- Email: [email protected]
Serum gamma glutamyl transpeptidase in liver disorders
Clin. Biochem. 6, 41-45 (1973)
SERUM GAMMA GLUTAMYL T R A N S P E P T I D A S E IN LIVER DISORDERS
P. M. KEANE, L. GARCIA, R. N. GUPTA and W. H. C. WALKER Clinical Chemistry Services, St. Joseph's Hospital and McMaster University Medical Centre, Hamilton, Ontario. (Received August ~3, 197Z)
SUMMARY 1. The levels of serum g a m m a g l u t a m y l transpeptidases (GGT) were estimated in 189 p a t i e n t s with diseases of the liver and biliary system and several non-hepatic disorders. 2. S e r u m a s p a r t a t e t r a n s a m i n a s e (AST), alanine t r a n s a m i n a s e ( A L T ) , and alkaline phosphatase (AP) were estimated on the same samples. 3. GGT is more sensitive an indicator of liver disorder t h a n AST or A L T except in infective and serum hepatitis. It readily distinguishes these conditions f r o m d r u g sensitivity jaundice. 4. In bone disease with elevated AP values, GGT levels were n o r m a l or slightly elevated. 5. A L T was consistently more sensitive t h a n AST in infective and ser u m hepatitis. In other liver disorders the relative sensitivities of A L T and AST showed no consistent pattern. GGT was invariably elevated when either t r a n s a m i n a s e was abnormal. I t can replace either one of the t r a n s a m i n a s e s but not both, w i t h improved diagnostic effect a n d w i t h o u t loss of useful data. 6. Elevations of GGT occurred in cerebral disorders and diabetes as well as in the reported cases (1) of myocardial i n f a r c t i o n and angina.
SINCE 1950, THERE HAS BEEN RAPIDLY INCREASING INTEREST in the diagnostic use of G G T as an indicator of liver disease. Jacobs (2) has briefly reviewed the relevant literature. The present work describes experience Correspondence: Dr. P. M. Keane, Department of Laboratory Medicine, St. Joseph's Hospital, Hamilton, Ontario.
42
K E A N E et al. GGT
"~ E
x ULN
ALT x ULN AST.x ULN
• o
"~ E
AP
XULN
5 GROUP
NO.I
co 1
2
3~
5 -
-
HEPATITIS DRUG SENSITIVITY
7
0
4
8
16 32 64 128
c° 1
2
O 0 ,
*
•
4
8
16 32 64 128
= o
:
0
0,,-.....-.,-------.~
~
2
4
8 16
~
XULN
2
4
8
10 0
--
:
8
16 32
:
57
-
a
16 •
:-
~-~
0
CHOLECYSTITIS 2 c
c 1
IlL
o c 1
3
16
:
:
: ~
12
2o MALIGNANCY
14
0
141
0:
:
:
6
:
2
~
I
I° PANCREATIC
MALIGNANCY
4
0
0
A L •
0
~
:
:=
:
:
0
0
m
~ - - ~
I
PANCREATITIS
•
•
•
01
4
0
ALCOHOLISM
3(}
0
16 m ' ~ ' - - e ' ~ ' e 10
CIRRHOSIS
23
0
4 4
CONGESTIVE 24 HEART FAILURE
0
BONE DISEASE
B 80
CEREBRAL DISORDERS
6 33
-
•
IO ~
2 5 . - ~ . - ~ 4
33 L , ~ ~ I
150 ~
-
33 16
9
~
0( 5(}
-
11
6 0 ~.
:
0
331~-.e..~---~ 116
4 8 ::
= 0 I e-e-e I
:
:
;
=
800
84
Fig. 1. Enzyme activities expressed in terms of times upper limit of normal (XULN) for disease groups.
of GGT which was added to the other liver function enzymes analysed in 3000 samples during the past 2 years. The clinical status of 189 patients with elevated GGT, elevated AP' or evidence of liver disorders has been reviewed together with the results of serum A L T and AST, with a view to assessing the sensitivity and specificity of serum GGT levels in liver disease. MATERIALS AND METHODS
The patient population selected for study consisted of 189 clinic and inpatients seen at St. Joseph's Hospital. GGT w a s measured at 37°C by the method of Szasz using L-7-glutam y l - p-nitroanilide as substrate (2). A P was determined at 37 ° on the SMA 12/60 (Technicon) with p-nitrophenyl phosphate as substrate (3). AST was measured at 43°C on the SMA 12/60 (4) and A L T was assayed kinetically at 37°C at 340 nm (5). All specimens were stored at 4°C and assayed within 96 hours. RESULTS
GGT activity w a s measured in 86 healthy men and 117 healthy women.
GGT IN LIVER DISORDERS
43
The male mean was 15.6 _ 6.9 (I.S.D.) ; the female mean was 11.0 ± 6.1. The coefficient of variation between batch was 6.5%. The upper limit of normal was set at 30 U / L . Upper limits for ALT and AST were set at 55 U / L and for AP' at 85 U / L . Results are displayed as 'times upper limit of normal ( X U L N ) ' to facilitate comparisons of different enzymes. Fig. 1 summarizes the data f r o m patients with diseases of liver, pancreas and bile duct and for the other disorders in which either GGT or A P were raised. DISCUSSION The enzyme methodologies, units and 'upper limits of normal' are directly comparable with these used in the work of Lure and Gambino (6). The results here reported complement and confirm the findings of these workers.
Hepatitis: There were 17 patients with probable serum hepatitis and 22 with no injection history diagnosed as infective hepatitis. There w a s no significant difference between the enzyme results of the 2 groups and they are displayed as a combined group in Fig. 1. This group contained the only 2 patients with liver disorder who had normal GGT values. Expressed in X U L N terms, the transaminases were always greater than GGT; A L T w a s more elevated than AST. These findings confirm those of other workers (6, 7). Drug Sensitivity: The cases in this group all showed greater elevation of GGT than of transaminases, a feature which they shared with nearly all other cases with liver disorders. The distinction between drug sensitivity and hepatitis is shown in Fig. 2.
30"~
• / /
•
•
/ /
Z .J
2O
/
/"
•
X ),.
/ /
0
•
10-
z
/ /
A/J
/
/
•
• •
eo °
,;
•
° e
•
•
='o
•
•
•
•
='o
20
0
60
70
80
ALT XULN
Fig. 2. GGT and ALT results compared for drug sensitivity group (A) and hepatitis group ( • ).
44
K E A N E et al.
Hepatic Malignancy; Pancreatitis: In 14 patients with carcinoma metastatic to the liver, GGT values were m a r k e d l y elevated with only moderate increases in t r a n s a m i n a s e s (6, 9), and similar changes w e r e p r e s e n t in the 4 cases of p r i m a r y carcinoma of the pancreas. In acute pancreatitis (8), markedly raised GGT values were associated with higher transaminase values.
Alcoholism: The 30 chronic alcoholics, all severe, had GGT values more elevated than t r a n s a m i n a s e s or A P (6, 10, 11, 12, 18, 1/,). Only one patient had an elevated GGT with normal t r a n s a m i n a s e s and AP.
Cirrhosis: The 23 cirrhotics all showed abnormal GGT values and all b u t 2 had elevated A P values. A S T and A L T were normal or mildly elevated with half the cases showing higher A S T values than ALT. congestive Failure: In all 24 patients in this group, t h e GGT values were m a r k e d l y elevated with A P less increased or normal (2 cases). Bone Disease: F o u r patients with P a g e t ' s disease and one with carcinoma of b r e a s t m e t a s t a t i c to bone showed elevations of A P with normal GGT values except in one case with an AP' 1 2 X U L N and GGT 2.7XULN. One of 2 patients on anticonvulsant t h e r a p y f o r epilepsy and 3 out of 4 with Cerebrovascular accidents showed elevations of GGT with variable elevations of AST, A L T and AP. This g r o u p deserves f u r t h e r longitudinal s t u d y (15). In none w a s there clinical evidence of hepatic disorder. F o u r patients with diabetes and essential h y p e r t e n s i o n (1) had GGT values f r o m 3 to 8 X U L N with no other enzyme abnormalities. These findings taken with the documented late rise in some cases of myocardial infarction (1) indicate that GGT is not entirely specific f o r liver disease. However, it does have a sensitivity in liver disease t h a t in all situations, except infective hepatitis, exceeds t h a t of A L T or AST. The failure of GGT to correlate with t r a n s a m i n a s e s or A P coupled with its reasonable specificity for liver diseases renders this enzyme a valuable addition to the test profile used to define liver function. It would a p p e a r to be reasonable to allow GGT to replace either one of A L T or A S T t h e r e b y increasing information w i t h o u t losing a n y t h i n g of diagnostic value.
GGT IN L I V E R D I S O R D E R S
45
REFERENCES 1. JACOBS, W. L. W. 7-Glutamyl-transpeptidase in diseases of the liver, cardiovascular system and diabetes mellitus. Clinica Chim. Acta 38, 419-434 (1972). 2. SZASZ, G. A kinetic photometric method for serum ~-glutamyl transpeptidase. Clin. Chem. 15, 124-136 (1969). 3. M O R G E N S T E R N , S., K E S S L E R , G., A U E R B A C H , J., FLOR, R. V. and K L E I N , B. An automated p-nitrophenylphosphate serum alkaline phosphatase procedure for the Auto Analyzer. Clin. Chem. 11, 876-888 (1965). $. M O R G E N S T E R N , S., O K L A N D E R , M., A U E R B A C H , J., K A U F M A N , J. and K L E I N , B. Automated determination of serum glutamic oxalacetic transaminase. Clin. Chem. 12, 95-111 (1966). 5. H E N R Y , R. J., CHIAMORI, N., GOLUB, O. J. and B E R K M A N , S. Revised spectrophotometric methods for the determination of giutamic-oxalacetic t r a n s a m i nase, glutamic-pyruvic transaminase, and lactic acid dehydrogenase. Amer. J. Clin. Path. 34, 381-398 (1960). 6. LUM, G. and GAMBINO, R. S. Serum g a m m a - g l u t a m y l t r a n s p e p t i d a s e activity as an indicator of disease of liver, pancreas, or bone. Clin. Chem. 18, 358-362 (1972). 7. A R O N S E N , K. F., H A N S O N , A. and N O S S L I N , B. The value of 7-glutamyl transpeptidase in d i f f e r e n t i a t i n g viral hepatitis from obstructive jaundice. Acta Chir. Scand. 130, 92-99 (1965). 8. R U T E N B E R G , A. M., GOLDBARG, J. A. and P I N E D A , E. P. Serum 7-glutamyl transpeptidase activity in hepatobiliary pancreatic disease. Gastroenterology 45, 43-48 (1963). 9. SZCZEKLIK, E., O R L O W S K I , M. and SZEWCZUK, A. Serum ~-glutamyl transpeptidase activity in liver disease. Gastroenterology 41, 353-359 (1961). 10. ZEIN, M. and DISCOMBE, G. Serum gamma-glutamyl transpeptidase as a diagnostic acid. Lancet ii, 748-750 (1970). 11. K O N T T I N E N , A., H A R T E L , G., and L O U H I J A , A. Multiple serum enzyme analyses in chronic alcoholics. Acta Med. Scand. 188, 257-264 (1970). 12. ROLLASON, J. G., P I N C H E R L E , G. and ROBINSON, D. Serum gamma-glutamyl t r a n s p e p t i d a s e in relation to alcohol consumption. Clinica Chim. Acta, 39, 75-80 (1972). 13. ROSALKI, S. B. and RAU, D. Serum ~-glutamyl transpeptidase activity in alcoholism. Clinica Chim. Acta 39, 41-47 (1972). 14. ROSALKI, S. B., RAU, D., L E H M A N N , D. and P R E N T I C E , M. Gamma-glutamyl transpeptidase in chronic alcoholism. Lancet ii, 1139 (1970). 15. E W E N , L. M. and G R I F F I T H S , J. Serum ~-glutamyl t r a n s p e p t i d a s e : elevated levels in certain neurological diseases. Clin. Chem. 17, 642 (1971).
SERUM GAMMA GLUTAMYL T R A N S P E P T I D A S E IN LIVER DISORDERS
P. M. KEANE, L. GARCIA, R. N. GUPTA and W. H. C. WALKER Clinical Chemistry Services, St. Joseph's Hospital and McMaster University Medical Centre, Hamilton, Ontario. (Received August ~3, 197Z)
SUMMARY 1. The levels of serum g a m m a g l u t a m y l transpeptidases (GGT) were estimated in 189 p a t i e n t s with diseases of the liver and biliary system and several non-hepatic disorders. 2. S e r u m a s p a r t a t e t r a n s a m i n a s e (AST), alanine t r a n s a m i n a s e ( A L T ) , and alkaline phosphatase (AP) were estimated on the same samples. 3. GGT is more sensitive an indicator of liver disorder t h a n AST or A L T except in infective and serum hepatitis. It readily distinguishes these conditions f r o m d r u g sensitivity jaundice. 4. In bone disease with elevated AP values, GGT levels were n o r m a l or slightly elevated. 5. A L T was consistently more sensitive t h a n AST in infective and ser u m hepatitis. In other liver disorders the relative sensitivities of A L T and AST showed no consistent pattern. GGT was invariably elevated when either t r a n s a m i n a s e was abnormal. I t can replace either one of the t r a n s a m i n a s e s but not both, w i t h improved diagnostic effect a n d w i t h o u t loss of useful data. 6. Elevations of GGT occurred in cerebral disorders and diabetes as well as in the reported cases (1) of myocardial i n f a r c t i o n and angina.
SINCE 1950, THERE HAS BEEN RAPIDLY INCREASING INTEREST in the diagnostic use of G G T as an indicator of liver disease. Jacobs (2) has briefly reviewed the relevant literature. The present work describes experience Correspondence: Dr. P. M. Keane, Department of Laboratory Medicine, St. Joseph's Hospital, Hamilton, Ontario.
42
K E A N E et al. GGT
"~ E
x ULN
ALT x ULN AST.x ULN
• o
"~ E
AP
XULN
5 GROUP
NO.I
co 1
2
3~
5 -
-
HEPATITIS DRUG SENSITIVITY
7
0
4
8
16 32 64 128
c° 1
2
O 0 ,
*
•
4
8
16 32 64 128
= o
:
0
0,,-.....-.,-------.~
~
2
4
8 16
~
XULN
2
4
8
10 0
--
:
8
16 32
:
57
-
a
16 •
:-
~-~
0
CHOLECYSTITIS 2 c
c 1
IlL
o c 1
3
16
:
:
: ~
12
2o MALIGNANCY
14
0
141
0:
:
:
6
:
2
~
I
I° PANCREATIC
MALIGNANCY
4
0
0
A L •
0
~
:
:=
:
:
0
0
m
~ - - ~
I
PANCREATITIS
•
•
•
01
4
0
ALCOHOLISM
3(}
0
16 m ' ~ ' - - e ' ~ ' e 10
CIRRHOSIS
23
0
4 4
CONGESTIVE 24 HEART FAILURE
0
BONE DISEASE
B 80
CEREBRAL DISORDERS
6 33
-
•
IO ~
2 5 . - ~ . - ~ 4
33 L , ~ ~ I
150 ~
-
33 16
9
~
0( 5(}
-
11
6 0 ~.
:
0
331~-.e..~---~ 116
4 8 ::
= 0 I e-e-e I
:
:
;
=
800
84
Fig. 1. Enzyme activities expressed in terms of times upper limit of normal (XULN) for disease groups.
of GGT which was added to the other liver function enzymes analysed in 3000 samples during the past 2 years. The clinical status of 189 patients with elevated GGT, elevated AP' or evidence of liver disorders has been reviewed together with the results of serum A L T and AST, with a view to assessing the sensitivity and specificity of serum GGT levels in liver disease. MATERIALS AND METHODS
The patient population selected for study consisted of 189 clinic and inpatients seen at St. Joseph's Hospital. GGT w a s measured at 37°C by the method of Szasz using L-7-glutam y l - p-nitroanilide as substrate (2). A P was determined at 37 ° on the SMA 12/60 (Technicon) with p-nitrophenyl phosphate as substrate (3). AST was measured at 43°C on the SMA 12/60 (4) and A L T was assayed kinetically at 37°C at 340 nm (5). All specimens were stored at 4°C and assayed within 96 hours. RESULTS
GGT activity w a s measured in 86 healthy men and 117 healthy women.
GGT IN LIVER DISORDERS
43
The male mean was 15.6 _ 6.9 (I.S.D.) ; the female mean was 11.0 ± 6.1. The coefficient of variation between batch was 6.5%. The upper limit of normal was set at 30 U / L . Upper limits for ALT and AST were set at 55 U / L and for AP' at 85 U / L . Results are displayed as 'times upper limit of normal ( X U L N ) ' to facilitate comparisons of different enzymes. Fig. 1 summarizes the data f r o m patients with diseases of liver, pancreas and bile duct and for the other disorders in which either GGT or A P were raised. DISCUSSION The enzyme methodologies, units and 'upper limits of normal' are directly comparable with these used in the work of Lure and Gambino (6). The results here reported complement and confirm the findings of these workers.
Hepatitis: There were 17 patients with probable serum hepatitis and 22 with no injection history diagnosed as infective hepatitis. There w a s no significant difference between the enzyme results of the 2 groups and they are displayed as a combined group in Fig. 1. This group contained the only 2 patients with liver disorder who had normal GGT values. Expressed in X U L N terms, the transaminases were always greater than GGT; A L T w a s more elevated than AST. These findings confirm those of other workers (6, 7). Drug Sensitivity: The cases in this group all showed greater elevation of GGT than of transaminases, a feature which they shared with nearly all other cases with liver disorders. The distinction between drug sensitivity and hepatitis is shown in Fig. 2.
30"~
• / /
•
•
/ /
Z .J
2O
/
/"
•
X ),.
/ /
0
•
10-
z
/ /
A/J
/
/
•
• •
eo °
,;
•
° e
•
•
='o
•
•
•
•
='o
20
0
60
70
80
ALT XULN
Fig. 2. GGT and ALT results compared for drug sensitivity group (A) and hepatitis group ( • ).
44
K E A N E et al.
Hepatic Malignancy; Pancreatitis: In 14 patients with carcinoma metastatic to the liver, GGT values were m a r k e d l y elevated with only moderate increases in t r a n s a m i n a s e s (6, 9), and similar changes w e r e p r e s e n t in the 4 cases of p r i m a r y carcinoma of the pancreas. In acute pancreatitis (8), markedly raised GGT values were associated with higher transaminase values.
Alcoholism: The 30 chronic alcoholics, all severe, had GGT values more elevated than t r a n s a m i n a s e s or A P (6, 10, 11, 12, 18, 1/,). Only one patient had an elevated GGT with normal t r a n s a m i n a s e s and AP.
Cirrhosis: The 23 cirrhotics all showed abnormal GGT values and all b u t 2 had elevated A P values. A S T and A L T were normal or mildly elevated with half the cases showing higher A S T values than ALT. congestive Failure: In all 24 patients in this group, t h e GGT values were m a r k e d l y elevated with A P less increased or normal (2 cases). Bone Disease: F o u r patients with P a g e t ' s disease and one with carcinoma of b r e a s t m e t a s t a t i c to bone showed elevations of A P with normal GGT values except in one case with an AP' 1 2 X U L N and GGT 2.7XULN. One of 2 patients on anticonvulsant t h e r a p y f o r epilepsy and 3 out of 4 with Cerebrovascular accidents showed elevations of GGT with variable elevations of AST, A L T and AP. This g r o u p deserves f u r t h e r longitudinal s t u d y (15). In none w a s there clinical evidence of hepatic disorder. F o u r patients with diabetes and essential h y p e r t e n s i o n (1) had GGT values f r o m 3 to 8 X U L N with no other enzyme abnormalities. These findings taken with the documented late rise in some cases of myocardial infarction (1) indicate that GGT is not entirely specific f o r liver disease. However, it does have a sensitivity in liver disease t h a t in all situations, except infective hepatitis, exceeds t h a t of A L T or AST. The failure of GGT to correlate with t r a n s a m i n a s e s or A P coupled with its reasonable specificity for liver diseases renders this enzyme a valuable addition to the test profile used to define liver function. It would a p p e a r to be reasonable to allow GGT to replace either one of A L T or A S T t h e r e b y increasing information w i t h o u t losing a n y t h i n g of diagnostic value.
GGT IN L I V E R D I S O R D E R S
45
REFERENCES 1. JACOBS, W. L. W. 7-Glutamyl-transpeptidase in diseases of the liver, cardiovascular system and diabetes mellitus. Clinica Chim. Acta 38, 419-434 (1972). 2. SZASZ, G. A kinetic photometric method for serum ~-glutamyl transpeptidase. Clin. Chem. 15, 124-136 (1969). 3. M O R G E N S T E R N , S., K E S S L E R , G., A U E R B A C H , J., FLOR, R. V. and K L E I N , B. An automated p-nitrophenylphosphate serum alkaline phosphatase procedure for the Auto Analyzer. Clin. Chem. 11, 876-888 (1965). $. M O R G E N S T E R N , S., O K L A N D E R , M., A U E R B A C H , J., K A U F M A N , J. and K L E I N , B. Automated determination of serum glutamic oxalacetic transaminase. Clin. Chem. 12, 95-111 (1966). 5. H E N R Y , R. J., CHIAMORI, N., GOLUB, O. J. and B E R K M A N , S. Revised spectrophotometric methods for the determination of giutamic-oxalacetic t r a n s a m i nase, glutamic-pyruvic transaminase, and lactic acid dehydrogenase. Amer. J. Clin. Path. 34, 381-398 (1960). 6. LUM, G. and GAMBINO, R. S. Serum g a m m a - g l u t a m y l t r a n s p e p t i d a s e activity as an indicator of disease of liver, pancreas, or bone. Clin. Chem. 18, 358-362 (1972). 7. A R O N S E N , K. F., H A N S O N , A. and N O S S L I N , B. The value of 7-glutamyl transpeptidase in d i f f e r e n t i a t i n g viral hepatitis from obstructive jaundice. Acta Chir. Scand. 130, 92-99 (1965). 8. R U T E N B E R G , A. M., GOLDBARG, J. A. and P I N E D A , E. P. Serum 7-glutamyl transpeptidase activity in hepatobiliary pancreatic disease. Gastroenterology 45, 43-48 (1963). 9. SZCZEKLIK, E., O R L O W S K I , M. and SZEWCZUK, A. Serum ~-glutamyl transpeptidase activity in liver disease. Gastroenterology 41, 353-359 (1961). 10. ZEIN, M. and DISCOMBE, G. Serum gamma-glutamyl transpeptidase as a diagnostic acid. Lancet ii, 748-750 (1970). 11. K O N T T I N E N , A., H A R T E L , G., and L O U H I J A , A. Multiple serum enzyme analyses in chronic alcoholics. Acta Med. Scand. 188, 257-264 (1970). 12. ROLLASON, J. G., P I N C H E R L E , G. and ROBINSON, D. Serum gamma-glutamyl t r a n s p e p t i d a s e in relation to alcohol consumption. Clinica Chim. Acta, 39, 75-80 (1972). 13. ROSALKI, S. B. and RAU, D. Serum ~-glutamyl transpeptidase activity in alcoholism. Clinica Chim. Acta 39, 41-47 (1972). 14. ROSALKI, S. B., RAU, D., L E H M A N N , D. and P R E N T I C E , M. Gamma-glutamyl transpeptidase in chronic alcoholism. Lancet ii, 1139 (1970). 15. E W E N , L. M. and G R I F F I T H S , J. Serum ~-glutamyl t r a n s p e p t i d a s e : elevated levels in certain neurological diseases. Clin. Chem. 17, 642 (1971).