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Primary treatment of propionic acidemia complicated by acute thiamine deficiency
Primary treatment of propionic acidemia complicated by acute thiamine deficiency Dietrich Matern, MD, Hans H. Seydewitz, PhD, Willy Lehnert, PhD, Helmut Niederhoff, MD, Jekabs U. Leititis, MD, and Matthias Brandis, MD From the Department of Pediatrics, Albert-Ludwigs-University, Freiburg, Germany
Propionic acidemia is often manifested during the neonatal period with vomiting, failure to thrive, lethargy, and hyperammonemic coma whencatabolism is prolonged. Mild lactic acidosis frequently accompanies metabolic decompensation. We present two patients with propionic acidemia whose initial manifestation was complicated by severe lactic acidosis caused by thiamine deficiency, which resulted from an inadequate supply of, and an increased need for, thiamine during metabolic stress. To prevent acute thiamine deficiency, we propose early vitamin supplementation during treatment of any severe metabolic decompensation accompanied by insufficient food intake. (J Pediatr 1996; 129:758-60)
Propionic acidemia (McKusick 23200, 23205) is an autosomal-recessive inborn error of branched-chain amino acid metabolism. It is caused by deficient activity of propionylcoenzyme A carboxylase (EC 6.4.1.3) and usually is manifested in the neonatal period or early infancy. Typically, the newborn infant's clinical condition deteriorates rapidly after a normal pregnancy and birth and a symptom-free interval. Initial symptoms are nonspecific and may include feeding problems, vomiting, failure to thrive, and often dehydration. Hyperammonemic coma develops progressively, and mild hyperlactacidemia may be observed) Diagnosis is estabfished by gas chromatography-mass spectrometry of a urine sample revealing specific metabolites. Confirmation by measurement of PCC activity in fibroblasts is recommended.1, 2 Severe hyperlactacidemia caused by thiamine deficiency is not a typical symptom of propionic acidemia. The deficiency usually results from inadequate vitamin intake or decreased intestinal absorption and may become acute during episodes of increased requirements, as in extreme catabolism or anabofism. We present two patients with PA complicated by thiamine deficiency. Presented in part at the 91st Annual Meeting of the Deutsche Gesellschaft for Kinderheilkunde, Krefeld, Germany, Sept. 8 to 10, 1995. Submitted for publication Feb. 7, 1996; accepted June 21, 1996. Reprint requests: Dietrich Matern, MD, University Children's Hospital, Mathildenstr. 1, D-79106 Freiburg,. Germany. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/22/75973
758
CASE
REPORTS
Pregnancy and birth were uneventful in both patients. Patient 1. At 6 days of age the fourth child of healthy, consanguineous parents of Indian origin had muscle hypotonia, feeding problems, and recurrent vomiting, which led to the initiation of intravenous fluid and glucose supplementation. A urine sample screened by GC-MS revealed characteristic metabolites of PA. Meanwhile, the 9-day-old boy required artificial ventilation, a metabolic acidosis with moderate hyperlactacidemia (11 retool/L; normal, 1 to 2 retool/L) had developed, and the boy was in a coma caused by hyperammonemia (748 ~nol/L; normal, -<40 wnol/L). The patient was transferred to our hospital. On his arrival, acute cardiac arrest necessitated cardiopulmonary resuscitation for 20 minutes. Hyperammonemiawas reduced to nearly normal values by the eleventh day of life with high-caloric parenteral nutrition and LCoA GC-MS PA PCC TPN
Coenzyme A Gas chromatography-mass spectrometry Propionic acidemia Propionyl-coenzyme A carboxylase Total parenteral nutrition
arginine. The patient slowly awakened from a 54-hour-long coma, during which the electroencephalogram revealed a burst-suppression pauem. At 14 days of age the patient was weaned from respiratory support, and feedings via a nasogastric tube were cautiously introduced. However, a paralytic ileus rendered the enteral feedings unsuccessful. Two days later a combined respiratory and metabolic acidosis developed and necessitated mechanical ventilation. Plasma lactic acid concentrations rose to 48 retool/L, paralleled by a decrease in blood pressure. Peritoneal dialysis was started to treat hyperlactacidemia. A blood sample drawn at this time eventually
The Journal of Pediatrics Volume 129, Number 5
Matern et al.
tgmol/L] 900
W
800
i,
*
_~ Thiamille in el~.hrooytes: 0.6 p.g/L[
A ~ - - :
~
759
20 [retool/L]
18 16
700
]administrationof 2 x 20 mg thiamine intra. . . . sly I I4
600 12 500
10 ~
Ammonia - i - in p l a s m a 400 •
Lactic acid in plasma
.8
300 200
10o
I
_______ Normal Range noI 43 44
-6 '1
~
4
, . . ~- . . . .
~.--,--. . . . . . .
i-I
I
45
46
I I- - -
47
-I~ . . . . . . . . . . . . . . . . . . . . . . 1
I
"*--t
"*t . . . . . .1 . . . .
48
49
50
51
52
I
-mI
53
54
55
Days of life
Fig. 1. Course of patient 2 with respect to ammonia, lactic acid, and thiamine levels.
revealed that a plasma concentration of thiamine was undetectable. Before a trial dose of thiamine could be administered, the child died of cardiorespiratory failure. Patient 2. The female patient is the second child of healthy, nonconsanguineous, white parents. During the neonatal period, she had to be awakened to feedings, drank reluctantly, and vomited recurrently. In her seventh week, she was hospitalized with dehydration and a tentative diagnosis of hypertrophic pyloric stenosis. At this time, she weighed 3830 gm (260 gm less than at birth), she required intravenous rehydration, and her pyloms appeared normal on a sonogram. On the following day, she became comatose because of marked hyperammonemia (881 ~mol/L; Fig. 1) and was immediately transferred to our hospital. Hemofiltration was initiated, and within 3 hours the ammonia level fell to 60 gmol/L and the patient awakened. By this time, the diagnosis of PA was established by GC-MS of a urine sample. Initially the patient was fed exclusively with intravenously administered glucose and lipids without vitamin supplements. On the second day an increasing hyperlactacidemia (18.7 mmol/L) worsened metabolic acidosis. After a blood sample was obtained for thiamine investigation (0.6 pg/L; normal, 1.7 to 6.7 jaglL), 40 mg of thiamine (11 mg/kg) was given intravenously and within 5 hours the acidosis had completely resolved. Measurement of PCC activity confirmed the diagnosis (5.9 pmol/min per milligram of protein; control values, 221 to 1742 pmol/min per milligram of protein3). The patient is now 9 months old and in stable and good condition.
METHODS Measurements of ammonia, lactic acid, and thiamine in plasma and erythrocytes, respectively, as well as GC-MS of the urine samples were performed as previously described.2, 4-6 Biochemical investigation of PCC was kindly performed by Dr. R. Baumgartner, University Children's Hospital, Basel, Switzerland)
Glucose
Lactate Dehydrogenase Pyruvate
Pyruvate Dehydrogenase
@
<
Lactate [Thiamine deficiency
]
v Acetyl-CoA
Fig. 2. Development ofhyperlactacidemia in thiamine deficiency.
DISCUSSION Thiamine (vitamin B1) is a cofactor for various biochemical reactions such as the oxidative decarboxylation of the o~-keto acids pyruvate and oL-ketoglutarate (Fig. 2). Its deficiency inhibits the entry of pyruvate into the citric acid cycle. Alternatively, accumulating pyruvate is dehydrogenated to lactic acid, which results in hyperlactacidemia. In the Western world, thiamine deficiency is most often the consequence of chronic alcohol abuse, as in Wemicke encephalopathy. In developing countries, chronically inadequate
760
Matern et al.
dietary thiamine intake leads to beriberi. In both of these chronic diseases, acute forms are known to be manifested by hyperlactacidemia, consequent metabolic acidosis, and cardiovascular shock. 7, s Enteral absorption of thiamine occurs mainly in the jejunum. Storage (primarily in the heart, brain, liver, and kidneys) amounts to approximately 25 mg in human beings, with a recommended daily allowance of 0.3 mg/day for newborn infants to 1.6 mg/day for the lactating woman. 9 Symptoms of vitamin deficiency in infants are manifested within 2 weeks of thiamine-free feedings. 1° Causes, alone or in combination, of thiamine deficiency are inadequate enteral or parenteral supply, inadequate enteral absorption, and increased consumption during metabolic stress. In PA, hyperlactacidemia is assumed to be caused by competitive inhibition of the pyruvate dehydrogenase complex by propionyl-CoA. 11 However, the high lactic acid concentrations that we observed have not yet been reported in PA. Thiamine deficiency in our patients had several causes. Both had feeding problems typical for PA. In patient 1, paralytic ileus hindered absorption even after enteral feedings containing thiamine were introduced. Patient 2 was admitted to the hospital with recurrent vomiting and dehydration. Accordingly, decreased vitamin stores can be postulated. In our care, both children received high-caloric total parenteral nutrition with glucose and lipids to overcome catabolism and restore anabolism. Both metabolic conditions require higher amounts of thiamine. Initially, however, TPN was not supplemented with vitamins. Patient 2 showed a prompt response, with rapid normalization of the acid-base status and the plasma lactic acid concentration, after thiamine was given. In the literature, thiamine deficiency has not been reported as a complication of PA. It may be caused by various mechanisms, such a s hyperemesis gravidarum and TPN without vitamin supplementation for patients with various diseases.12, 13 Byrd et al. 14 reported a patient with methylmalonic acidemia in whom hyperlactacidemia developed because of thiamine deficiency. This was attributed to an inadequate thiamine intake and not to the underlying metabolic disease. In view of these observations, the known causes of thiamine deficiency, and the histories of our patients, we believe that thiamine deficiency is also a potential complication of PA. Our patients had hyperammonemic coma; however, they received different treatments. Hemofiltration or dialysis was not feasible for patient 1 because of his circulatory instability. Therefore his ammonia level could be reduced only by reversing catabolism and administrating L-arginine. Patient 2 was well enough to undergo this procedure, and normal ammonia levels were measured after 3 hours of hemofiltration. Thus the time that patient 2 was comatose was less than 20 hours, more than 30 hours shorter than patient 1. Because
The Journal of Pediatrics November 1996
duration of coma is an important prognostic factor, t we believe that children with significant hyperammonemia should immediately be transferred to a center where hemofiltration can be performed, even if the underlying disorder is not yet known and the child is still not comatose. We conclude that all children requiring TPN should receive vitamin supplements whenever they have a disease favoring catabolism or their history suggests a reduced vitamin intake, or both. Furthermore, the rapid normalization of hyperammonemia can best be achieved by hemofiltration, which mandates immediate transfer of patients with hyperammonemia to a dialysis unit.
REFERENCES
1. Fenton WA, Rosenberg LE. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th ed. McGraw-Hill, 1995:1423-51. 2. Lehnert W, Sperl W, Suormala T, Baumgartner ER. Propionic acidemia: clinical, biochemical and therapeutic aspects: experience in 30 patients. Eur J Pediatr 1994; 153(Suppl 1):$68-$80. 3. Suormala T, Wick H, Bonjour JP, Baumgartner ER. Rapid differential diagnosis of carboxylase deficiencies and evaluation for biotin-responsiveness in a single blood sample. Clin Chim Acta 1985;145:151-62. 4. Da Fonseca-Wollheim F. Die direkte Plasmaammoniak-Bestimmung ohne Enteiweissng. Z Klin Chem Klin Biochem 1973;11:426-31. 5. Noll F: L-Lactate. In: Bergmeyer HU, editor. Methods of enzymatic analysis. 3rd ed. Weinheim, Germany: Chemie, 1984: 582-8. 6. Ishii K, Saral K, Sanemori H, Kawasaki T. Analysis of thiamine and its phosphate esters by high-performance liquid chromatography. Annal Biochem 1979;97:191-5. 7. Campbell CH. The severe lacticacidosis of thiamine deficiency: acute pernicious or fulminating beriberi. Lancet 1984;2:446-9. 8. Reuler JB, Rirard DE, Cooney TG. Wernicke's encephalopathy. N Engl J Med 1985;312:1035-9. 9. Committee on Dietary Allowances, Food and Nutrition Board, National Research Council. Recommended dietary allowances. 9th ed. Washington (DC): National Academy of Sciences, 1980. 10. Greene HL. Vitamins and trace elements. In: Ghadimi H, editor. Total parenteral nutrition: promises and premises. New York: John Wiley & Sons, 1975:351-71. 11. Gregersen N. Studies on the effect of saturated and unsaturated short-chain monocarboxylic acids on the energy metabolism of rat liver mitochondria. Pedlatr Res 1979;13:1227-30. 12. Rotman P, Hassin D, Mouallem M, Barkai G, Farfel Z. Wernicke's encephalopathy in hyperemesis gravidarum: association with abnormal liver function. Isr J Med Sci 1994;30:225-8. 13. Oriot D, Wood C, Gottesman R, Huault G. Severe lactic acidosis related to acute thiamine deficiency. JPEN J Parenter Enteral Nutr 1991;15:105-9. 14. Byrd DJ, Schweitzer-Krantz S, Ringe H, Marquardt I, Offner G. Thiamin~(Vitamin-B1)-Mangel bei Methylmalonazidurie mit Laktatazidose: Biochemische Laborbefunde. Monatsschr Kinderheilkd 1994;142:S 102(P452).
Propionic acidemia is often manifested during the neonatal period with vomiting, failure to thrive, lethargy, and hyperammonemic coma whencatabolism is prolonged. Mild lactic acidosis frequently accompanies metabolic decompensation. We present two patients with propionic acidemia whose initial manifestation was complicated by severe lactic acidosis caused by thiamine deficiency, which resulted from an inadequate supply of, and an increased need for, thiamine during metabolic stress. To prevent acute thiamine deficiency, we propose early vitamin supplementation during treatment of any severe metabolic decompensation accompanied by insufficient food intake. (J Pediatr 1996; 129:758-60)
Propionic acidemia (McKusick 23200, 23205) is an autosomal-recessive inborn error of branched-chain amino acid metabolism. It is caused by deficient activity of propionylcoenzyme A carboxylase (EC 6.4.1.3) and usually is manifested in the neonatal period or early infancy. Typically, the newborn infant's clinical condition deteriorates rapidly after a normal pregnancy and birth and a symptom-free interval. Initial symptoms are nonspecific and may include feeding problems, vomiting, failure to thrive, and often dehydration. Hyperammonemic coma develops progressively, and mild hyperlactacidemia may be observed) Diagnosis is estabfished by gas chromatography-mass spectrometry of a urine sample revealing specific metabolites. Confirmation by measurement of PCC activity in fibroblasts is recommended.1, 2 Severe hyperlactacidemia caused by thiamine deficiency is not a typical symptom of propionic acidemia. The deficiency usually results from inadequate vitamin intake or decreased intestinal absorption and may become acute during episodes of increased requirements, as in extreme catabolism or anabofism. We present two patients with PA complicated by thiamine deficiency. Presented in part at the 91st Annual Meeting of the Deutsche Gesellschaft for Kinderheilkunde, Krefeld, Germany, Sept. 8 to 10, 1995. Submitted for publication Feb. 7, 1996; accepted June 21, 1996. Reprint requests: Dietrich Matern, MD, University Children's Hospital, Mathildenstr. 1, D-79106 Freiburg,. Germany. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/22/75973
758
CASE
REPORTS
Pregnancy and birth were uneventful in both patients. Patient 1. At 6 days of age the fourth child of healthy, consanguineous parents of Indian origin had muscle hypotonia, feeding problems, and recurrent vomiting, which led to the initiation of intravenous fluid and glucose supplementation. A urine sample screened by GC-MS revealed characteristic metabolites of PA. Meanwhile, the 9-day-old boy required artificial ventilation, a metabolic acidosis with moderate hyperlactacidemia (11 retool/L; normal, 1 to 2 retool/L) had developed, and the boy was in a coma caused by hyperammonemia (748 ~nol/L; normal, -<40 wnol/L). The patient was transferred to our hospital. On his arrival, acute cardiac arrest necessitated cardiopulmonary resuscitation for 20 minutes. Hyperammonemiawas reduced to nearly normal values by the eleventh day of life with high-caloric parenteral nutrition and LCoA GC-MS PA PCC TPN
Coenzyme A Gas chromatography-mass spectrometry Propionic acidemia Propionyl-coenzyme A carboxylase Total parenteral nutrition
arginine. The patient slowly awakened from a 54-hour-long coma, during which the electroencephalogram revealed a burst-suppression pauem. At 14 days of age the patient was weaned from respiratory support, and feedings via a nasogastric tube were cautiously introduced. However, a paralytic ileus rendered the enteral feedings unsuccessful. Two days later a combined respiratory and metabolic acidosis developed and necessitated mechanical ventilation. Plasma lactic acid concentrations rose to 48 retool/L, paralleled by a decrease in blood pressure. Peritoneal dialysis was started to treat hyperlactacidemia. A blood sample drawn at this time eventually
The Journal of Pediatrics Volume 129, Number 5
Matern et al.
tgmol/L] 900
W
800
i,
*
_~ Thiamille in el~.hrooytes: 0.6 p.g/L[
A ~ - - :
~
759
20 [retool/L]
18 16
700
]administrationof 2 x 20 mg thiamine intra. . . . sly I I4
600 12 500
10 ~
Ammonia - i - in p l a s m a 400 •
Lactic acid in plasma
.8
300 200
10o
I
_______ Normal Range noI 43 44
-6 '1
~
4
, . . ~- . . . .
~.--,--. . . . . . .
i-I
I
45
46
I I- - -
47
-I~ . . . . . . . . . . . . . . . . . . . . . . 1
I
"*--t
"*t . . . . . .1 . . . .
48
49
50
51
52
I
-mI
53
54
55
Days of life
Fig. 1. Course of patient 2 with respect to ammonia, lactic acid, and thiamine levels.
revealed that a plasma concentration of thiamine was undetectable. Before a trial dose of thiamine could be administered, the child died of cardiorespiratory failure. Patient 2. The female patient is the second child of healthy, nonconsanguineous, white parents. During the neonatal period, she had to be awakened to feedings, drank reluctantly, and vomited recurrently. In her seventh week, she was hospitalized with dehydration and a tentative diagnosis of hypertrophic pyloric stenosis. At this time, she weighed 3830 gm (260 gm less than at birth), she required intravenous rehydration, and her pyloms appeared normal on a sonogram. On the following day, she became comatose because of marked hyperammonemia (881 ~mol/L; Fig. 1) and was immediately transferred to our hospital. Hemofiltration was initiated, and within 3 hours the ammonia level fell to 60 gmol/L and the patient awakened. By this time, the diagnosis of PA was established by GC-MS of a urine sample. Initially the patient was fed exclusively with intravenously administered glucose and lipids without vitamin supplements. On the second day an increasing hyperlactacidemia (18.7 mmol/L) worsened metabolic acidosis. After a blood sample was obtained for thiamine investigation (0.6 pg/L; normal, 1.7 to 6.7 jaglL), 40 mg of thiamine (11 mg/kg) was given intravenously and within 5 hours the acidosis had completely resolved. Measurement of PCC activity confirmed the diagnosis (5.9 pmol/min per milligram of protein; control values, 221 to 1742 pmol/min per milligram of protein3). The patient is now 9 months old and in stable and good condition.
METHODS Measurements of ammonia, lactic acid, and thiamine in plasma and erythrocytes, respectively, as well as GC-MS of the urine samples were performed as previously described.2, 4-6 Biochemical investigation of PCC was kindly performed by Dr. R. Baumgartner, University Children's Hospital, Basel, Switzerland)
Glucose
Lactate Dehydrogenase Pyruvate
Pyruvate Dehydrogenase
@
<
Lactate [Thiamine deficiency
]
v Acetyl-CoA
Fig. 2. Development ofhyperlactacidemia in thiamine deficiency.
DISCUSSION Thiamine (vitamin B1) is a cofactor for various biochemical reactions such as the oxidative decarboxylation of the o~-keto acids pyruvate and oL-ketoglutarate (Fig. 2). Its deficiency inhibits the entry of pyruvate into the citric acid cycle. Alternatively, accumulating pyruvate is dehydrogenated to lactic acid, which results in hyperlactacidemia. In the Western world, thiamine deficiency is most often the consequence of chronic alcohol abuse, as in Wemicke encephalopathy. In developing countries, chronically inadequate
760
Matern et al.
dietary thiamine intake leads to beriberi. In both of these chronic diseases, acute forms are known to be manifested by hyperlactacidemia, consequent metabolic acidosis, and cardiovascular shock. 7, s Enteral absorption of thiamine occurs mainly in the jejunum. Storage (primarily in the heart, brain, liver, and kidneys) amounts to approximately 25 mg in human beings, with a recommended daily allowance of 0.3 mg/day for newborn infants to 1.6 mg/day for the lactating woman. 9 Symptoms of vitamin deficiency in infants are manifested within 2 weeks of thiamine-free feedings. 1° Causes, alone or in combination, of thiamine deficiency are inadequate enteral or parenteral supply, inadequate enteral absorption, and increased consumption during metabolic stress. In PA, hyperlactacidemia is assumed to be caused by competitive inhibition of the pyruvate dehydrogenase complex by propionyl-CoA. 11 However, the high lactic acid concentrations that we observed have not yet been reported in PA. Thiamine deficiency in our patients had several causes. Both had feeding problems typical for PA. In patient 1, paralytic ileus hindered absorption even after enteral feedings containing thiamine were introduced. Patient 2 was admitted to the hospital with recurrent vomiting and dehydration. Accordingly, decreased vitamin stores can be postulated. In our care, both children received high-caloric total parenteral nutrition with glucose and lipids to overcome catabolism and restore anabolism. Both metabolic conditions require higher amounts of thiamine. Initially, however, TPN was not supplemented with vitamins. Patient 2 showed a prompt response, with rapid normalization of the acid-base status and the plasma lactic acid concentration, after thiamine was given. In the literature, thiamine deficiency has not been reported as a complication of PA. It may be caused by various mechanisms, such a s hyperemesis gravidarum and TPN without vitamin supplementation for patients with various diseases.12, 13 Byrd et al. 14 reported a patient with methylmalonic acidemia in whom hyperlactacidemia developed because of thiamine deficiency. This was attributed to an inadequate thiamine intake and not to the underlying metabolic disease. In view of these observations, the known causes of thiamine deficiency, and the histories of our patients, we believe that thiamine deficiency is also a potential complication of PA. Our patients had hyperammonemic coma; however, they received different treatments. Hemofiltration or dialysis was not feasible for patient 1 because of his circulatory instability. Therefore his ammonia level could be reduced only by reversing catabolism and administrating L-arginine. Patient 2 was well enough to undergo this procedure, and normal ammonia levels were measured after 3 hours of hemofiltration. Thus the time that patient 2 was comatose was less than 20 hours, more than 30 hours shorter than patient 1. Because
The Journal of Pediatrics November 1996
duration of coma is an important prognostic factor, t we believe that children with significant hyperammonemia should immediately be transferred to a center where hemofiltration can be performed, even if the underlying disorder is not yet known and the child is still not comatose. We conclude that all children requiring TPN should receive vitamin supplements whenever they have a disease favoring catabolism or their history suggests a reduced vitamin intake, or both. Furthermore, the rapid normalization of hyperammonemia can best be achieved by hemofiltration, which mandates immediate transfer of patients with hyperammonemia to a dialysis unit.
REFERENCES
1. Fenton WA, Rosenberg LE. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th ed. McGraw-Hill, 1995:1423-51. 2. Lehnert W, Sperl W, Suormala T, Baumgartner ER. Propionic acidemia: clinical, biochemical and therapeutic aspects: experience in 30 patients. Eur J Pediatr 1994; 153(Suppl 1):$68-$80. 3. Suormala T, Wick H, Bonjour JP, Baumgartner ER. Rapid differential diagnosis of carboxylase deficiencies and evaluation for biotin-responsiveness in a single blood sample. Clin Chim Acta 1985;145:151-62. 4. Da Fonseca-Wollheim F. Die direkte Plasmaammoniak-Bestimmung ohne Enteiweissng. Z Klin Chem Klin Biochem 1973;11:426-31. 5. Noll F: L-Lactate. In: Bergmeyer HU, editor. Methods of enzymatic analysis. 3rd ed. Weinheim, Germany: Chemie, 1984: 582-8. 6. Ishii K, Saral K, Sanemori H, Kawasaki T. Analysis of thiamine and its phosphate esters by high-performance liquid chromatography. Annal Biochem 1979;97:191-5. 7. Campbell CH. The severe lacticacidosis of thiamine deficiency: acute pernicious or fulminating beriberi. Lancet 1984;2:446-9. 8. Reuler JB, Rirard DE, Cooney TG. Wernicke's encephalopathy. N Engl J Med 1985;312:1035-9. 9. Committee on Dietary Allowances, Food and Nutrition Board, National Research Council. Recommended dietary allowances. 9th ed. Washington (DC): National Academy of Sciences, 1980. 10. Greene HL. Vitamins and trace elements. In: Ghadimi H, editor. Total parenteral nutrition: promises and premises. New York: John Wiley & Sons, 1975:351-71. 11. Gregersen N. Studies on the effect of saturated and unsaturated short-chain monocarboxylic acids on the energy metabolism of rat liver mitochondria. Pedlatr Res 1979;13:1227-30. 12. Rotman P, Hassin D, Mouallem M, Barkai G, Farfel Z. Wernicke's encephalopathy in hyperemesis gravidarum: association with abnormal liver function. Isr J Med Sci 1994;30:225-8. 13. Oriot D, Wood C, Gottesman R, Huault G. Severe lactic acidosis related to acute thiamine deficiency. JPEN J Parenter Enteral Nutr 1991;15:105-9. 14. Byrd DJ, Schweitzer-Krantz S, Ringe H, Marquardt I, Offner G. Thiamin~(Vitamin-B1)-Mangel bei Methylmalonazidurie mit Laktatazidose: Biochemische Laborbefunde. Monatsschr Kinderheilkd 1994;142:S 102(P452).