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ETHANOL AND NEONATAL BILIRUBIN LEVELS
108 insulin hypoglycxmia and tetracosactrin (’ Synacthen’) may be reduced-sometimes substantially-in recently driedout chronic alcoholics. We
hope to publish these findings in detail in the near future.
JULIUS MERRY.
West Park Area
Hospital, Epsom. Laboratory, Epsom.
VINCENT MARKS.
ETHANOL AND NEONATAL BILIRUBIN LEVELS SiR,ňIn the first few days of life, bilirubin accumulates in the blood because hepatic-removal mechanisms are not yet sufficiently developed. McLeanshowed that, in comparison with phenobarbitone,2-4 alcohol is a negligible inducer of the microsomal liver-enzyme system. Yet, when 20% ethanol was substituted for drinking-water in rats, the microsomal system doubled its hydroxylating activity in one week. Lieber and DeCarli5 demonstrated that ethanol, in the rat as well as in man, acts like phenobarbitone in the induction of drug metabolising enzymes and hypertrophy of smooth endoplasmic reticulum (S.E.R.). Moreover, after 48 hours of ethyl-alcohol consumption these effects were evident in human liver biopsies. While oxidative enzyme activity rises first after increase in the membranes of the S.E.R., induction eventually involves enzyme systems for reduction, hydrolysis, and glucuronidation.6 In our reproductive-physiology unit, ethanol was slowly given (118 g.) to 10 normal pregnant women intravenously, 8 in early labour and 2 before elective repeat csesarean sections. No harmful effects were observed in the mother or the infants (no one-minute Apgar score below 8). 10 patients were selected as controls. All toxaemic patients, diabetics, and Rh-sensitised cases were excluded from the study. Infant serum-bilirubin (s.B.) levels were recorded at birth and during the first five days of life (table I). Mean daily levels TABLE I-EFFECT OF ETHANOL ON CONCENTRATION OF TOTAL SERUMBILIRUBIN
(S.B.)
IN NEONATAL PERIOD
(MEANS ± S.E. GROUPS)
OBTAINED ON
EACH DAY FOR CONTROL AND ETHANOL
Numbers of infants studied.
of s.B. were significantly lower in the ethanol-treated group. In infants whose mothers completed ethanol infusions at least two hours before delivery the highest level of neonatal s.B. was 5-7 mg. per 100 ml. (table n). 9 of the 10 control infants, and 1 whose mother completed her ethanol infusion one hour before delivery, had peak s.B. levels above this level. Whether induced microsomal glucuronyl-transferase enzyme, enhanced hepatic biliary excretion, or alternative glucuronide-conjugating systems are stimulated remains to be further elucidated. The reported deleterious effects of raised s.B. in the newborn on the motor and mental scores of infants at eight months of agemake efforts to prevent this occurrence advisable. Although caution is necessary until possible harmful effects on other enzyme systems can 1. 2. 3. 4. 5. 6. 7.
TABLE II-MAXIMUM LEVEL OF TOTAL S.B. IN NEONATAL PERIOD (MAXIMUM FOR EACH SUBJECT DURING FIRST FIVE DAYS OF LIFE)
McLean, A. E. M. Lancet, 1968, ii, 1035. Maurer, H. M., Wolff, J. A., Finster, M., Poppers, P. J., Pantuck, E., Kautzman, R., Conney, A. H. ibid. p. 122. Trolle, D. ibid. 1968, i, 251. Catz, C., Yaffee, S. J. Am. J. Dis. Child. 1962, 104, 516. Lieber, C. S., DeCarli, L. M. Science, N.Y. 1968, 162, 917. Rubin, E., Lieber, C. S. Ann. intern. Med. 1968, 69, 1063. Boggs, T. R., Hardy, W. W., Burnett, H. H. J. Pediat. 1967, 71, 553.
Difference between maximum neonatal S.B. in control and treated groups is significant (r<0.025). * Duration from cessation of ethanol treatment to delivery. t Mean s.E.
be evaluatedthis apparently innocuous procedure may prove beneficial in prophylaxis against neonatal hyperbilirubinsemia in mature, as well as premature, babies. Department of Obstetrics and Gynecology, and Department of Pediatrics, Brooklyn-Cumberland Medical Center, Brooklyn, New York.
R. WALTMAN F. BONURA G. NIGRIN
C. PIPAT.
TYPE-II GM1 GANGLIOSIDOSIS ? SIR,-Dr. Pinsky and his colleagues 9 have reported on a patient with a GM1 ganglioside accumulation in the brain without hepatosplenomegaly or osseous defects. According to Derry et a1.1o such disease should be differentiated from generalised GM1 gangliosidosis. We report here some new biochemical data of a patient without clinical Hurler’s syndrome symptoms who apparently has type-II GM1
gangliosidosis. Thin-layer chromatography of the gangliosides and other glycolipids of frozen brain tissue shows obvious GMJ ganglioside storage, identical to the accumulation in generalised gangliosidosis. There was no ganglioside or glycolipid abnormality in the liver, in contrast with the observations in our first patient with GM1 gangliosidosis.11 Enzymatic analysis of the brain grey matter showed P-galactosidase activity, at pH 4-5 and 0-1 M ionic strength, of 10-0 (normal 15-3-18-3) mpmoles per hour per mg. dry weight. In the liver, however, P-galactosidase activity at pH 4-5 and 0-1 M ionic strength was only 4% of the normal value of 32040 m[.Lmoles of p-nitrophenol released per hour per mg. protein. p-galactosidase activity in the leucocytes was also reduced to about 7% of the normal value (for children aged 0-5 20-0-56-0, and for adults 40-0-74-4, m per hour per mg. protein). oc-fucosidase activity in the liver of the patient was 3 times higher than the mean value in control livers, an indication of a true lysosomal deficiency. 12 In order to establish the familial character of the disease we investigated P-galactosidase activity in the leucocytes of the family according to the method of Kint.13 The leucocytes of the father and the mother had an activity of 19-6 and 38-0 m[Lmoles per hour per mg. protein 8. 9. 10. 11. 12. 13.
Conney, A. H. Pharmac. Rev. 1967, 19, 317. Pinsky, L., Callahan, J. W., Wolfe, L. S. Lancet, 1968, ii, 1080. Derry, D., Fawcett, J. S., Andermann, F., Wolfe, L. S. Neurology, Minneap. 1968, 18, 340. Hooft, C., Senesael, L., Delbeke, M. J., Dacremont, G., Kint, J. A. Eur. Neurol. 1969, 2, 225. Van Hoof. F., Hers, H. G. Eur. J. Biochem. 1968, 7, 34. Kint, J. A. Archs int. Physiol. Biochim. 1968, 76, 935.
hope to publish these findings in detail in the near future.
JULIUS MERRY.
West Park Area
Hospital, Epsom. Laboratory, Epsom.
VINCENT MARKS.
ETHANOL AND NEONATAL BILIRUBIN LEVELS SiR,ňIn the first few days of life, bilirubin accumulates in the blood because hepatic-removal mechanisms are not yet sufficiently developed. McLeanshowed that, in comparison with phenobarbitone,2-4 alcohol is a negligible inducer of the microsomal liver-enzyme system. Yet, when 20% ethanol was substituted for drinking-water in rats, the microsomal system doubled its hydroxylating activity in one week. Lieber and DeCarli5 demonstrated that ethanol, in the rat as well as in man, acts like phenobarbitone in the induction of drug metabolising enzymes and hypertrophy of smooth endoplasmic reticulum (S.E.R.). Moreover, after 48 hours of ethyl-alcohol consumption these effects were evident in human liver biopsies. While oxidative enzyme activity rises first after increase in the membranes of the S.E.R., induction eventually involves enzyme systems for reduction, hydrolysis, and glucuronidation.6 In our reproductive-physiology unit, ethanol was slowly given (118 g.) to 10 normal pregnant women intravenously, 8 in early labour and 2 before elective repeat csesarean sections. No harmful effects were observed in the mother or the infants (no one-minute Apgar score below 8). 10 patients were selected as controls. All toxaemic patients, diabetics, and Rh-sensitised cases were excluded from the study. Infant serum-bilirubin (s.B.) levels were recorded at birth and during the first five days of life (table I). Mean daily levels TABLE I-EFFECT OF ETHANOL ON CONCENTRATION OF TOTAL SERUMBILIRUBIN
(S.B.)
IN NEONATAL PERIOD
(MEANS ± S.E. GROUPS)
OBTAINED ON
EACH DAY FOR CONTROL AND ETHANOL
Numbers of infants studied.
of s.B. were significantly lower in the ethanol-treated group. In infants whose mothers completed ethanol infusions at least two hours before delivery the highest level of neonatal s.B. was 5-7 mg. per 100 ml. (table n). 9 of the 10 control infants, and 1 whose mother completed her ethanol infusion one hour before delivery, had peak s.B. levels above this level. Whether induced microsomal glucuronyl-transferase enzyme, enhanced hepatic biliary excretion, or alternative glucuronide-conjugating systems are stimulated remains to be further elucidated. The reported deleterious effects of raised s.B. in the newborn on the motor and mental scores of infants at eight months of agemake efforts to prevent this occurrence advisable. Although caution is necessary until possible harmful effects on other enzyme systems can 1. 2. 3. 4. 5. 6. 7.
TABLE II-MAXIMUM LEVEL OF TOTAL S.B. IN NEONATAL PERIOD (MAXIMUM FOR EACH SUBJECT DURING FIRST FIVE DAYS OF LIFE)
McLean, A. E. M. Lancet, 1968, ii, 1035. Maurer, H. M., Wolff, J. A., Finster, M., Poppers, P. J., Pantuck, E., Kautzman, R., Conney, A. H. ibid. p. 122. Trolle, D. ibid. 1968, i, 251. Catz, C., Yaffee, S. J. Am. J. Dis. Child. 1962, 104, 516. Lieber, C. S., DeCarli, L. M. Science, N.Y. 1968, 162, 917. Rubin, E., Lieber, C. S. Ann. intern. Med. 1968, 69, 1063. Boggs, T. R., Hardy, W. W., Burnett, H. H. J. Pediat. 1967, 71, 553.
Difference between maximum neonatal S.B. in control and treated groups is significant (r<0.025). * Duration from cessation of ethanol treatment to delivery. t Mean s.E.
be evaluatedthis apparently innocuous procedure may prove beneficial in prophylaxis against neonatal hyperbilirubinsemia in mature, as well as premature, babies. Department of Obstetrics and Gynecology, and Department of Pediatrics, Brooklyn-Cumberland Medical Center, Brooklyn, New York.
R. WALTMAN F. BONURA G. NIGRIN
C. PIPAT.
TYPE-II GM1 GANGLIOSIDOSIS ? SIR,-Dr. Pinsky and his colleagues 9 have reported on a patient with a GM1 ganglioside accumulation in the brain without hepatosplenomegaly or osseous defects. According to Derry et a1.1o such disease should be differentiated from generalised GM1 gangliosidosis. We report here some new biochemical data of a patient without clinical Hurler’s syndrome symptoms who apparently has type-II GM1
gangliosidosis. Thin-layer chromatography of the gangliosides and other glycolipids of frozen brain tissue shows obvious GMJ ganglioside storage, identical to the accumulation in generalised gangliosidosis. There was no ganglioside or glycolipid abnormality in the liver, in contrast with the observations in our first patient with GM1 gangliosidosis.11 Enzymatic analysis of the brain grey matter showed P-galactosidase activity, at pH 4-5 and 0-1 M ionic strength, of 10-0 (normal 15-3-18-3) mpmoles per hour per mg. dry weight. In the liver, however, P-galactosidase activity at pH 4-5 and 0-1 M ionic strength was only 4% of the normal value of 32040 m[.Lmoles of p-nitrophenol released per hour per mg. protein. p-galactosidase activity in the leucocytes was also reduced to about 7% of the normal value (for children aged 0-5 20-0-56-0, and for adults 40-0-74-4, m per hour per mg. protein). oc-fucosidase activity in the liver of the patient was 3 times higher than the mean value in control livers, an indication of a true lysosomal deficiency. 12 In order to establish the familial character of the disease we investigated P-galactosidase activity in the leucocytes of the family according to the method of Kint.13 The leucocytes of the father and the mother had an activity of 19-6 and 38-0 m[Lmoles per hour per mg. protein 8. 9. 10. 11. 12. 13.
Conney, A. H. Pharmac. Rev. 1967, 19, 317. Pinsky, L., Callahan, J. W., Wolfe, L. S. Lancet, 1968, ii, 1080. Derry, D., Fawcett, J. S., Andermann, F., Wolfe, L. S. Neurology, Minneap. 1968, 18, 340. Hooft, C., Senesael, L., Delbeke, M. J., Dacremont, G., Kint, J. A. Eur. Neurol. 1969, 2, 225. Van Hoof. F., Hers, H. G. Eur. J. Biochem. 1968, 7, 34. Kint, J. A. Archs int. Physiol. Biochim. 1968, 76, 935.