occurred following the treatment of hyperglycemia and ketoacidosis (one twin). It was related to unknown G-6-PD deficiency. The fall in glucose availability after the treatment of hyper-glycemia is proposed as a possible etiology for hemolysis.
Key words: Glucose-6-phosphate dehydrogenase deficiency, Hemolysis, IgA, Type 1 diabetes.
Type 1 diabetes mellitus is characterized by insulin deficiency resulting from immune-mediated pancreatic beta-cell destruction. It has been reported that the incidence of childhood type 1 diabetes mellitus has increased in recent years(1). Glucose-6-phosphate dehydrogenase (G-6-PD) is a cytoplasmic enzyme expressed in all tissues, that is essential for a cell’s capacity to withstand oxidant stress. G-6-PD deficiency is the commonest enzymopathy of humans, affecting over 400million people worldwide and is one of the important causes of hemolytic anemia and neonatal jaundice(2,3). Blood glucose normalization-induced hemolysis in three adolescents with type 1 diabetes mellitus at onset associated with unknown G-6-PD deficiency has been reported(4). We report the occurrence of hemolysis due to G-6-PD deficiency in a pair of male twins following the control of hyperglycemia in DKA.
Case Report
Case record: Twin 1
A 4-year-old boy was hospitalized in May 2002 for severe ketoacidosis (Table I). Two days after rehydration and treatment with continuous i.v. insulin infusion (0.05-0.1 IU/kg BW/h) ketoacidosis remission was easily obtained. He then received subcutaneous intensive insulin injection therapy (1.0 IU/kg BW/24-h: three regular times before meals and one intermediate before bedtime). Euglycemia was attained within 4 days with blood glucose concentrations ranging from 105-165 mg/dL. On day 7 he developed jaundice and pallor. Hematological evaluation at that time showed the following: hemoglobin level (Hb) 10.3 g/dL, reticulocytes 10%, direct bilirubin 1.77 mg/dL, increased urobilinogen in urine. The diagnosis of hemolytic anemia was considered. Causes for hemolytic anemia such as hereditary hemoglobinopathies, hereditary sphero-cytosis and autoimmune hemolytic anemia–due to drugs or infection–were excluded (normal Hb electrophoresis, normal red blood cell resistance, negative Coombs reaction and absence of cryoimmunoglobulins in the blood). Hemolytic anemia was due to G-6-PD deficiency (0 IU/1012 erythrocytes, Sigma enzymatic quantitative method, normal values140-370). Hemolysis ceased spontaneously and hemoglobin increased gradually over next 3 weeks.
Case record: Twin 2
The twin brother of the patient above was hospitalized on the same admission day for polyuria. Hematological and biochemical examination on admission are shown in Table I. He received a 48 h subcutaneous intensive insulin injection therapy (1.0 IU/kg BW/ 24-h: three regular times before meals and one intermediate before bedtime). This was followed by subcutaneous 12 hourly injections of mixed insulin (regular and intermediate) at the same dose as above. Blood glucose concentrations became normal by the 4th day and ranged between 85 and 145 mg/dL. On the 7th day he also developed jaundice and pallor. Hematological assessment diagnosed hemolysis: Hb 8.1 g/dL, reticulocytes 12%, direct bilirubin 5.5 mg/dL. Causes for hemolytic anemia such as hereditary hemo-globinopathies, hereditary spherocytosis and autoimmune hemolytic anemia–due to drugs or infection–were excluded (normal Hb electrophoresis, normal red blood cell resistance, negative Coombs reaction and absence of cryoimmunoglobulins in the blood). Hemolytic anemia was due to G-6-PD deficiency. Hemolysis ceased spontaneously and hemoglobin increased gradually.
Discussion
The most interesting point in this report is the fact that both twins developed diabetes mellitus type 1 concurrently, and also the fact that they both had G-6-PD deficiency and developed a hemolytic syndrome. The concurrent manifestation of diabetes mellitus type 1 in these twins implies that the prenatal or early postnatal period during which the twins were exposed to the same environment may have played an important role in addition to their being genetically identical(5). A higher prevalence of G-6-PD deficiency is reported in patients with diabetes mellitus type 1 than in healthy population(6). An explanation has been put forward to explain why patients with diabetes type 1, who are more likely to have G-6-PD deficiency, are, therefore, prone to develop hemolysis under certain conditions, such as drug administration, food (fava beans), toxic agents (naphthalene) or infections. However, during the hemolytic episode, neither of the twins was exposed to any of the above agents. Hemolysis due to G-6-PD deficiency has been reported in patients with diabetes type 1 having hyperglycemia or hypoglycemia(7). Ketoacidosis as a cause of hemolysis in these patients is controversial(8). A report from Alexandria(8) supports the concept that the Mediterranean type variant of G-6-PD deficiency may be complicated by hemolysis in diabetes mellitus type 1. Hemolysis appeared when hyperglycemia was corrected and relative euglycemia was obtained. It was speculated that the blood glucose normalization in diabetes induced a stressing glucose deprivation for the energy dependent functions of red blood cells similar to that which results from repeated episodes of hyperglycemia(8). There is a similarity of the hemolytic syndrome noticed by these twin brothers at the onset of diabetes mellitus type 1 to that reported in three Italian adolescents(4). There have been very few reports in the literature. It is a rare manifestation even in areas in which diabetes and G-6-PD deficiency are common such as Sardinia(4,9). The Mediterranean type variant of G-6-PD deficiency may be complicated by hemolytic crises in diabetes type 1 regardless of the severity of ketoacidosis. In conclusion, hemolysis may be attributed to relative hypoglycemia during hyperglycemia correction. G-6-PD should be assessed in diabetic type 1 patients and in case of deficiency one should be less aggressive in treating hyperglycemia to avoid rapidly induced euglycemia, which may cause hemolysis in these patients. If hemolysis does occur, however, the patient recovers spontaneously.
Funding: None
Competing interest: None declared.
References
1. Kida K, Mimura G, Ito T, Murakami K, Ashkenazi I, Larson, Z. Incidence of type 1 diabetes mellitus in children aged 0-14 in Japan, 1986-1990, including an analysis for seasonality of onset and month of birth: JDS study. The data committee for childhood diabetes of Japan Diabetes Society (JDS). Diabetes Med 2000; 17: 59-63.
2. Ruwende C, Hill A. Glucose-6-phosphate dehydrogenase deficiency and malaria. J Mol Med1998; 76: 581-588.
3. Wan GH, Tsai SC, Chiu DT. Decreased blood activity of glucose-6-phosphate dehydrogenase associated with increased risk for dia-betes mellitus. Endocrine 2002; 19: 191-195.
4. Vanelli M, Lucentini L, Picco P, Galanello R, Chiari G, Adinolfi B, et al. Blood glucose normalization-induced haemolysis in three adolescents with type 1 diabetes mellitus at onset and unknown G-6-PD deficiency. J Pediatr Endocr Metab 1996; 9: 193-196.
5. Petersen JS, Kyvik KO, Bingley PJ, Gale EA, Green A, Dyrberg T, et al. Population based study of prevalence of islet cell autoantibodies in monozygotic and dizygotic Danish twin pairs with insulin dependent diabetes mellitus. Br Med J 1997; 314: 1575-1579.
6. Niazi GA. Glucose-6-phosphate dehydrogenase deficiency and diabetes mellitus. Int J Hematol 1991; 54: 295-298.
7. Shalev O, Eliakim R, Lugassy GZ, Menczel J. Hypoglycemia-induced hemolysis in glucose-6-phosphate dehydrogenase deficiency. Acta Haematol 1985; 74: 227-229.
8. Shalev O, Wollner A, Menczel J. Diabetes ketoacidosis does not precipitate haemolysis in patients with the Mediterranean variant of glucose - 6 - phosphate dehydrogenase deficiency. B Med J 1984; 288: 179-180.
9. Pietrapertosa A, Palma A, Campanale D, Delios G, Vitucci A, Tannoia N. Genotype and phenotype correlation in glucose-6-phosphate dehydrogenase deficiency. Hematol 2001; 86: 30-35.(Medhat Haroun)
Abstract:
We report hemolysis due to glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in two Egyptian monozygotic brothers, at the onset of diabetes type 1. Hemolysis occurred following the treatment of hyperglycemia and ketoacidosis (one twin). It was related to unknown G-6-PD deficiency. The fall in glucose availability after the treatment of hyper-glycemia is proposed as a possible etiology for hemolysis.
Key words: Glucose-6-phosphate dehydrogenase deficiency, Hemolysis, IgA, Type 1 diabetes.
Type 1 diabetes mellitus is characterized by insulin deficiency resulting from immune-mediated pancreatic beta-cell destruction. It has been reported that the incidence of childhood type 1 diabetes mellitus has increased in recent years(1). Glucose-6-phosphate dehydrogenase (G-6-PD) is a cytoplasmic enzyme expressed in all tissues, that is essential for a cell’s capacity to withstand oxidant stress. G-6-PD deficiency is the commonest enzymopathy of humans, affecting over 400million people worldwide and is one of the important causes of hemolytic anemia and neonatal jaundice(2,3). Blood glucose normalization-induced hemolysis in three adolescents with type 1 diabetes mellitus at onset associated with unknown G-6-PD deficiency has been reported(4). We report the occurrence of hemolysis due to G-6-PD deficiency in a pair of male twins following the control of hyperglycemia in DKA.
Case Report
Case record: Twin 1
A 4-year-old boy was hospitalized in May 2002 for severe ketoacidosis (Table I). Two days after rehydration and treatment with continuous i.v. insulin infusion (0.05-0.1 IU/kg BW/h) ketoacidosis remission was easily obtained. He then received subcutaneous intensive insulin injection therapy (1.0 IU/kg BW/24-h: three regular times before meals and one intermediate before bedtime). Euglycemia was attained within 4 days with blood glucose concentrations ranging from 105-165 mg/dL. On day 7 he developed jaundice and pallor. Hematological evaluation at that time showed the following: hemoglobin level (Hb) 10.3 g/dL, reticulocytes 10%, direct bilirubin 1.77 mg/dL, increased urobilinogen in urine. The diagnosis of hemolytic anemia was considered. Causes for hemolytic anemia such as hereditary hemoglobinopathies, hereditary sphero-cytosis and autoimmune hemolytic anemia–due to drugs or infection–were excluded (normal Hb electrophoresis, normal red blood cell resistance, negative Coombs reaction and absence of cryoimmunoglobulins in the blood). Hemolytic anemia was due to G-6-PD deficiency (0 IU/1012 erythrocytes, Sigma enzymatic quantitative method, normal values140-370). Hemolysis ceased spontaneously and hemoglobin increased gradually over next 3 weeks.
Case record: Twin 2
The twin brother of the patient above was hospitalized on the same admission day for polyuria. Hematological and biochemical examination on admission are shown in Table I. He received a 48 h subcutaneous intensive insulin injection therapy (1.0 IU/kg BW/ 24-h: three regular times before meals and one intermediate before bedtime). This was followed by subcutaneous 12 hourly injections of mixed insulin (regular and intermediate) at the same dose as above. Blood glucose concentrations became normal by the 4th day and ranged between 85 and 145 mg/dL. On the 7th day he also developed jaundice and pallor. Hematological assessment diagnosed hemolysis: Hb 8.1 g/dL, reticulocytes 12%, direct bilirubin 5.5 mg/dL. Causes for hemolytic anemia such as hereditary hemo-globinopathies, hereditary spherocytosis and autoimmune hemolytic anemia–due to drugs or infection–were excluded (normal Hb electrophoresis, normal red blood cell resistance, negative Coombs reaction and absence of cryoimmunoglobulins in the blood). Hemolytic anemia was due to G-6-PD deficiency. Hemolysis ceased spontaneously and hemoglobin increased gradually.
Discussion
The most interesting point in this report is the fact that both twins developed diabetes mellitus type 1 concurrently, and also the fact that they both had G-6-PD deficiency and developed a hemolytic syndrome. The concurrent manifestation of diabetes mellitus type 1 in these twins implies that the prenatal or early postnatal period during which the twins were exposed to the same environment may have played an important role in addition to their being genetically identical(5). A higher prevalence of G-6-PD deficiency is reported in patients with diabetes mellitus type 1 than in healthy population(6). An explanation has been put forward to explain why patients with diabetes type 1, who are more likely to have G-6-PD deficiency, are, therefore, prone to develop hemolysis under certain conditions, such as drug administration, food (fava beans), toxic agents (naphthalene) or infections. However, during the hemolytic episode, neither of the twins was exposed to any of the above agents. Hemolysis due to G-6-PD deficiency has been reported in patients with diabetes type 1 having hyperglycemia or hypoglycemia(7). Ketoacidosis as a cause of hemolysis in these patients is controversial(8). A report from Alexandria(8) supports the concept that the Mediterranean type variant of G-6-PD deficiency may be complicated by hemolysis in diabetes mellitus type 1. Hemolysis appeared when hyperglycemia was corrected and relative euglycemia was obtained. It was speculated that the blood glucose normalization in diabetes induced a stressing glucose deprivation for the energy dependent functions of red blood cells similar to that which results from repeated episodes of hyperglycemia(8). There is a similarity of the hemolytic syndrome noticed by these twin brothers at the onset of diabetes mellitus type 1 to that reported in three Italian adolescents(4). There have been very few reports in the literature. It is a rare manifestation even in areas in which diabetes and G-6-PD deficiency are common such as Sardinia(4,9). The Mediterranean type variant of G-6-PD deficiency may be complicated by hemolytic crises in diabetes type 1 regardless of the severity of ketoacidosis. In conclusion, hemolysis may be attributed to relative hypoglycemia during hyperglycemia correction. G-6-PD should be assessed in diabetic type 1 patients and in case of deficiency one should be less aggressive in treating hyperglycemia to avoid rapidly induced euglycemia, which may cause hemolysis in these patients. If hemolysis does occur, however, the patient recovers spontaneously.
Funding: None
Competing interest: None declared.
References
1. Kida K, Mimura G, Ito T, Murakami K, Ashkenazi I, Larson, Z. Incidence of type 1 diabetes mellitus in children aged 0-14 in Japan, 1986-1990, including an analysis for seasonality of onset and month of birth: JDS study. The data committee for childhood diabetes of Japan Diabetes Society (JDS). Diabetes Med 2000; 17: 59-63.
2. Ruwende C, Hill A. Glucose-6-phosphate dehydrogenase deficiency and malaria. J Mol Med1998; 76: 581-588.
3. Wan GH, Tsai SC, Chiu DT. Decreased blood activity of glucose-6-phosphate dehydrogenase associated with increased risk for dia-betes mellitus. Endocrine 2002; 19: 191-195.
4. Vanelli M, Lucentini L, Picco P, Galanello R, Chiari G, Adinolfi B, et al. Blood glucose normalization-induced haemolysis in three adolescents with type 1 diabetes mellitus at onset and unknown G-6-PD deficiency. J Pediatr Endocr Metab 1996; 9: 193-196.
5. Petersen JS, Kyvik KO, Bingley PJ, Gale EA, Green A, Dyrberg T, et al. Population based study of prevalence of islet cell autoantibodies in monozygotic and dizygotic Danish twin pairs with insulin dependent diabetes mellitus. Br Med J 1997; 314: 1575-1579.
6. Niazi GA. Glucose-6-phosphate dehydrogenase deficiency and diabetes mellitus. Int J Hematol 1991; 54: 295-298.
7. Shalev O, Eliakim R, Lugassy GZ, Menczel J. Hypoglycemia-induced hemolysis in glucose-6-phosphate dehydrogenase deficiency. Acta Haematol 1985; 74: 227-229.
8. Shalev O, Wollner A, Menczel J. Diabetes ketoacidosis does not precipitate haemolysis in patients with the Mediterranean variant of glucose - 6 - phosphate dehydrogenase deficiency. B Med J 1984; 288: 179-180.
9. Pietrapertosa A, Palma A, Campanale D, Delios G, Vitucci A, Tannoia N. Genotype and phenotype correlation in glucose-6-phosphate dehydrogenase deficiency. Hematol 2001; 86: 30-35.(Medhat Haroun)