European Journal of Haematology
CASE REPORT
Glucose-6-phosphate dehydrogenase deficiency: an unusual cause of acute jaundice after paracetamol overdose Simon Phillpotts, Elliot Tash, Sambit Sen Department of Gastroenterology, Luton and Dunstable University Hospital NHS Trust, Luton, UK
Abstract Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest human enzyme defect causing haemolytic anaemia after exposure to specific triggers. Paracetamol-induced haemolysis in G6PD deficiency is a rare complication and mostly reported in children. We report the first case (to the best of our knowledge) of acute jaundice without overt clinical features of a haemolytic crisis, in an otherwise healthy adult female following paracetamol overdose, due to previously undiagnosed G6PD deficiency. It is important that clinicians consider this condition when a patient presents following a paracetamol overdose with significant and disproportionate jaundice, without transaminitis or coagulopathy. Key words paracetamol; haemolysis; anaemia; Glucose-6-phosphate deficiency; Glucose-6-phosphate dehydrogenase Correspondence Dr Simon Phillpotts, Department of Gastroenterology, Luton and Dunstable University Hospital, Lewsey Road, Luton, Bedfordshire LU4 0DZ, UK. e-mail: [email protected] Accepted for publication 24 March 2014
Glucose-6-phosphate dehydrogenase (G6PD) is a catalytic enzyme involved in the production of nicotinamide adenine dinucleotide phosphate (NADPH) via the pentose phosphate pathway. NADPH provides an erythrocyte cell membrane defence against oxidative damage (1). Glucose-6-phosphate dehydrogenase deficiency is the most common human enzyme defect, affecting over 400 million people worldwide. It is prevalent in malarial endemic areas: Africa, Southern Europe, the Middle East, South-East Asia and Pacific islands (1). The majority of people with G6PD deficiency remain asymptomatic. However, they may develop neonatal jaundice or haemolytic anaemia, the latter due to specific triggers such as fava beans, infections and drugs (2). Paracetamol is the most common drug taken in overdose in the UK and accounts for 48% of admissions to poisons units, resulting in 100–200 deaths per year, usually due to liver failure (3). Paracetamol-induced haemolysis due to G6PD deficiency is a rare complication (4–8), usually reported in children. Presentation with acute jaundice without the typical and more common features of a haemolytic crisis in adults has very rarely been reported (9).
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
doi:10.1111/ejh.12330
Case report
A 27-year-old female of Pakistani origin was admitted to hospital following an intentional 11 g (196 mg/kg) paracetamol overdose. She had no past medical or drug history and specifically had never been jaundiced or anaemic. She had three healthy children and was unaware of any family history of haematological disorders. A 4-hour postingestion paracetamol level was 129 mg/L [treatment level for N-acetylcysteine (NAC) being 100 mg/ L] and was therefore administered intravenous NAC according to the national guidelines (10). Within 36 h, she developed significant jaundice (total bilirubin 145 lM from 35 lM), but unusually for paracetamol overdose, all liver enzymes remained entirely normal, as did the prothrombin time (at presentation and throughout admission). She was clinically very stable, with no evidence of encephalopathy or renal dysfunction. The jaundice was therefore disproportionate and unexpected. There were no clinical features of a typical haemolytic crisis, and only after closer scrutiny of her full blood count was a mild anaemia (haemoglobin: 96 g/L from 113 g/L) noted, suggesting jaundice secondary to haemolysis. The bilirubin was then split
1
Phillpotts et al.
Paracetamol-induced haemolysis in G6PD
and was found to be predominantly unconjugated (conjugated fraction 3 lM). The overall clinical scenario suggested a previously undiagnosed haemolytic disorder presenting solely with jaundice, precipitated by paracetamol overdose. Subsequent investigation on day three of her admission showed a negative direct coombs test and normal haemoglobin electrophoresis, however confirmed G6PD deficiency on enzyme assay (4.74 IU/gHb). Within 4 d of ingestion, her bilirubin had begun to normalise (42 lM). Discussion
There has been conflicting evidence over whether paracetamol can induce haemolysis through G6PD deficiency. A randomised controlled trial in children concluded that it did not (5). Conversely, a number of case reports do suggest a causal link between haemolytic episodes in those with known G6PD deficiency and paracetamol ingestion (4, 6–8). There are very few reports of G6PD deficiency being diagnosed as a result of a haemolytic episode following paracetamol ingestion (11, 12). We found only one previous report of an adult male presenting with acute jaundice, rather than the typical features of a haemolytic crisis, following paracetamol overdose, where subsequent investigations revealed haemolysis, leading to a diagnosis of previously undetected G6PD deficiency (9). It has been reported that NAC does not cause haemolysis (7) and may confer some protection to the erythrocyte cell membrane through an increase in NADPH (1), a cofactor that reduces glutathione. Glutathione enters the seleniumdependent glutathione peroxidase pathway detoxifying hydrogen peroxide and organic peroxides, protecting the erythrocytes against oxidative stress that may ultimately lead to haemolysis (13). As patients with G6PD deficiency have reduced NADPH and glutathione levels, any ‘boost’ to these pathways resulting in a reduction in oxidative damage must be advantageous. Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive condition, commonly affecting males. Having two X chromosomes means that females with one defective gene (heterozygote) will be normal carriers. Less commonly, those inheriting two defective genes (often born from a consanguineous relationship) develop the deficient (homozygous) phenotype. Rarely, the heterozygous female can manifest enzyme deficiency (2), due to inactivation of one X chromosome ‘lyonisation’. Our patient did not give any family history of consanguinity. We report the first case (to the best of our knowledge) of acute jaundice without overt clinical features of a haemolytic crisis, in an otherwise healthy adult female following paracetamol overdose, due to previously undiagnosed G6PD deficiency. It is important that clinicians consider this condition when a patient presents following a paracetamol overdose with significant and disproportionate jaundice, without
2
transaminitis or coagulopathy. The haemolysis may be quite subtle, as in this case, and only evident on subsequent laboratory investigations (such as spilt bilirubin and haemolysis work up). In today’s geographically mobile population, G6PD is no longer limited to malarial endemic areas, just as this case was encountered in the United Kingdom. Administering NAC to patients with known G6PD and an overdose of paracetamol may offer some protection against haemolysis, even if serum paracetamol levels are below conventional treatment thresholds (10). Funding
None. Disclosure
No conflict to declare. References 1. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008;371:64–74. 2. Luzzatto L. Glucose 6-phosphate dehydrogenase deficiency: from genotype to phenotype. Haematologica 2006;91:1303– 6. 3. Hawkins LC, Edwards JN, Dargan PI. Impact of restricting paracetamol pack sizes on paracetamol poisoning in the United Kingdom: a review of the literature. Drug Saf 2007;30:465–79. 4. Heintz B, Bock TA, Kierdorf H, Maurin N. Haemolytic crisis after acetaminophen in glucose-(6)-phosphate dehydrogenase deficiency. Klin Wochenschr 1989;67:1068. 5. Cottafava F, Nieri S, Franzone G, Sanguinetti M, Bertolazzi L. Ravera G [Double-blind controlled comparison of placebo and paracetamol in patients with G-6-PD deficiency]. Pediatr Med Chir 1990;12:631–7. 6. Wright RO, Perry HE, Woolf AD, Shannon MW. Hemolysis after acetaminophen overdose in a patient with glucose-6phosphate dehydrogenase deficiency. J Toxicol Clin Toxicol 1996;34:731–4. 7. Sklar GE. Hemolysis as a potential complication of acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency. Pharmacotherapy 2002;22:656– 8. 8. Oliver M, Coton T, Badens C, Dehan C, Lena-Russo D, Moalic JL. Homozygous G6PD deficiency and propacetamol induced hemolysis. Haematologica 2001;86:987–8. 9. Walz B, Riecken B. A young man with acute generalised jaundice and intermittent epigastric pain. Dtsch Med Wochenschr 2008;133:129–32. 10. Paracetamol overdose: new guidance on treatment with intravenous acetylcysteine. Drug Safety Update 2012;6:A1. Available from: http://www.mhra.gov.uk.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Phillpotts et al.
11. Ruha AM, Seldem B. Hemolytic anemia after acetaminophen overdose in patient with glucose-6-phosphate dehydrogenase deficiency. Am J Med 2001;110:240–1. 12. Minucci A, De Luca D, Torti E, Concolino P, Maurizi P, Giardina B, Zuppi C, Capoluongo E. Acute haemolytic crisis due to concomitant presence of infection and possible altered
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Paracetamol-induced haemolysis in G6PD
acetaminophen catabolism in a Philipino child carrying the G6PD-Vanua Lava mutation. Ann Clin Biochem 2011;48:282–5. 13. Aliciguzel Y, Aslan M. N-acetyl cysteine, L-cysteine, and beta-mercaptoethanol augment selenium-glutathione peroxidase activity in glucose-6-phosphate dehydrogenase-deficient human erythrocytes. Clin Exp Med 2004;4:50–5.
3
CASE REPORT
Glucose-6-phosphate dehydrogenase deficiency: an unusual cause of acute jaundice after paracetamol overdose Simon Phillpotts, Elliot Tash, Sambit Sen Department of Gastroenterology, Luton and Dunstable University Hospital NHS Trust, Luton, UK
Abstract Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest human enzyme defect causing haemolytic anaemia after exposure to specific triggers. Paracetamol-induced haemolysis in G6PD deficiency is a rare complication and mostly reported in children. We report the first case (to the best of our knowledge) of acute jaundice without overt clinical features of a haemolytic crisis, in an otherwise healthy adult female following paracetamol overdose, due to previously undiagnosed G6PD deficiency. It is important that clinicians consider this condition when a patient presents following a paracetamol overdose with significant and disproportionate jaundice, without transaminitis or coagulopathy. Key words paracetamol; haemolysis; anaemia; Glucose-6-phosphate deficiency; Glucose-6-phosphate dehydrogenase Correspondence Dr Simon Phillpotts, Department of Gastroenterology, Luton and Dunstable University Hospital, Lewsey Road, Luton, Bedfordshire LU4 0DZ, UK. e-mail: [email protected] Accepted for publication 24 March 2014
Glucose-6-phosphate dehydrogenase (G6PD) is a catalytic enzyme involved in the production of nicotinamide adenine dinucleotide phosphate (NADPH) via the pentose phosphate pathway. NADPH provides an erythrocyte cell membrane defence against oxidative damage (1). Glucose-6-phosphate dehydrogenase deficiency is the most common human enzyme defect, affecting over 400 million people worldwide. It is prevalent in malarial endemic areas: Africa, Southern Europe, the Middle East, South-East Asia and Pacific islands (1). The majority of people with G6PD deficiency remain asymptomatic. However, they may develop neonatal jaundice or haemolytic anaemia, the latter due to specific triggers such as fava beans, infections and drugs (2). Paracetamol is the most common drug taken in overdose in the UK and accounts for 48% of admissions to poisons units, resulting in 100–200 deaths per year, usually due to liver failure (3). Paracetamol-induced haemolysis due to G6PD deficiency is a rare complication (4–8), usually reported in children. Presentation with acute jaundice without the typical and more common features of a haemolytic crisis in adults has very rarely been reported (9).
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
doi:10.1111/ejh.12330
Case report
A 27-year-old female of Pakistani origin was admitted to hospital following an intentional 11 g (196 mg/kg) paracetamol overdose. She had no past medical or drug history and specifically had never been jaundiced or anaemic. She had three healthy children and was unaware of any family history of haematological disorders. A 4-hour postingestion paracetamol level was 129 mg/L [treatment level for N-acetylcysteine (NAC) being 100 mg/ L] and was therefore administered intravenous NAC according to the national guidelines (10). Within 36 h, she developed significant jaundice (total bilirubin 145 lM from 35 lM), but unusually for paracetamol overdose, all liver enzymes remained entirely normal, as did the prothrombin time (at presentation and throughout admission). She was clinically very stable, with no evidence of encephalopathy or renal dysfunction. The jaundice was therefore disproportionate and unexpected. There were no clinical features of a typical haemolytic crisis, and only after closer scrutiny of her full blood count was a mild anaemia (haemoglobin: 96 g/L from 113 g/L) noted, suggesting jaundice secondary to haemolysis. The bilirubin was then split
1
Phillpotts et al.
Paracetamol-induced haemolysis in G6PD
and was found to be predominantly unconjugated (conjugated fraction 3 lM). The overall clinical scenario suggested a previously undiagnosed haemolytic disorder presenting solely with jaundice, precipitated by paracetamol overdose. Subsequent investigation on day three of her admission showed a negative direct coombs test and normal haemoglobin electrophoresis, however confirmed G6PD deficiency on enzyme assay (4.74 IU/gHb). Within 4 d of ingestion, her bilirubin had begun to normalise (42 lM). Discussion
There has been conflicting evidence over whether paracetamol can induce haemolysis through G6PD deficiency. A randomised controlled trial in children concluded that it did not (5). Conversely, a number of case reports do suggest a causal link between haemolytic episodes in those with known G6PD deficiency and paracetamol ingestion (4, 6–8). There are very few reports of G6PD deficiency being diagnosed as a result of a haemolytic episode following paracetamol ingestion (11, 12). We found only one previous report of an adult male presenting with acute jaundice, rather than the typical features of a haemolytic crisis, following paracetamol overdose, where subsequent investigations revealed haemolysis, leading to a diagnosis of previously undetected G6PD deficiency (9). It has been reported that NAC does not cause haemolysis (7) and may confer some protection to the erythrocyte cell membrane through an increase in NADPH (1), a cofactor that reduces glutathione. Glutathione enters the seleniumdependent glutathione peroxidase pathway detoxifying hydrogen peroxide and organic peroxides, protecting the erythrocytes against oxidative stress that may ultimately lead to haemolysis (13). As patients with G6PD deficiency have reduced NADPH and glutathione levels, any ‘boost’ to these pathways resulting in a reduction in oxidative damage must be advantageous. Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive condition, commonly affecting males. Having two X chromosomes means that females with one defective gene (heterozygote) will be normal carriers. Less commonly, those inheriting two defective genes (often born from a consanguineous relationship) develop the deficient (homozygous) phenotype. Rarely, the heterozygous female can manifest enzyme deficiency (2), due to inactivation of one X chromosome ‘lyonisation’. Our patient did not give any family history of consanguinity. We report the first case (to the best of our knowledge) of acute jaundice without overt clinical features of a haemolytic crisis, in an otherwise healthy adult female following paracetamol overdose, due to previously undiagnosed G6PD deficiency. It is important that clinicians consider this condition when a patient presents following a paracetamol overdose with significant and disproportionate jaundice, without
2
transaminitis or coagulopathy. The haemolysis may be quite subtle, as in this case, and only evident on subsequent laboratory investigations (such as spilt bilirubin and haemolysis work up). In today’s geographically mobile population, G6PD is no longer limited to malarial endemic areas, just as this case was encountered in the United Kingdom. Administering NAC to patients with known G6PD and an overdose of paracetamol may offer some protection against haemolysis, even if serum paracetamol levels are below conventional treatment thresholds (10). Funding
None. Disclosure
No conflict to declare. References 1. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008;371:64–74. 2. Luzzatto L. Glucose 6-phosphate dehydrogenase deficiency: from genotype to phenotype. Haematologica 2006;91:1303– 6. 3. Hawkins LC, Edwards JN, Dargan PI. Impact of restricting paracetamol pack sizes on paracetamol poisoning in the United Kingdom: a review of the literature. Drug Saf 2007;30:465–79. 4. Heintz B, Bock TA, Kierdorf H, Maurin N. Haemolytic crisis after acetaminophen in glucose-(6)-phosphate dehydrogenase deficiency. Klin Wochenschr 1989;67:1068. 5. Cottafava F, Nieri S, Franzone G, Sanguinetti M, Bertolazzi L. Ravera G [Double-blind controlled comparison of placebo and paracetamol in patients with G-6-PD deficiency]. Pediatr Med Chir 1990;12:631–7. 6. Wright RO, Perry HE, Woolf AD, Shannon MW. Hemolysis after acetaminophen overdose in a patient with glucose-6phosphate dehydrogenase deficiency. J Toxicol Clin Toxicol 1996;34:731–4. 7. Sklar GE. Hemolysis as a potential complication of acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency. Pharmacotherapy 2002;22:656– 8. 8. Oliver M, Coton T, Badens C, Dehan C, Lena-Russo D, Moalic JL. Homozygous G6PD deficiency and propacetamol induced hemolysis. Haematologica 2001;86:987–8. 9. Walz B, Riecken B. A young man with acute generalised jaundice and intermittent epigastric pain. Dtsch Med Wochenschr 2008;133:129–32. 10. Paracetamol overdose: new guidance on treatment with intravenous acetylcysteine. Drug Safety Update 2012;6:A1. Available from: http://www.mhra.gov.uk.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Phillpotts et al.
11. Ruha AM, Seldem B. Hemolytic anemia after acetaminophen overdose in patient with glucose-6-phosphate dehydrogenase deficiency. Am J Med 2001;110:240–1. 12. Minucci A, De Luca D, Torti E, Concolino P, Maurizi P, Giardina B, Zuppi C, Capoluongo E. Acute haemolytic crisis due to concomitant presence of infection and possible altered
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Paracetamol-induced haemolysis in G6PD
acetaminophen catabolism in a Philipino child carrying the G6PD-Vanua Lava mutation. Ann Clin Biochem 2011;48:282–5. 13. Aliciguzel Y, Aslan M. N-acetyl cysteine, L-cysteine, and beta-mercaptoethanol augment selenium-glutathione peroxidase activity in glucose-6-phosphate dehydrogenase-deficient human erythrocytes. Clin Exp Med 2004;4:50–5.
3
