SerumGamma-GlutamylTranspeptidaseActivityas an

Indicatorof Diseaseof Liver, Pancreas,or Bone

Gifford Lum and S. Raymond Gambino

Serum y.glutamyl tra nspeptidase (GGT), leucine GGT activity is increased in cases of viral hepatitis,
aminopeptidase, alkaline phosphatase, alanine cholecystitis, chronic hepatitis, fatty liver, chol-
aminotransferase,and aspartateaminotransferase angitis, cholelithiasis, metastatic carcinoma to the
activities were assayed in controls and in patients liver, congestive heart failure, chronic alcoholism,
with liver, pancreatic, or bone disease. GGT post-myocardial infarction, epilepsy, and brain
activity was above normal in all forms of liver tumors (1-8).
disease studied (viral hepatitis, cirrhosis, chole- We became interested in GGT because we were
cystitis, metastatic carcinoma to liver, pancreatic concerned with the general problem of elucidating
carcinoma, liver granuloma, and acute pancrea. which tissue is the source of increased serum
titis). GGT more sensitively indicated hepatic ALP activity. The conventional means of separating
disease than did alkaline phosphatase, much mpre ALP isoenzymes-by electrophoresis, heat in-
so than did leucine aminopeptidase. GGT was activation, or chemical inhibition-were unattrac-
disproportionately more active in relation to the tive to us because they often are insensitive and
transaminases in cases of intra- or extrahepatic give equivocal results. In an effort to differentiate
biliary obstruction; the reverse was true in cases of between the isoenzymes of ALP originating in bone
viral hepatitis. GGT activity was normal in children, and liver by the use of a single enzyme assay, we
adolescents, and pregnant women, and in cases undertook a study of GGT and LAS. is and GGT do
of bone disease and renal failure. Kinetic measure- not suffer from the drawbacks of ALP because LAS
ment of GGT activity offers a simple, sensitive, and GGT appear to be more nearly specific for hepa-
and direct means for distinguishing whether bone tobiliary disease. In addition, LAS and GGT activity
or liver is the source of increased serum alkaline parallels that of ALP in hepatobiliary disease. We
phosphatase activity. Activity was highest in also studied ASP and ALT in an attempt to find pat-
obstructive liver disease. terns of increased enzyme activity that would aid
in the differential diagnosis of hepatic disease.
Additional Keyphrases pancreatic, hepatic, and hepa-
tobiliary disease #{149}diagnostic aid #{149}relative usefulnes8 of Materials and Methods
various enzyme assays for differential diagnosis. chronic
alcoholism #{149}heart disease #{149}normal values for adults, The patient population consisted of 230 clinic
children, pregnant women #{149} reticulum cell sarcoma and inpatients at the Columbia-Presbyterian
Medical Center, New York, N. Y.
GGT and LAS were measured kinetically at 25#{176}C
Abnormally high activity of serum GGT appears
on the Model 2000 spectrophotometer (Gilford
to be specific for diseases of the liven, biiary tract,
Instrument Labs., Inc., Oberlin, Ohio 44074). GGT
and pancreas. Interest in GGT has focused on its
was measured by the method of Szasz, with L-y-
value in the diagnosis of various liver diseases.
glutamyl-p-nitroanilide as substrate (9), and LAS
was assayed by using leucine-p-nitroanilide as sub-
From the Clinical Chemistry Laboratory, Presbyterian
Hospital, 630 West 168th St., New York, N. Y. 10032.
strate (10). ALP activity was determined at 37#{176}C
1 abbreviations used: GOT, y-glutamyl trans- on the SMA 12/60 (Technicon Corp., Tarrytown,
peptidase (no EC number yet assigned). Other abbreviations N. Y. 10591), with p-nitrophenol phosphate sub-
were editorially changed in manuscript to conform with recently
recommended standard abbreviations [J. Clin. Pat hol. 24, strate (11). AST (uv assay) was measured at
656 (1971)]. In the past GOT has often been used as an abbrevia- 37#{176}Con the SMA 12/60, and AAT was assayed
tion for AST, as has OPT instead of ALT. AST, aspartate amino- kinetically at 340 nm at 35#{176}C with the Model 8600
transf erase (1-aspartate: 2-oxoglutarate aminotransferase, EC
2.6.1.1); ALT, alanine aminotransferase (i.-alanine: 2-oxoglutarate Reaction Rate Analyzer (LKB Instrument Corp.,
aminotransferase, EC 2.6.1.2); LAs, leucine aminopeptidase Inc., Rockville, Md. 20852) (12). GGT, LAS, and
(i,-leucyl-peptide hydrolase, EC 3.4.1.1); and ALP, alkaline AAT were assayed within 48-60 h after the serum
phosphatase (orthophosphoric monoester phosphohydrolase,
EC 3.1.3.1).
sample was collected, and ALP and AST within
Received Dec. 17, 1971; accepted Jan. 31, 1972. 24 h. All specimens were stored at 4#{176}C before

358 CLINICAL CHEMISTRY, Vol. 18, No. 4, 1972

assay if they were not assayed within 3 h of biliary tract obstruction. GGT was normal in cases
collection. of acute cholecystitis without biliary obstruction.
In 13 cases of cholangitis and hepatic abscess,
Results where high ALP activities are found, GGT was rn-
creased to the same extent as was ALP activity,
GGT activity was measured in a total of 80 while LAS was only moderately increased.
sera from hospital patients (half were women and In our series of 12 patients with metastatic
half men) who were free of known liver, renal, or carcinoma to the liver with primary sites located
pancreatic disease. The mean for men was 13.6 in the lung, ovary, stomach, and skin, GGT ac-
6.9 U/liter (range 2-39) and for women 10.9 6.4 tivity was extremely high as compared to that of
U/liter (range 2-36). No significant difference the transaminases. This confirms reports in the
was found between the mean value of GGT ac- literature in which GGT assay has been suggested
tivity between males and females. The mean as being useful in detection of hepatic metastases
activity of LAS in the same group was 10.4 4.3 (1, 3). We found normal GGT activity in several
U/liter. patients with cancer in which the liver was not
The upper limit of normal for GGT was set at involved. In patients with hematologic disorders
30 U/liter, for LAS 22 U/liter, for AST and ALT (leukemia) or lymphomas, GGT activity was in-
50 U/liter, and for ALP 85 U/liter. We have sum- creased if there was evidence of hepatic infiltration
marized all of our data in Table 1. In addition to by leukemic cells or liver involvement by
the absolute activities of all five enzymes studied, lymphoma.
we have also chosen to express our results (the mean GGT activity was greatest in cases of primary
change in enzyme activity) as times (X) upper carcinoma of the head of the pancreas and adeno-
limit of normal. Hence an absolute value of 120 carcinoma of the bile duct. LAS was far less sen-
U/liter for GGT would be expressed as 4.0 X the sitive for detecting obstructive pancreatic neo-
upper limit of normal, i.e., 120 divided by 30. plasm.
By reporting our results in this way, it is easier In chronic alcoholics, GGT appears to be a
to compare relative changes among a variety of sensitive indicator of hepatic damage, with the
enzyme assays. highest activities seen in the sickest patient. The
Table 1 summarizes the data for patients with greatest increase in GGT was found in a case of
diseases of the liver, pancreas, and (or) bile duct; a chronic alcoholic with delirium tremens and
diseases of bone; and for patients with isolated pneumonia. As have others, we have seen several
elevation of ALP. patients with chronic alcoholism whose GGT ac-
tivity was increased but whose other liver enzyme
Discussion activities were normal (2, 5).
In cirrhosis of the liver, GGr and ALP were both
The data presented in Table 1 make it readily increased, whereas AST activity was moderately
apparent that serum GGT activity is increased in abnormal and that of ALT was normal, a trans-
all the forms of liver disease we studied, with the aminase pattern commonly seen in cirrhosis.
highest activities being seen in extra- or intra- In patients with liver granulomas, including
hepatic obstructive disease. In viral hepatitis, miuiary tuberculosis and sarcoidosis, we found
whether antigen-positive or -negative, activities both GGT and ALP to be elevated, with borderline
of the transaminases were disproportionately in- elevations of the transaminases. If there was no
creased as compared to that of GGT, indicating liver involvement by granuloma, then GGT was
acute hepatic cellular necrosis. There is suggestive normal.
evidence that the ALT/GGT ratio may best dis- In acute pancreatitis, GGT activity was in-
criminate between obstructive hepatic disease creased, often concomitantly with normal ALP
and viral hepatitis (13). Our data indicate that the activity. Although GGT activity is increased in
disproportionate increase in transaminase ac- cases of acute pancreatitis, the increase is not
tivity as compared to GGT activity is characteristic diagnostic of, or specific for, pancreatitis because
of viral hepatitis, whereas the disproportionate its elevation may reflect concomitant hepatic
increase in GGT activity as compared to trans- damage in an alcoholic.
aminase activity (with a ALT/GGT ratio of less In the patients with congestive heart failure,
than 1.8) suggests obstructive hepatobiliary dis- increased ALP and GGT activities were secondary
ease rather than hepatitis. to hepatic damage.
In cases of cholecystitis or cholelithiasis, GGT The data in Table 1 show that if an increased
was more sensitive than either the ALP or LAS, ALP was of osseous origin, GGT activity was always
showing a mean increase of sevenfold the upper normal-this was true of Pagets disease, hyper-
limit of normal. The increase in GGT often preceded thyroidism (14), metastatic cancer to bone, and
the rise of ALP in cases of surgically proven hyperparathyroidism. In Table 1 we have not

CLINICAL CHEMISTRY, Vol. 18, No. 4, 1972 359

 Table 1. Comparison of Enzyme Patterns in Indicated Diseases
Disease Mean change Range
(No. cases) Enzyme U/liter times normal U/lit.r No. .1ev., %
Diseases of liver, pancreas, and bile duct
Hepatitis (17) GGT 156 5.2 23-388 94
ALP 213 2.5 107-575 100
LAS 35 1.6 18-52 88
AST 1820 36.5 186-5040 100
ALT 1580 31.0 208-5320 100
Cholecystitisorcholelithiasis GGT 210 7.0 47-420 100
(8) ALP 255 3.0 79-625 75
LAS 26 1.2 15-58 50
AST 78 1.5 38-173 50
ALT 91 1.8 16-320 50
Cholangitis (13) GGT 249 8.3 71-520 100
ALP 593 7.0 170-975 100
LAS 46 2.1 19-97 77
AST 100 2.0 31-325 77
ALT 95 1.9 23-220 77
Carcinoma metastatic to liver GGT 396 13.2 208-820 100
(12) ALP 560 6.6 240-925 100
LAS 35 1.6 19-58 75
AST 220 4.4 57-900 100
ALT 150 3.0 14-720 83

Alcoholics (5) GGT 99 3.3 27-850 80

ALP 110 1.3 75-140 80
LAS 22 1.0 15-35 20
AST 80 1.6 9-212 60
ALT 35 0.7 9-57 20

Cirrhosis of liver (6) GGT 132 4.4 26-256 83

ALP 298 3.5 93-700 100
LAS 31 1.4 15-44 67
AST 100 2.0 36-237 83
ALT 45 0.9 11-77 33

Granuloma of liver (5) GGT 303 10.1 116-740 100

ALP 425 5.0 191-700 100
LAS 33 1.5 19-44 60
AST 75 1.5 59-97 100
ALT 70 1.4 50-115 80
Pancreatitis acute (10) GGT 300 10.0 165-520 100
ALP 440 5.2 35-1227 80
LAS 42 1.9 12-68 80
AST 75 1.5 38-134 80
ALT 55 1.1 20-105 40
Primary carcinoma of GGT 590 19.6 264-1040 100
pancreas or bile duct (4) ALP 1200 14.2 700-2250 100
LAS 51 2.3 35-68 100
AST 55 1.1 26-93 50
ALT 55 1.1 22-105 50

Congestive heart failure (9) GGT 180 6.0 58-568 100

ALP 170 2.0 131-294 100
LAS 33 1.5 16-62 78
AST 40 0.8 23-81 33
ALT 40 0.8 13-159 33
(contd)

360 CLINICAL CHEMISTRY, Vol. 18, No. 4, 1972

 Table 1. (Continued)
Disease Mean change Rang.
(No. cases) Enzyme U/liter times normal U/liter No. eI.v., %

Diseases of bone
Pagets disease (7) GGT 18 0.6 5-32 14
ALP 780 9.2 475-1175 100
LAS 13 0.6 8-26 14
AST 30 0.6 24-42 0
ALT 15 0.3 4-30 0

Hyperthyroid (10) GGT 15 0.5 6-24 0

ALP 110 1.3 47-222 70
LAS 15 0.7 5-29 10
AST 25 0.5 14-40 0
ALT 30 0.6 14-81 10

Carcinoma, metastatic to GGT 30 1.0 13-54 25

bone (4) ALP 560 6.6 167-730 100
LAS 13 0.6 7-15 0
AST 40 0.8 25-60 25
ALT 35 0.7 14-52 25

Hyperparathyroid (3) GGT 15 0.5 11-18 0

ALP 194 2.3 75-450 67
LAS 13 0.6 7-16 0
AST 40 0.8 20-54 33
ALT 30 0.6 22-49 0

Normal adolescents (10) GGT 18 0.6 5-45 10

ALP 305 3.6 157-450 100
LAS 18 0.8 5-61 10
AST 35 0.7 23-58 20
ALT 15 0.3 9-31 0

Diseases accompanied by increased alkaline phosphalase activity

Pregnant patients at term GGT 9 0.3 2-21 0

(14) ALP 136 1.6 105-179 100
LAS 146 6.6 80-312 100
AST 55 1.1 29-87 21
ALT 15 0.3 2-29 0
Renal failure (9) GGT 18 0.6 6-52 11
ALP 102 1.2 51-164 67
LAS 11 0.5 7-19 0
AST 75 1.5 2-325 45
ALT 40 0.8 8-137 22
Gilberts disease (4) GGT 12 0.4 2-23 0
ALP 76 0.9 58-150 25
LAS 11 0.5 8-18 0
AST 25 0.5 23-28 0
ALT 15 0.3 14-25 0

included one patient who had one of the highest secondary to bone growth, GGT activity was
ALP activities ever measured at the Presbyterian normal. In pregnant patients at term, serum
Hospital (3800 U/liter, or 45-fold increase above placental ALP and LAS activities were increased,
normal). This patient, whose GGT activity was but GGT activity was normal, suggesting that in
normal, was found at autopsy to have reticulum pregnant patients with liver disease, GOT would be
cell sarcoma of the bone, with no liver involve- helpful in making an accurate differential diag-
ment. nosis.
In children and adolescents, who normally have Although the highest OGT activities are found in
an increased ALP activity (as compared to adults) the brush border of the proximal convoluted

CLINICAL CHEMISTRY, Vol. 18, No. 4, 1972 361

tubules of the kidney (1), we found serum GOT 2. Zein, M., and Discombe, G., Serum gamma-glutamyl
transpeptidase as a diagnostic aid. Lancet ii, 748 (1970).
activity to be normal in patients with renal
3. Rutenburg, A., Goldbarg, J., and Pineda, E., Serum gamma-
failure. Slightly increased or normal GOT activity glutamyl transpeptidase activity in hepatobiliary pancreatic
has been reported in a number of patients with disease. Gastroenterology 45, 43 (1963).
renal disease (1). Much lower GGT activities are 4. Szasz, G., Rosenthal, P., and Fritzsche, W., Die gamma-
found in the liver, spleen, pancreas, and intestine. glutamyl transpeptidase Aktivit#{228}t
im Serum bei hepatobilaren
Erkrankungen. Deut. Med. Wochenschr. 38, 1911 (1969).
In the hepatic parenchyma, GOT activity appears
5. Konttinen, A., H#{228}rtel,
G., and Louhija, A., Multiple serum
to be concentrated in the microsomes (15), which enzyme analyses in chronic alcoholics. Acta Med. Scand. 188,
suggests that the increased GOT activity seen in 257 (1970).
epileptic patients may be secondary to induction 6. Ravens, K., et al., Gamma-glutamyl transpeptidase in myo-
of microsoinal enzymes by various drugs such as cardial infarction. Circulation 39, 693 (1969).
diphenylhy dantoin (Dilantin) and phenobarbi- 7. Ewen, L. M., and Grifliths, J., Patterns of enzyme activity
following myocardial infarction and ischemia. Amer. J. Clin.
tal (16). Pathol. 56, 614 (1971).
In patients with Gilberts disease (chronic 8. Ewen, L. M., and Griffiths, J., Serum gamma-glutamyl
unconjugated hyperbilirubinemia), GGT activity transpeptidase: Elevated levels in certain neurological diseases.
was normal, as were the activities of all the other CLIN. CHEM. 17, 642 (1971). (Abstract).
hepatic enzymes, indicating the benign nature of 9. Szasz, G., A kinetic photometric method for serum gamma-
glutamyl transpeptidase. CLIN. CHEM. 15, 124 (1969).
this syndrome.
10. Szasz, G., A kinetic photometric method for serum leucine
In a patient with pulmonary infarction (our aminopeptidase. Amer. J. Clin. Pat hot. 47,607 (1967).
Autopsy No. 24220) GOT activity was normal, but 11. Morgenstern, S., Kessler, G., Auerbach, J., Flor, R. V.,
ALP activity was increased to 550 U/liter (6.5 X and Klein, B., An automated p-nitrophenylphosphate serum
normal). An increase in ALP after pulmonary alkaline phosphatase procedure for the AutoAnalyzer. CLIN.
CHEM. 11, 876 (1965).
infarction has been reported (17, 18).
12. Henry, R. J., Chiamori, N., Golub, 0. J., and Berkman, S.,
Finally, we mention the increased ALP and GOT
Revised spectrophotometric methods for the determination
activities seen in cases of myocardial infarction, of glutamic oxalacetic transaminase, glutamic-pyruvic trans-
not related to congestive heart failure (7). Thus, aminase, and lactic dehydrogenase. Amer. J. Clin. Pathol. 34,
381 (1960).
GOT is not absolutely specific for disease in the
13. Aronsen, K. F., Hanson, A., Nosslin, B., The value of
right upper quadrant, and it cannot be used for gamma-glutamyl transpeptidase in differentiating viral hepatitis
differential diagnosis during recovery from a from obstructive jaundice. Ada Chir. Scand. 130, 92 (1965).
myocardial infarction or in epilepsy (7, 8). Ewen 14. Cassar, J., and Joseph, S., Alkaline phosphatase levels
and Griffiths work (8) also suggests that we in thyroid disease. Clin. Chim. Acta 23, 33 (1969).
should study ALP and GGT in patients with a 15. Szewczuk, A., A soluble form of gamma-glutamyl trans-
variety of healing lesions, because young fibro- peptidase in human tissue. Clin. Chim. Ada 14, 608 (1968).
16. Rosalki, S. B., Plasma gamma-glutamyl transpeptidase
blasts and budding capillaries contain increased elevation in patients receiving enzyme-inducing drugs. Lancet
amounts of ALP and GOT. Ii, 376 (1971).
17. Nikkilh, E. A., Serum alkaline phosphatase activity in
References pulmonary infarction. Scand. J. Clin. Lab. Invest. 11, 405 (1959).
1. Orlowski, M., The role of gamma-glutamyl transpeptidase in 18. Dijkman, J. H., and Kloppenborg, P. W. C., Increased
the internal diseases clinic. Arch. Immunol. Ther. Ezp. 11, 1 serum alkaline phosphatase activity in pulmonary infarction.
(1963). Ada Med. ,Scand. 180, 273 (1966).

362 CLINICAL CHEMISTRY, Vol. 18, No. 4, 1972