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Thrombocytopenic purpura and anemia in a breast-fed infant whose mother was treated with valproic acid
The Journal of Pediatrics' Volume 130, Number 6
StahI, Neiderud, and Vinge
100 1
Thrombocytopenic purpura and anemia in a breast-fed infant whose mother was treated with valproic acid Malffhias M, S. Stahl, MD, Jan Neiderud, MD, PhD, a n d Ellen Vinge, MD, PhD From the Pharmacoepidemiology Unit, The Medical Products Agency, Uppsala, the Department of Paediatrics, County Hospital, Helsingborg, and the Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden Valproic acid is an antiepileptic drug in widespread use. The possibility of various hematologic side effects with this drug is well recognized. We describe a breastfed infant with thrombocytopenic purpura, anemia, and reticulocytosis, whose mother was treated with valproic acid. As the mother stopped breast-feeding, the infant recovered. (J Pediatr 1997; 130:1001-3) CASE
RE]PORT
A 3-month.-old male infant, whose mother was treated with sodium valproate, 600 mg twice daily, as monotherapy for epilepsy, had a 2-week history of increasing petechiae and minor hematoma on the lower part of the legs. Petechiae were also found on the face, the mink, and the arms. The infant had a slight cold and was pale, but otherwise physical examination was unremarkable. Rectal temperature was 37.2 ° C. Platelet count was 7 x 109/I, (reference range, 125 to 400 x 109/L),blood hemoglobin, 82 gm/L (reference range, 131 to 163 gin/L), and mean corpuscular volume, 78 fl (reference range, 82 to 105 fl). The differential count showed a small increase in leukocyte count (12.1 x 109/[,; reference range, 4.0 to 10.0 x 109/L) and a lymphocytosis (8.0 x 109/L; reference range, 1.2 to 4.0 x 109fL). Sedimentation rate was 10 mm/hr, and C-reactive protein was not increased. The mother' s platelet count was 113 x 109/L(other hematologic parameters were not analyzed in the mother, but 1 week earlier, her blood hemoglobin was 118 gin/L). Serum valproic acid was 46 Nnol/L (6.6 pg/ml) in the infant (therapeutic range for adults, 350 to 7130 Nnol/L, corresponding to 50 to 100 pg/ml). During the following month, the platelet count ranged between 2 and 4 x 109/L (Figure), and new petechiae continued to appear, but the patient's condition was stable. There was reticulocytosis (4.9% to 5.5%; reference range, 0.2% to 1.5%); blood hemoglobin was 80 to 95 gin/L; and mean corpuscular volume was 76 to 81 fl. A blood smear showed normal findings, and spherocytes were absent. Testing for osmotic fragility was normal. Serum haptoglobin 2 days after admission was low (0.06 gin/L; reference range, 0.45 to 2.75 gmfL) but had increased to 1.27 gm/L 1.5 months later. The leukocyte differential count remained essentially unchanged. There was no hematuria, and fecal occult blood test results were negative. Liver test results were normal, including bilirubin and albumin levSubmitted for publication Aug. 7, 1996; accepted Oct. 10, 1996. Reprint requests: Matthias Stahl, MD, Pharmacia & Upjohn, Consumer Healthcare, Box 941, S-25109 Helsingborg, Sweden. Copyright © 1997 by Mosby-Year Book, Inc. 0022-3476/97/$5.00 + 0 9/22/78634
els. The serum creatinine level was likewise normal. Serologic test results for toxoplasmosis, rubella, cytomegalovirus, and herpes simplex vires were negative, both in the child and the mother, and there were no antibodies against thrombocyte-specific antigens (Capmre-P method). Direct Coombs test and a bone marrow examination were not performed. Because the child was well and happy and signs of ongoing bleeding were absent, there was a decision to "wait and see," according to the policy of the department. Eight days after admission, the mother interrupted breast-feeding for 5 days without any change in the platelet count. After 1 month, she stopped breast-feeding (platelet count was then 2 x 109/%). Five, 12, and 19 days later, the platelet counts were 3, 3, and 9 x 109/L, respectively (Figure). On day 12 after cessation of breast-feeding, valproic acid was not detectable in the serum of the infant. On days 35, 83, and 87, the platelet count had increased to 113, 313, and 400 x 109/L, respectively, and around day 35, the petechiae had resolved. A normalization of blood hemoglobin and the reticulocytes occurred between days 12 and 19. At age 815 months, platelet count was 396 x 109/L. DISCUSSION To our knowledge, this is the first report of an infant with thrombocytopenia and anemia presumably induced by valproic acid transfer through breast milk. Valproic acid may cause a variety of blood cell disorders including bone marrow toxicity. 1, 2 Immune hemolytic anemia 3 and erythrocyte aplasia 4 have been reported. In a study of 60 patients (average age 14.6 years) receiving long-term valproate therapy, one third of the patients demonstrated at least one hematologic abnormality. 1 The most common findings were thrombocytopenia and macrocytosis. ] Reticulocytosis occurs in some patients but does not seem to account for the macrocytosis, nor do deficiencies of folate or vitamin B12.1 A few patients also have anemia. 1 With regard to thrombocytopenia, the mechanism may be immunologic or concentration dependent. 5-7 In a study of 306 children with epilepsy with a mean age of 9.1 years (range, 1 to 18 years) and treated with
10 0 2
Stahl, Neiderud, and Vinge
The Journal of Pediatrics June 1997
5-500 E ~400 "o°¢
E
.300 m_.
.200 8 t-"
,100 ~-
IPetechiael ~
i ,Breast - feedinq
I H
t~
1.5
v
-o
1.0 0.5
p
i i ii i i iili i iiiiiiiiii ]ii i I
._~ 0.0 ,~2:::::::::::~................. :':':i...................... ;............... ~.................. ;::'::;.............. ::::::::::::::::::::::................. ~...................................... "i...................................... ~....................................... i ...................................... , -5 0 5 10 15 20 25 30 , 35 > Weeks
Figure. Thrombocytopenic purpura in a breast-fed infant whose mother was treated with valproic acid. Recovery of the platelet count is seen after cessation of breast-feeding.
valproic acid, thrombocytopenia developed in 64 (platelet count, -<150 x 109/L).7 Platelet levels less than 100 x 109/L were seen in 32 patients (mean platelet count, 76 x 109/L; range, 18 to 99x 109/L); the mean peak valproate level was 1158 pmol/L (167 pg/ml) with a range from 686 to 1428 ~ o F L (99 to 206 lag/ml). Signs of bleeding developed in eight patients (diffuse petechiae, hematomas, or nose bleeding).7 The half-life of valproic acid in newborn infants has been estimated to be 47 + 15 hours (range, 32 to 80 hours) and in infants between 10 days and 2 months, half-lives of 9 to 22 hours were found. 8 In older infants, the half-lives were 7 to 12 hours, s The valproic acid metabolite profile has been determined in infants of around age 4 months and older after oral dosing. 9 The main metabolites considered potentially toxic were found in low concentrations in plasma, but the interindividual variability was large and the half-lives were not calculated.9 In samples of breast milk, valproic acid and one of its metabolites (3-keto) were present in concentrations that were 2.7% and 7.4% of those in maternal serum, respectively, but toxic metabolites were not analyzed. 8' 10No data were found on serum concentrations of metabolites of valproic acid in breast-fed infants at age 3 months or older. The possible role of the metabolites in the development of thrombocytopenia or other blood cell disorders is unknown. It seems unlikely that transplacental transfer of valproic acid contributed to any greater extent to the thrombocytopenia in our case because there were no petechiae immediately after birth, in spite of the physical stress during delivery. It is noticeable that
5 weeks after defivery, the dose was doubled (3 weeks later, the mother's serum valproic acid was 548 pmol/L [i.e., 79 Ng/ml]), and the infant's petechiae appeared 6 weeks later. Initial serum haptoglobin was low, possibly indicating hemolysis. However, haptoglobin determinations are difficult to interpret at this age because very low values of haptoglobin may be seen in healthy infants and children. The thrombocytopenia and anemia remained unchanged for about 1 month. The concomitant depression of both platelets and hemoglobin is not typical of idiopathic thrombocytopenic purpura. Furthermore, because the abnormalities seen are well known with valproic acid, the association in time, the normalization of platelets, hemoglobin, and reticulocytes between 12 and 35 days after breast-feeding was stopped, and the fact that no other cause was found in spite of extensive investigations argue for valproic acid or its metabolites or both transferred by breast milk as the cause. However, a concentration-dependent toxic effect of the parent drug alone seems less likely because of its low concentration in the infant. The possibility of valproic acid causing hematologic adverse effects in the infant by transfer to breast milk should be borne in mind. REFERENCES
1. May RB' Sunder TR' Hemat°l°gic manifestati°ns °f l°ng-term valproate therapy. Epilepsia 1993;34:1098-101. 2. Ganick DJ, Sunder T, Finley JL. Severe hematologic toxicity of valproic acid: a report of four patients. Am J Pediatr Hematol Oncol 1990;12:80-5. 3. Kaya IS, Dilmen U, Toppare M, Senses DA. Valproic acid-in-
The Journal of Pediatrics Volume 130, Number 6
4. 5.
6.
7.
duced pancytopenia and Coomb's test positivity. Lancet 1991; 337:1227-8. MacDougall LG. Pure red cell aplasia associated with sodium valproate ~:herapy.JAMA 1982;257:53-4. Ban" RD, C0peland SA, Stockwell ML, Morris N, Kelton JC. Valproic acid and immune thrombocytopenia. Arch Dis Child 1982;57:681-4. Gidal B, Spencer N, Maly M, Pitterle M, Williams E, Collins M, et al. Valproate-mediateddisturbancesof hemostasis:relationship to dose and plasma concentration.Neurology 1994;44:1418-22. Delgado MR, Riela AR, Mills J, Browne R, Roach S. Thrombocytopenia secondary to high valproate levels in children with epilepsy. J Child Neurol 1994;9:311-4.
Mawal, Paradis, and Qureshi
1003
8. Nan H, Kuhnz W, Egger H-J, Rating D, Helge H. Anficonvulsants during pregnancy and lactation: transplacental, maternal and neonatal pharmacokinetics. Clin Phaxmacoldnet 1982;7: 508-43. 9. Battino D, Estienne M, Avanzini G. Clinical pharmacokinefics of antiepileptic drugs in paediatric patients, part I, phenobarbital, primidone, valproic acid, ethosuximide and mesuximide. Clin Pharmacokinet 1995;29:257-86. 10. Nan H, Rating D, Koch S, H~user I, Helge H. Valproic acid and its metabolites: placental transfer, neonatal pharmacoldnetics, transfer via mother's milk and clinical status in neonates of epileptic mothers. J Pharmacol Exp Ther 1981;219: 768-77.
Developmental profile of mitochondrial glycine N-acyltransferase in human liver Yogesh Mawal, PhD, Khazal Paradis, MD, and Ijaz A, Qureshi, PhD From the Divisions of Medical Genetics and Gastroenterology, Department of Pediatrics and Centre de Recherche, H6pital Sainte-Justine, University of Montreal, Montreal, Quebec, Canada
Objective: To study the developmental profile of glycine N-acyltransferase (GAT) in the livers of children of various ages and to compare the total and specific GAT activity with that of the adult control subjects. Methods: We measured the specific and the total mitochondrial activity of GAT in liver samples taken from 13 children 4 hours to 11 years of age. The samples were compared with those of control adults aged 24 to 40 years. Samples, either from liver-transplant donors or from autopsy, from those who died of a disorder not related to the liver, were obtained between 6 and 36 hours after death. Results: At 4 hours after bidh, very low specific activity and the total liver mitochondrial activity were observed (0.19 IJmol/min per milligram protein and 210 pmoi/min), with a steady increase up to age 7 months (2.51 IJmol/min per milligram protein and 812 IJmol/min). The mean specific and total GAT activity in children (n = 5) aged 18 months to 11 years was 6.38 ± 0.13 and 1389 ± 43 and in control adults aged 24 to 40 years (n = 3) was 6.5 ± 0.3 and 1461 ± 71 pmol/min per milligram protein and pmol/min, respectively. These specific and total GAT activity values from children aged 18 months to 11 years were not statistically significant (by analysis of variance and Mann-Whitney test) in comparison with the corresponding activity values from the adult control subjects. Conclusions: Our results indicate that up to age 7 months, children have only 5% to 40% of liver GAT-specific activity, whereas the peak activity is achieved at 18 months and remains constant until age 40 years. The delayed development of GAT in children may thus compromise the detoxification of various drugs and xenobiotics. (J Pediatr 1997; 130:1003- 7)
Supported by a grant (MT-9124) from the Medical Research Council of Canada and by Biopedia. Submitted for publication April 17, 1996; accepted Nov. 12, 1996. Reprint requests: Ijaz A. Qureshi, PhD, Genetique Medicale, Centre de Recherche~ H6pital Sainte-Justine, 3175 C6te Sainte Catherine, Montrral, Qurbec H3T 1C5, Canada. Copyright © 1997 by Mosby-Year Book, Inc. 0022-3476/97/$5.00 + 0 9/22/79365
Many carboxylic acid xenobiofics, including benzoate and acetylsalicylate, are conjugated with an amino acid, primarily glycine, before excretion. The conjugation involves a two-step pathway, initiated by the activation of carboxylic acid to the coenzyme A thioester by a medium-chain fatty acyl: CoA ligase (adenosine monophosphate; EC 6.2.1.2). l The mitochondrial glycine N-acyltransferase then transfers
StahI, Neiderud, and Vinge
100 1
Thrombocytopenic purpura and anemia in a breast-fed infant whose mother was treated with valproic acid Malffhias M, S. Stahl, MD, Jan Neiderud, MD, PhD, a n d Ellen Vinge, MD, PhD From the Pharmacoepidemiology Unit, The Medical Products Agency, Uppsala, the Department of Paediatrics, County Hospital, Helsingborg, and the Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden Valproic acid is an antiepileptic drug in widespread use. The possibility of various hematologic side effects with this drug is well recognized. We describe a breastfed infant with thrombocytopenic purpura, anemia, and reticulocytosis, whose mother was treated with valproic acid. As the mother stopped breast-feeding, the infant recovered. (J Pediatr 1997; 130:1001-3) CASE
RE]PORT
A 3-month.-old male infant, whose mother was treated with sodium valproate, 600 mg twice daily, as monotherapy for epilepsy, had a 2-week history of increasing petechiae and minor hematoma on the lower part of the legs. Petechiae were also found on the face, the mink, and the arms. The infant had a slight cold and was pale, but otherwise physical examination was unremarkable. Rectal temperature was 37.2 ° C. Platelet count was 7 x 109/I, (reference range, 125 to 400 x 109/L),blood hemoglobin, 82 gm/L (reference range, 131 to 163 gin/L), and mean corpuscular volume, 78 fl (reference range, 82 to 105 fl). The differential count showed a small increase in leukocyte count (12.1 x 109/[,; reference range, 4.0 to 10.0 x 109/L) and a lymphocytosis (8.0 x 109/L; reference range, 1.2 to 4.0 x 109fL). Sedimentation rate was 10 mm/hr, and C-reactive protein was not increased. The mother' s platelet count was 113 x 109/L(other hematologic parameters were not analyzed in the mother, but 1 week earlier, her blood hemoglobin was 118 gin/L). Serum valproic acid was 46 Nnol/L (6.6 pg/ml) in the infant (therapeutic range for adults, 350 to 7130 Nnol/L, corresponding to 50 to 100 pg/ml). During the following month, the platelet count ranged between 2 and 4 x 109/L (Figure), and new petechiae continued to appear, but the patient's condition was stable. There was reticulocytosis (4.9% to 5.5%; reference range, 0.2% to 1.5%); blood hemoglobin was 80 to 95 gin/L; and mean corpuscular volume was 76 to 81 fl. A blood smear showed normal findings, and spherocytes were absent. Testing for osmotic fragility was normal. Serum haptoglobin 2 days after admission was low (0.06 gin/L; reference range, 0.45 to 2.75 gmfL) but had increased to 1.27 gm/L 1.5 months later. The leukocyte differential count remained essentially unchanged. There was no hematuria, and fecal occult blood test results were negative. Liver test results were normal, including bilirubin and albumin levSubmitted for publication Aug. 7, 1996; accepted Oct. 10, 1996. Reprint requests: Matthias Stahl, MD, Pharmacia & Upjohn, Consumer Healthcare, Box 941, S-25109 Helsingborg, Sweden. Copyright © 1997 by Mosby-Year Book, Inc. 0022-3476/97/$5.00 + 0 9/22/78634
els. The serum creatinine level was likewise normal. Serologic test results for toxoplasmosis, rubella, cytomegalovirus, and herpes simplex vires were negative, both in the child and the mother, and there were no antibodies against thrombocyte-specific antigens (Capmre-P method). Direct Coombs test and a bone marrow examination were not performed. Because the child was well and happy and signs of ongoing bleeding were absent, there was a decision to "wait and see," according to the policy of the department. Eight days after admission, the mother interrupted breast-feeding for 5 days without any change in the platelet count. After 1 month, she stopped breast-feeding (platelet count was then 2 x 109/%). Five, 12, and 19 days later, the platelet counts were 3, 3, and 9 x 109/L, respectively (Figure). On day 12 after cessation of breast-feeding, valproic acid was not detectable in the serum of the infant. On days 35, 83, and 87, the platelet count had increased to 113, 313, and 400 x 109/L, respectively, and around day 35, the petechiae had resolved. A normalization of blood hemoglobin and the reticulocytes occurred between days 12 and 19. At age 815 months, platelet count was 396 x 109/L. DISCUSSION To our knowledge, this is the first report of an infant with thrombocytopenia and anemia presumably induced by valproic acid transfer through breast milk. Valproic acid may cause a variety of blood cell disorders including bone marrow toxicity. 1, 2 Immune hemolytic anemia 3 and erythrocyte aplasia 4 have been reported. In a study of 60 patients (average age 14.6 years) receiving long-term valproate therapy, one third of the patients demonstrated at least one hematologic abnormality. 1 The most common findings were thrombocytopenia and macrocytosis. ] Reticulocytosis occurs in some patients but does not seem to account for the macrocytosis, nor do deficiencies of folate or vitamin B12.1 A few patients also have anemia. 1 With regard to thrombocytopenia, the mechanism may be immunologic or concentration dependent. 5-7 In a study of 306 children with epilepsy with a mean age of 9.1 years (range, 1 to 18 years) and treated with
10 0 2
Stahl, Neiderud, and Vinge
The Journal of Pediatrics June 1997
5-500 E ~400 "o°¢
E
.300 m_.
.200 8 t-"
,100 ~-
IPetechiael ~
i ,Breast - feedinq
I H
t~
1.5
v
-o
1.0 0.5
p
i i ii i i iili i iiiiiiiiii ]ii i I
._~ 0.0 ,~2:::::::::::~................. :':':i...................... ;............... ~.................. ;::'::;.............. ::::::::::::::::::::::................. ~...................................... "i...................................... ~....................................... i ...................................... , -5 0 5 10 15 20 25 30 , 35 > Weeks
Figure. Thrombocytopenic purpura in a breast-fed infant whose mother was treated with valproic acid. Recovery of the platelet count is seen after cessation of breast-feeding.
valproic acid, thrombocytopenia developed in 64 (platelet count, -<150 x 109/L).7 Platelet levels less than 100 x 109/L were seen in 32 patients (mean platelet count, 76 x 109/L; range, 18 to 99x 109/L); the mean peak valproate level was 1158 pmol/L (167 pg/ml) with a range from 686 to 1428 ~ o F L (99 to 206 lag/ml). Signs of bleeding developed in eight patients (diffuse petechiae, hematomas, or nose bleeding).7 The half-life of valproic acid in newborn infants has been estimated to be 47 + 15 hours (range, 32 to 80 hours) and in infants between 10 days and 2 months, half-lives of 9 to 22 hours were found. 8 In older infants, the half-lives were 7 to 12 hours, s The valproic acid metabolite profile has been determined in infants of around age 4 months and older after oral dosing. 9 The main metabolites considered potentially toxic were found in low concentrations in plasma, but the interindividual variability was large and the half-lives were not calculated.9 In samples of breast milk, valproic acid and one of its metabolites (3-keto) were present in concentrations that were 2.7% and 7.4% of those in maternal serum, respectively, but toxic metabolites were not analyzed. 8' 10No data were found on serum concentrations of metabolites of valproic acid in breast-fed infants at age 3 months or older. The possible role of the metabolites in the development of thrombocytopenia or other blood cell disorders is unknown. It seems unlikely that transplacental transfer of valproic acid contributed to any greater extent to the thrombocytopenia in our case because there were no petechiae immediately after birth, in spite of the physical stress during delivery. It is noticeable that
5 weeks after defivery, the dose was doubled (3 weeks later, the mother's serum valproic acid was 548 pmol/L [i.e., 79 Ng/ml]), and the infant's petechiae appeared 6 weeks later. Initial serum haptoglobin was low, possibly indicating hemolysis. However, haptoglobin determinations are difficult to interpret at this age because very low values of haptoglobin may be seen in healthy infants and children. The thrombocytopenia and anemia remained unchanged for about 1 month. The concomitant depression of both platelets and hemoglobin is not typical of idiopathic thrombocytopenic purpura. Furthermore, because the abnormalities seen are well known with valproic acid, the association in time, the normalization of platelets, hemoglobin, and reticulocytes between 12 and 35 days after breast-feeding was stopped, and the fact that no other cause was found in spite of extensive investigations argue for valproic acid or its metabolites or both transferred by breast milk as the cause. However, a concentration-dependent toxic effect of the parent drug alone seems less likely because of its low concentration in the infant. The possibility of valproic acid causing hematologic adverse effects in the infant by transfer to breast milk should be borne in mind. REFERENCES
1. May RB' Sunder TR' Hemat°l°gic manifestati°ns °f l°ng-term valproate therapy. Epilepsia 1993;34:1098-101. 2. Ganick DJ, Sunder T, Finley JL. Severe hematologic toxicity of valproic acid: a report of four patients. Am J Pediatr Hematol Oncol 1990;12:80-5. 3. Kaya IS, Dilmen U, Toppare M, Senses DA. Valproic acid-in-
The Journal of Pediatrics Volume 130, Number 6
4. 5.
6.
7.
duced pancytopenia and Coomb's test positivity. Lancet 1991; 337:1227-8. MacDougall LG. Pure red cell aplasia associated with sodium valproate ~:herapy.JAMA 1982;257:53-4. Ban" RD, C0peland SA, Stockwell ML, Morris N, Kelton JC. Valproic acid and immune thrombocytopenia. Arch Dis Child 1982;57:681-4. Gidal B, Spencer N, Maly M, Pitterle M, Williams E, Collins M, et al. Valproate-mediateddisturbancesof hemostasis:relationship to dose and plasma concentration.Neurology 1994;44:1418-22. Delgado MR, Riela AR, Mills J, Browne R, Roach S. Thrombocytopenia secondary to high valproate levels in children with epilepsy. J Child Neurol 1994;9:311-4.
Mawal, Paradis, and Qureshi
1003
8. Nan H, Kuhnz W, Egger H-J, Rating D, Helge H. Anficonvulsants during pregnancy and lactation: transplacental, maternal and neonatal pharmacokinetics. Clin Phaxmacoldnet 1982;7: 508-43. 9. Battino D, Estienne M, Avanzini G. Clinical pharmacokinefics of antiepileptic drugs in paediatric patients, part I, phenobarbital, primidone, valproic acid, ethosuximide and mesuximide. Clin Pharmacokinet 1995;29:257-86. 10. Nan H, Rating D, Koch S, H~user I, Helge H. Valproic acid and its metabolites: placental transfer, neonatal pharmacoldnetics, transfer via mother's milk and clinical status in neonates of epileptic mothers. J Pharmacol Exp Ther 1981;219: 768-77.
Developmental profile of mitochondrial glycine N-acyltransferase in human liver Yogesh Mawal, PhD, Khazal Paradis, MD, and Ijaz A, Qureshi, PhD From the Divisions of Medical Genetics and Gastroenterology, Department of Pediatrics and Centre de Recherche, H6pital Sainte-Justine, University of Montreal, Montreal, Quebec, Canada
Objective: To study the developmental profile of glycine N-acyltransferase (GAT) in the livers of children of various ages and to compare the total and specific GAT activity with that of the adult control subjects. Methods: We measured the specific and the total mitochondrial activity of GAT in liver samples taken from 13 children 4 hours to 11 years of age. The samples were compared with those of control adults aged 24 to 40 years. Samples, either from liver-transplant donors or from autopsy, from those who died of a disorder not related to the liver, were obtained between 6 and 36 hours after death. Results: At 4 hours after bidh, very low specific activity and the total liver mitochondrial activity were observed (0.19 IJmol/min per milligram protein and 210 pmoi/min), with a steady increase up to age 7 months (2.51 IJmol/min per milligram protein and 812 IJmol/min). The mean specific and total GAT activity in children (n = 5) aged 18 months to 11 years was 6.38 ± 0.13 and 1389 ± 43 and in control adults aged 24 to 40 years (n = 3) was 6.5 ± 0.3 and 1461 ± 71 pmol/min per milligram protein and pmol/min, respectively. These specific and total GAT activity values from children aged 18 months to 11 years were not statistically significant (by analysis of variance and Mann-Whitney test) in comparison with the corresponding activity values from the adult control subjects. Conclusions: Our results indicate that up to age 7 months, children have only 5% to 40% of liver GAT-specific activity, whereas the peak activity is achieved at 18 months and remains constant until age 40 years. The delayed development of GAT in children may thus compromise the detoxification of various drugs and xenobiotics. (J Pediatr 1997; 130:1003- 7)
Supported by a grant (MT-9124) from the Medical Research Council of Canada and by Biopedia. Submitted for publication April 17, 1996; accepted Nov. 12, 1996. Reprint requests: Ijaz A. Qureshi, PhD, Genetique Medicale, Centre de Recherche~ H6pital Sainte-Justine, 3175 C6te Sainte Catherine, Montrral, Qurbec H3T 1C5, Canada. Copyright © 1997 by Mosby-Year Book, Inc. 0022-3476/97/$5.00 + 0 9/22/79365
Many carboxylic acid xenobiofics, including benzoate and acetylsalicylate, are conjugated with an amino acid, primarily glycine, before excretion. The conjugation involves a two-step pathway, initiated by the activation of carboxylic acid to the coenzyme A thioester by a medium-chain fatty acyl: CoA ligase (adenosine monophosphate; EC 6.2.1.2). l The mitochondrial glycine N-acyltransferase then transfers