Acta Med Scand 205: 313-316, 1979
Changes in Amylase, Hepatic Enzymes and Bilirubin in Serum upon Initiation of Alcohol Abstinence J. Wadstein and G. Skude' From the Departments of Clinical Chemistry and Alcohol Diseases, University of Lund, Malmo General Hospital, Malmii. Sweden
ABSTRACT. The serum levels of bilirubin, aspartate aminotransferase (ASAT), y-glutamyltransferase (GT), and pancreatic isoamylase were determined in 156 alcohol addicts during the first 9 days upon initiation of alcohol abstinence. During this period decreasing activities were recorded for S-bilirubin and S-ASAT but patients possessing moderately increased serum activity of GT showed no decrease. Increased activities of S-ASAT and S-GT were still frequently seen at the end of the observation period. For S-pancreatic isoamylase, both decreases and increases from initial activities were frequently found. In patients with low activities initially, the Spancreatic isoamylase activity increased during the observation period and thus, pathologically increased activities were recorded more often 9 days after alcohol withdrawal than on arrival at the hospital. K e g words: alcoholism, aspartate aminotransferase, bilirubin, gamma-glutamyltransferase, isoamylase.
Acta Med Scand 205: 313, 1979. Increased serum activities of aspartate aminotransferase (ASAT) and alanine aminotransferase ( A L A T ) as well as y-glutamyltransferase (GT) a r e frequently seen in alcohol addicts ( I , 3 , 7 , 8 , 15, 18, 22). T h e elevation of S-ASAT is regularly more pronounced than that of S - A L A T (8, 16, 18). It is also known that the serum activities of A S A T a n d A L A T may increase for some d a y s after ethanol intake. Specific determination of the pancreatic isoamylase activity in serum has disclosed decreased levels t o be a common finding in chronic alcoholics o n admission t o hospital (18). T h e present study was undertaken t o disclose successive changes in the serum levels of bilirubin, ASAT, GT and pancreatic isoamylase in a series of alcoholics upon initiation of alcohol abstinence. PATIENTS A N D METHODS The patient series consisted of 156 male inpatients, at the Department of Alcohol Diseases, Malmo General Hos-
pital, aged 25-70 years (mean 44). They had been hospitalized after a period of heavy alcohol consumption. During hospitalization the patients were treated with a high protein-calorie diet, vitamin injections (Parentrovite@) as well as nitrazepam (Mogadon@),clomethiazole (Heminevrin@),promethazine (Lergigan@)and dixyrazine (Esucos@) in selected cases. None of the patients developed delirium tremens or had clinical or biochemical signs of liver cirrhosis. Blood samples were drawn immediately after arrival at the hospital, before any treatment was instituted, as well as every third day during the hospitalization. The laboratory parameters studied were S-bilirubin, S-ASAT, S-GT, S-salivary and S-pancreatic isoamylase, and S-albumin. Albumin was determined in a Technicon AutoAnalyzer with bromcresol green, the other techniques used were as described previously (18). The patients were grouped into five or six classes on the basis of their initial laboratory values and each class was followed separately. For S-bilirubin, S-ASAT, and S-GT, the classes were: normal range, 1-2, 3-5, 5-10, 10-20, and more than 20 times the values of the upper normal limit; for S-pancreatic isoamylase: increased activity, normal range except its lowest limit, lowest limit of normal range, moderately, and severely decreased activity (Fig. 1). RESULTS O n arrival a t the hospital, 15% of the patients had a n elevated serum concentration of bilirubin, i.e. above 20 pmol/l (1.2 mg/100 ml). At the end of the observation period o f 9 days S-bilirubin was elevated in 1.3 % of t h e patients. T h e serum activity of A S A T was increased initially in 70% of the patients. During t h e observation period t h e mean activities of the various groups decreased (Fig. I). However, only patients with moderate initial increase showed a complete normalization. Thus, 36% of the patients still had a I Present address: Department of Clinical Chemistry, Central Hospital, S-38100 Kalmar, Sweden.
ASAT=aspartate aminotransferase, ALAT=alanine aminotransferase, GT=y-glutamyltransferase.
Abbreviations:
J . Wudstein und C . Skude
3 14
u/ I
u/ I
#at/ i
pkat/l
900 r-Pancreatic isoamylase
350
800
300 7 00
250
600
ZOO
-
15 14
13 12
- 11 -
10
- 9
500
- 8
150
400 100 3 00
50 200
0 100
Pht/ I
U/I
0
2000 1800 1600 1400 1200
1wO 800 600
400
Fig. I . Changes upon initiation of alcohol abstinence in the mean serum concentrations of ASAT, GT and pancreatic isoamylase. Class ranges are indicated.
200
0 0
3
9
QAY
pathologically high S-ASAT activity after 9 days of ethanol abstinence. Initially, 66% of the patients had an increased activity of S-GT. During the observation period there was no change in the groups whose initial activity had been slightly increased. Decreasing activities, however, were recorded in patients with initially high S-GT activities, i.e. more than 5 times the upper normal limit (Fig. 1). After 9 days of abstinence, 74% of all patients had an increased S-GT activity. The serum activity of pancreatic isoamylase was initially increased in 15 % and decreased in 15 % of the patients. During the abstinence period there was
a decrease in the patients with initially elevated values (Fig. 1). However, patients whose initial pancreatic serum isoamylase activity was low or normal showed a rise during the abstinence period, at the end of which 34% had a pathologically increased activity and only 5 % a decreased activity. No correlation was found between pancreatic isoamylase activity and activities of S-ASAT or S-GT. The salivary isoarnylase activity in serum, which did not show any significant changes during the observation period, was unrelated to the initial pancreatic isoamylase activity. Nor did the serum level of albumin show any
Enzymes in alcohol abstinence
significant changes during the observation period. The mean serum albumin concentration on admission was not correlated to the initial pancreatic serum isoamylase activity. The albumin levels of the various groups (of S-pancreatic isoamylase activity) were 43, 43, 45, 43, and 44 g/l, respecti ve I y .
DISCUSSION The initial frequencies of pathological serum levels of the studied parameters are in good agreement with earlier reports (7, 8, I I , 12, 14, IS, 18, 21, 22, 73). The results of the present study clearly show that, although there was a tendency towards normalization of increased activities for S-ASAT and S-GT during the observation period, i.e. the first 9 days of abstinence, only patients with moderately increased serum activities normalized their serum levels. Patients with higher initial values remained on an elevated level even at the end of that period. This was especially the case for S-GT. Thus, it can be concluded that determination of S-GT at least 9 days after alcohol withdrawal can still be used as a measure of previous heavy alcohol consumption. An elevated S-ASAT activity 9 days after withdrawal of alcohol indicates that the initial activity presumably would have been more than twice the upper normal limit. Patients who initially displayed laboratory signs of acute pancreatic involvement, i.e. increased pancreatic serum isoamylase activity, showed a tendency towards normalization of their activity. However, the activity decreased more slowly than is commonly seen in cases of acute pancreatitis. In the latter cases, as well as in the acute hyperamylasemia following endoscopic retrograde pancreatography , a complete normalization is usually seen in about S days (19). The delayed normalization seen in the present patients may be related to the finding of a successive increase in the pancreatic serum isoamylase activity in the patients who initially had low or normal levels. This finding may be interpreted as a depressing effect of ethanol on the pancreatic secretion; i.v. ethanol administration is known to reduce the pancreatic output of enzymes in humans (9). Another explanation may be the deficient nutrition during the drinking period which is known to occur in about one-third of chronic alcoholics. Thus, a reduced pancreatic serum isoamylase activity can frequently be re-
3 15
corded in patients with severe malnutrition (17) and pancreatic dysfunction is well documented in protein-calorie malnutrition (2, 13,20). Mezey and Potter (10) found a normalization of the pancreatic trypsin output in chronic alcoholics following adequate diet, despite continued ethanol intake. The absence of a positive correlation between the albumin concentration and pancreatic isoamylase activity in serum on admission, however, supports the former explanation. Nor was there any positive correlation between the salivary and the pancreatic serum isoamylase activities. As the patients in the present study were grouped according to their initial enzyme activities, it was possible to demonstrate the very slow reduction of slightly and moderately increased activities of S-ASAT and S-GT. No significant delayed increase in the serum levels of ASAT or GT could be demonstrated. The delayed increase in the serum activity of pancreatic amylase could be demonstrated because specific determination of the pancreatic serum isoamylase activity was performed and the patients were divided into classes based on the initial levels of their serum activities.
REFERENCES 1. Bang, N . U., Iversen, K . , Jagt, T. & Madsen, S.:
2.
3.
4.
5. 6. 7. 8. 9. 10.
Serum glutamic oxaloacetic transaminase activity in acute and chronic alcoholism. JAMA 168: 156, 1958. Barbezat, G. 0. & Hansen, J. D. L.: The exocrine pancreas and protein-calorie malnutrition. Pediatrics 42: 77, 1968. Brohult, I., Carlson, L. A. & Reichard, H.: Serumenzyme activities, cholesterin and triglycerides in serum after intake of alcohol. Scand J Clin Lab Invest (Suppl) 92: 82, 1966. The Committee on Enzymes of the Scandinavian Society for Clinical Chemistry and Clinical Physiology: Recommended methods for the determination of four enzymes in blood. Scand J Clin Lab Invest 33:291, 1974. Jellinek, E. M.: The withdrawal syndrome in alcoholism. Can Med Assoc J 81: 536, 1959. - The disease concept of alcoholism. Hillhouse Press, New Haven 1960. Johansson, B. G. & Medhus, A.: Increase in plasma a-lipoproteins in chronic alcoholics after acute abuse. Acta Med Scand 195: 273, 1974. Konttinen, A,, Hartel, G. & Louhija, A,: Multiple serum enzyme analysis in chronic alcoholics. Acta Med Scand 188: 257, 1970. Marin, G . , Ward, N. & Fischer, R.: Effect of ethanol on pancreatic and biliary secretions in humans. Am J Dig Dis 18: 825, 1973. Mezey, E. 8t Potter, J.: Changes in endocrine Actti Med Scand 205
3 16
1I .
12.
13.
14. 15.
16.
J . Wudstein and C. Skude pancreatic function produced by altered dietary protein intake in drinking alcoholics. Johns Hopkins Med J 138: 7, 1976. Myrhed, M.: Alcohol consumption in relation to factors associated with ischemic heart disease. Acta Med Scand (Suppl) 567, 1974. Myrhed, M. & Bergstrom, K.: Nfigra leverenzymer hos alkoholdiskordanta tvillingpar. In: Annual meeting of the Swedish Society of Medical Sciences, Stockholm 1973. Pelaez, M. J., Gonzales, P. A. & Velez, A. H.: Estudio de la function pancreatica en pacientes desnutridos. Antioquia Med 16: 41, 1966. Rosalki, S. B . : Screening test for alcoholism. Lancet 2:843, 1973. Rosalki, S. B. & Rau, D.: Serum y-glutamyl transpeptidase activity in alcoholism. Clin Chim Acta 39:41, 1972. Salum, I.: Delirium tremens and certain other acute sequels of alcohol abuse. Acta Phychiatr Scand (Suppl) 235, 1972.
17. Skude, G.: Unpublished results. 18. Skude, G. & Wadstein, J.: Amylase, hepatic enzymes and bilirubin in serum in chronic alcoholics. Acta Med Scand 201: 53, 1977. 19. Skude, G., Wehlin, L., Maruyama, T. & Ariyama, J.: Hyperamylasemia after duodenoscopy and retrograde cholangiopancreatography. Gut 17: 127, 1976. 20. Tandon, B. N., George, P. K., Sama, S. K. Ramachandran, K . & Gandhi, P. C.: Exocrine pancreatic function in protein calorie malnutrition disease of adults. Am J Clin Nutr 22: 1476, 1969. 21. Thaler, H.: Alkohol und Leberschaden. Dtsch Med Wochenschr 23: 1213, 1969. 22. Wallerstedt, S. & Olsson, R.: Personal communication. 23. Wallgren, H. & Barry, 111, H.: Actions of alcohol, parts 1-11. Elsevier, Amsterdam, London and New York 1970.
Changes in Amylase, Hepatic Enzymes and Bilirubin in Serum upon Initiation of Alcohol Abstinence J. Wadstein and G. Skude' From the Departments of Clinical Chemistry and Alcohol Diseases, University of Lund, Malmo General Hospital, Malmii. Sweden
ABSTRACT. The serum levels of bilirubin, aspartate aminotransferase (ASAT), y-glutamyltransferase (GT), and pancreatic isoamylase were determined in 156 alcohol addicts during the first 9 days upon initiation of alcohol abstinence. During this period decreasing activities were recorded for S-bilirubin and S-ASAT but patients possessing moderately increased serum activity of GT showed no decrease. Increased activities of S-ASAT and S-GT were still frequently seen at the end of the observation period. For S-pancreatic isoamylase, both decreases and increases from initial activities were frequently found. In patients with low activities initially, the Spancreatic isoamylase activity increased during the observation period and thus, pathologically increased activities were recorded more often 9 days after alcohol withdrawal than on arrival at the hospital. K e g words: alcoholism, aspartate aminotransferase, bilirubin, gamma-glutamyltransferase, isoamylase.
Acta Med Scand 205: 313, 1979. Increased serum activities of aspartate aminotransferase (ASAT) and alanine aminotransferase ( A L A T ) as well as y-glutamyltransferase (GT) a r e frequently seen in alcohol addicts ( I , 3 , 7 , 8 , 15, 18, 22). T h e elevation of S-ASAT is regularly more pronounced than that of S - A L A T (8, 16, 18). It is also known that the serum activities of A S A T a n d A L A T may increase for some d a y s after ethanol intake. Specific determination of the pancreatic isoamylase activity in serum has disclosed decreased levels t o be a common finding in chronic alcoholics o n admission t o hospital (18). T h e present study was undertaken t o disclose successive changes in the serum levels of bilirubin, ASAT, GT and pancreatic isoamylase in a series of alcoholics upon initiation of alcohol abstinence. PATIENTS A N D METHODS The patient series consisted of 156 male inpatients, at the Department of Alcohol Diseases, Malmo General Hos-
pital, aged 25-70 years (mean 44). They had been hospitalized after a period of heavy alcohol consumption. During hospitalization the patients were treated with a high protein-calorie diet, vitamin injections (Parentrovite@) as well as nitrazepam (Mogadon@),clomethiazole (Heminevrin@),promethazine (Lergigan@)and dixyrazine (Esucos@) in selected cases. None of the patients developed delirium tremens or had clinical or biochemical signs of liver cirrhosis. Blood samples were drawn immediately after arrival at the hospital, before any treatment was instituted, as well as every third day during the hospitalization. The laboratory parameters studied were S-bilirubin, S-ASAT, S-GT, S-salivary and S-pancreatic isoamylase, and S-albumin. Albumin was determined in a Technicon AutoAnalyzer with bromcresol green, the other techniques used were as described previously (18). The patients were grouped into five or six classes on the basis of their initial laboratory values and each class was followed separately. For S-bilirubin, S-ASAT, and S-GT, the classes were: normal range, 1-2, 3-5, 5-10, 10-20, and more than 20 times the values of the upper normal limit; for S-pancreatic isoamylase: increased activity, normal range except its lowest limit, lowest limit of normal range, moderately, and severely decreased activity (Fig. 1). RESULTS O n arrival a t the hospital, 15% of the patients had a n elevated serum concentration of bilirubin, i.e. above 20 pmol/l (1.2 mg/100 ml). At the end of the observation period o f 9 days S-bilirubin was elevated in 1.3 % of t h e patients. T h e serum activity of A S A T was increased initially in 70% of the patients. During t h e observation period t h e mean activities of the various groups decreased (Fig. I). However, only patients with moderate initial increase showed a complete normalization. Thus, 36% of the patients still had a I Present address: Department of Clinical Chemistry, Central Hospital, S-38100 Kalmar, Sweden.
ASAT=aspartate aminotransferase, ALAT=alanine aminotransferase, GT=y-glutamyltransferase.
Abbreviations:
J . Wudstein und C . Skude
3 14
u/ I
u/ I
#at/ i
pkat/l
900 r-Pancreatic isoamylase
350
800
300 7 00
250
600
ZOO
-
15 14
13 12
- 11 -
10
- 9
500
- 8
150
400 100 3 00
50 200
0 100
Pht/ I
U/I
0
2000 1800 1600 1400 1200
1wO 800 600
400
Fig. I . Changes upon initiation of alcohol abstinence in the mean serum concentrations of ASAT, GT and pancreatic isoamylase. Class ranges are indicated.
200
0 0
3
9
QAY
pathologically high S-ASAT activity after 9 days of ethanol abstinence. Initially, 66% of the patients had an increased activity of S-GT. During the observation period there was no change in the groups whose initial activity had been slightly increased. Decreasing activities, however, were recorded in patients with initially high S-GT activities, i.e. more than 5 times the upper normal limit (Fig. 1). After 9 days of abstinence, 74% of all patients had an increased S-GT activity. The serum activity of pancreatic isoamylase was initially increased in 15 % and decreased in 15 % of the patients. During the abstinence period there was
a decrease in the patients with initially elevated values (Fig. 1). However, patients whose initial pancreatic serum isoamylase activity was low or normal showed a rise during the abstinence period, at the end of which 34% had a pathologically increased activity and only 5 % a decreased activity. No correlation was found between pancreatic isoamylase activity and activities of S-ASAT or S-GT. The salivary isoarnylase activity in serum, which did not show any significant changes during the observation period, was unrelated to the initial pancreatic isoamylase activity. Nor did the serum level of albumin show any
Enzymes in alcohol abstinence
significant changes during the observation period. The mean serum albumin concentration on admission was not correlated to the initial pancreatic serum isoamylase activity. The albumin levels of the various groups (of S-pancreatic isoamylase activity) were 43, 43, 45, 43, and 44 g/l, respecti ve I y .
DISCUSSION The initial frequencies of pathological serum levels of the studied parameters are in good agreement with earlier reports (7, 8, I I , 12, 14, IS, 18, 21, 22, 73). The results of the present study clearly show that, although there was a tendency towards normalization of increased activities for S-ASAT and S-GT during the observation period, i.e. the first 9 days of abstinence, only patients with moderately increased serum activities normalized their serum levels. Patients with higher initial values remained on an elevated level even at the end of that period. This was especially the case for S-GT. Thus, it can be concluded that determination of S-GT at least 9 days after alcohol withdrawal can still be used as a measure of previous heavy alcohol consumption. An elevated S-ASAT activity 9 days after withdrawal of alcohol indicates that the initial activity presumably would have been more than twice the upper normal limit. Patients who initially displayed laboratory signs of acute pancreatic involvement, i.e. increased pancreatic serum isoamylase activity, showed a tendency towards normalization of their activity. However, the activity decreased more slowly than is commonly seen in cases of acute pancreatitis. In the latter cases, as well as in the acute hyperamylasemia following endoscopic retrograde pancreatography , a complete normalization is usually seen in about S days (19). The delayed normalization seen in the present patients may be related to the finding of a successive increase in the pancreatic serum isoamylase activity in the patients who initially had low or normal levels. This finding may be interpreted as a depressing effect of ethanol on the pancreatic secretion; i.v. ethanol administration is known to reduce the pancreatic output of enzymes in humans (9). Another explanation may be the deficient nutrition during the drinking period which is known to occur in about one-third of chronic alcoholics. Thus, a reduced pancreatic serum isoamylase activity can frequently be re-
3 15
corded in patients with severe malnutrition (17) and pancreatic dysfunction is well documented in protein-calorie malnutrition (2, 13,20). Mezey and Potter (10) found a normalization of the pancreatic trypsin output in chronic alcoholics following adequate diet, despite continued ethanol intake. The absence of a positive correlation between the albumin concentration and pancreatic isoamylase activity in serum on admission, however, supports the former explanation. Nor was there any positive correlation between the salivary and the pancreatic serum isoamylase activities. As the patients in the present study were grouped according to their initial enzyme activities, it was possible to demonstrate the very slow reduction of slightly and moderately increased activities of S-ASAT and S-GT. No significant delayed increase in the serum levels of ASAT or GT could be demonstrated. The delayed increase in the serum activity of pancreatic amylase could be demonstrated because specific determination of the pancreatic serum isoamylase activity was performed and the patients were divided into classes based on the initial levels of their serum activities.
REFERENCES 1. Bang, N . U., Iversen, K . , Jagt, T. & Madsen, S.:
2.
3.
4.
5. 6. 7. 8. 9. 10.
Serum glutamic oxaloacetic transaminase activity in acute and chronic alcoholism. JAMA 168: 156, 1958. Barbezat, G. 0. & Hansen, J. D. L.: The exocrine pancreas and protein-calorie malnutrition. Pediatrics 42: 77, 1968. Brohult, I., Carlson, L. A. & Reichard, H.: Serumenzyme activities, cholesterin and triglycerides in serum after intake of alcohol. Scand J Clin Lab Invest (Suppl) 92: 82, 1966. The Committee on Enzymes of the Scandinavian Society for Clinical Chemistry and Clinical Physiology: Recommended methods for the determination of four enzymes in blood. Scand J Clin Lab Invest 33:291, 1974. Jellinek, E. M.: The withdrawal syndrome in alcoholism. Can Med Assoc J 81: 536, 1959. - The disease concept of alcoholism. Hillhouse Press, New Haven 1960. Johansson, B. G. & Medhus, A.: Increase in plasma a-lipoproteins in chronic alcoholics after acute abuse. Acta Med Scand 195: 273, 1974. Konttinen, A,, Hartel, G. & Louhija, A,: Multiple serum enzyme analysis in chronic alcoholics. Acta Med Scand 188: 257, 1970. Marin, G . , Ward, N. & Fischer, R.: Effect of ethanol on pancreatic and biliary secretions in humans. Am J Dig Dis 18: 825, 1973. Mezey, E. 8t Potter, J.: Changes in endocrine Actti Med Scand 205
3 16
1I .
12.
13.
14. 15.
16.
J . Wudstein and C. Skude pancreatic function produced by altered dietary protein intake in drinking alcoholics. Johns Hopkins Med J 138: 7, 1976. Myrhed, M.: Alcohol consumption in relation to factors associated with ischemic heart disease. Acta Med Scand (Suppl) 567, 1974. Myrhed, M. & Bergstrom, K.: Nfigra leverenzymer hos alkoholdiskordanta tvillingpar. In: Annual meeting of the Swedish Society of Medical Sciences, Stockholm 1973. Pelaez, M. J., Gonzales, P. A. & Velez, A. H.: Estudio de la function pancreatica en pacientes desnutridos. Antioquia Med 16: 41, 1966. Rosalki, S. B . : Screening test for alcoholism. Lancet 2:843, 1973. Rosalki, S. B. & Rau, D.: Serum y-glutamyl transpeptidase activity in alcoholism. Clin Chim Acta 39:41, 1972. Salum, I.: Delirium tremens and certain other acute sequels of alcohol abuse. Acta Phychiatr Scand (Suppl) 235, 1972.
17. Skude, G.: Unpublished results. 18. Skude, G. & Wadstein, J.: Amylase, hepatic enzymes and bilirubin in serum in chronic alcoholics. Acta Med Scand 201: 53, 1977. 19. Skude, G., Wehlin, L., Maruyama, T. & Ariyama, J.: Hyperamylasemia after duodenoscopy and retrograde cholangiopancreatography. Gut 17: 127, 1976. 20. Tandon, B. N., George, P. K., Sama, S. K. Ramachandran, K . & Gandhi, P. C.: Exocrine pancreatic function in protein calorie malnutrition disease of adults. Am J Clin Nutr 22: 1476, 1969. 21. Thaler, H.: Alkohol und Leberschaden. Dtsch Med Wochenschr 23: 1213, 1969. 22. Wallerstedt, S. & Olsson, R.: Personal communication. 23. Wallgren, H. & Barry, 111, H.: Actions of alcohol, parts 1-11. Elsevier, Amsterdam, London and New York 1970.
