Clinical Importance of Gamma Glutamyltransferase in the Ankara-Pursaklar Region of Turkey

Abstract

Objective:

The aim of this study is to determine the etiologies of serum gamma glutamyltransferase (GGT) elevation and relations between multiple etiologies prevalent in the Pursaklar region of Ankara in Turkey.

Patients and Methods:

The patients referred to the Family Medicine and Internal Medicine departments with various complaints from the Pursaklar region of Ankara between July 2000 and July 2002 were evaluated, and values for GGT, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) levels were determined. GGT elevation was classified as being associated with hepatic, biliary, and other origins.

Results:

For GGT elevation, hepatobiliary etiologies were more prevalent. The most prevalent hepatic etiology was nonalcoholic steatohepatitis, followed by biliary etiologies. The most prevalent etiology of biliary origin was cholelithiasis. Other etiologies, in order of prevalence, were drug exposure and urinary infection. There were no gender-related differences for distribution of GGT elevation; however, the GGT values for women were higher than those for men.

Although well established in developed countries, observations made by doctors in Turkey evaluating causes of increased serum GGT values could be very helpful to clinicians in less developed areas.

Introduction

The pathology producing elevated activities of GGT is at times difficult to determine because of the numerous etiologies that can produce high levels. GGT exists in various body compartments. Hepatocytes and biliary epithelial cells constitute major sources of the enzyme. However, it has also been detected in the kidney, spleen, brain, and seminal vesicles. Therefore, it is essential to investigate a wide range of etiologies in patients with high GGT levels.

GGT, as a microsomal enzyme, plays a role in secretory and absorptive events in the hepatobiliary system.[1] It is involved with glutation synthase in the gamma-glutamyl cycle, which allows absorption of amino acids from glomerular filtrate and the intestinal lumen.

GGT has a high sensitivity for biliary pathology. In patients with high GGT levels, pathology of the biliary system should be the first to be considered. Higher serum levels are present in biliary obstruction than in parenchymal events. The superiority of GGT over alkaline phosphatase, which acts in a similar manner, is its stability in various bone pathologies. In addition, GGT frequently is increased during liver disorders such as intrahepatic cholestasis, acute hepatitis, and alcoholic liver disease, which affect the biliary system. GGT elevation in alcoholic hepatitis is due to microsomal enzyme induction. It has also been observed that ethanol increases GGT synthesis in hepatoma cells.[2] Isolated GGT elevation can be the only indicator of alcoholic liver disease. Serum GGT elevation has been found to be more than 2-fold in chronic alcoholic patients compared with the control group.[3] Thus, serum GGT concentration is a valuable screening test to determine alcohol consumption.[4] However, no correlation has been detected between hepatic and serum concentrations of GGT.[5]

Clinically, GGT is very useful to observe cholestasis due to parenteral nutrition and the effect of ursodeoxycholic acid, a secondary bile acid used as a therapeutic agent. It is striking that despite its high sensitivity in hepatobiliary events, GGT has no considerable specificity. In one study, only 32.4% of the patients with high GGT levels had hepatobiliary pathology.[6] In addition to pancreatic events, myocardial infarction, renal failure, diabetes mellitus, and chronic obstructive lung disease can also increase GGT levels.[7] There are also reports of transient increases due to drug use.

This study aimed to investigate the etiologies of GGT elevations in patients living in the Ankara-Pursaklar region and differences between the etiologies identified and other causes that had been determined by previous studies. The relation and correlations between GGT and age, gender, ALP, and ALT were also studied.

Methods

This is a descriptive, observational, cross-sectional study performed in the Pursaklar regional hospital, which is a metropolitan hospital of Fatih University Medical School.

Patients

The study involved 100 patients with high serum GGT levels who had been seen in the Family Practice and Internal Medicine clinics in the Ankara-Pursaklar region (within our hospital's Pursaklar department) between July 2000 and July 2002. All were from the Ankara-Pursaklar region, a suburban/rural area. Detailed history, physical examination, and laboratory and ultrasonographic evaluations of the patients were performed. The study was conducted by the family physicians and specialists from internal medicine and biochemistry departments.

Methods

Serum ALP, ALT, and GGT levels were measured spectrophotometrically with the Hitachi 912 (Roche Diagnostics Co., Mannheim, Germany).

GGT levels were measured by a standard method recommended by the International Federation of Clinical Chemistry (IFCC). GGT in serum specimens transfers the gamma-glutamyl group of L-gamma-glutamyl-3-carboxy-4-nitroanilide to glycylglycine. The amount of 5-amino-2-nitrobenzoate liberated is proportional to GGT activity and can be measured photometrically. The laboratory results, which are periodically inspected and accredited by international laboratories, were interpreted by the faculty laboratory personnel. Serum GGT levels between 11 and 50 U/L were considered within reference values.

Patients' serum ALP and ALT levels were also studied. ALP levels were measured by an optimized standard method recommended by the Deutschen Gesellschaft fur Klinische Chemie (German Society of Clinical Chemistry). With regard to this process, in the presence of magnesium and zinc ions, p-nitrophenyl phosphate is hydrolyzed by phosphatases to form phosphate and nitrophenol. The p-nitrophenol released is proportional to the ALP activity and is measured photometrically. Reference values for ALP were determined as 0-270 U/L, whereas this range was between 0 and 42 U/L for ALT. ALT levels were measured by a standard method recommended by IFCC that depends on the activation of pyridoxal phosphate. In this method, ALT in the serum catalyzes the reaction between alpha-ketoglutarate and L-alanine, in which the products are L-glutamate and pyruvate. The pyruvate increase is measured in a subsequent indicator reaction that is catalyzed by lactate dehydrogenase in the presence of nicotinamide adenine dinucleotide (NADH). The rate of decrease in NADH is directly proportional to the rate of pyruvate formation and, thus, the activity of ALT. The reference values were determined in light of the values stated on the kits provided by the companies.

The GGT/ALT and ALP/GGT ratios of all the patients were calculated. The results were confirmed by testing blood samples several times in laboratory analyses. Laboratory staff was blinded to the clinical features of the patients.

All the patients were then evaluated for age, gender, previous diseases, drugs in use, and other diseases in their family. A radiologist performed the ultrasonographic examinations and the results were recorded in detail. The patients who were thought to have hepatic etiologies were studied through total viral hepatitis tests (HbsAg, AntiHbs, Anti HCV, Anti-HAV IgM and IgG), and the diagnosis of chronic hepatitis was based on the results of liver biopsy. In addition to the hepatic profiles, antinuclear antibody, antimitochondrial antibody, serum copper, ceruloplasmin levels, and serum ferritin levels were studied for the patients suspected of having nonalcoholic steatohepatitis. The diagnosis of nonalcoholic steatohepatitis was established through the previous diagnosis of gastroenterology clinic, hepatic computed tomography, and the results of liver biopsy. The diagnoses of cholelithiasis and choledocholithiasis were established through abdominal ultrasonography or the results of the endoscopic biliary studies that were performed at another center before the patients' application to our center. The diagnoses of acute and chronic cholecystitis were based on the findings of clinical examination and biochemistry and previously established gastroenterology diagnoses. For each etiology other than that of hepatobiliary origin, illness-specific diagnostic criteria were used. The drugs used and personal habits of each patient were scrutinized.

In light of the results of the laboratory tests and physical examination, the most probable etiologies underlying high GGT levels were identified as “hepatic,” “biliary,” and “others.” The patients were classified into 6 age groups: 19 years of age or younger; between 20 and 29 years of age; between 30 and 39 years of age; between 40 and 49 years of age; between 50 and 59 years of age; and 60 years of age or older.

Statistical Analyses

GGT, ALP, and ALT levels and GGT/ALT and ALP/GGT ratios of 3 diagnostic groups were compared with Mann-Whitney-U test. The correlations of the parameters of the age groups were also evaluated through multivariate analysis. A P value of < .05 was considered statistically significant; all tests were 2-tailed. The statistical analyses were performed with SPSS for Windows.

Results

General Evaluation of the Etiologies of Higher GGT Levels

The study involved 100 patients. The most prevalent etiology of higher GGT levels was hepatic in origin, whereas biliary etiologies were less frequent (Figure 1). Nonalcoholic steatohepatitis was the most prevalent among hepatic etiologies (70%), followed by acute hepatitis (11%), chronic hepatitis (11%), cirrhosis (2%), metastasis (2%), hydatic cyst (2%), and hepatic mass (2%) (Figure 2). Cholelithiasis was the most prevalent among biliary etiologies (33%), followed by choledocholithiasis (27%), acute cholecystitis (27%), and chronic cholecystitis (13%) (Figure 3). Among the etiologies other than those specified (40%) were drug usage (18%) and urinary tract infection (18%), with considerable rates. The etiologies classified as “others” involved a wide range of etiologies (Figure 4). Among the drugs, “nonsteroid anti-inflammatory drugs” were the most prevalent etiology for high GGT levels (40%) (Figure 5).

Figure 1.

General causes of GGT elevation

Figure 2.

Hepatic causes of GGT elevation

Figure 3.

Biliary causes of GGT elevation

Figure 4.

Other causes of GGT elevation

Figure 5.

Drugs associated with GGT elevation

ALT and ALP Levels in Groups

ALT and ALP enzyme levels were within reference values in 42% of the “hepatic” group, whereas in the “biliary” group, neither of the enzymes was within the reference values. ALT levels were high in 51% of the “hepatic” group, and ALP levels were high in 80% of the “biliary” group. However, both enzymes were within reference values in 47.5% of the “others” group (Table 1).

Table 1.

ALP and ALT Status of Groups

	Causes of GGT elevation
	Hepatic		Biliary		Others
	n	%	n	%	n	%
Reference value	19	42	0	0	19	47.5
ALP	3	6.7	7	46.7	7	17.5
ALT	10	22	3	20	10	25
ALP and ALT	13	28.9	5	33.3	4	10
Total	45	100	15	100	40	100

Mean Values of Group Parameters

GGT, ALP, and ALT levels and GGT/ALT and ALP/GGT ratios of all groups were compared with the Mann-Whitney-U independent groups test. In general, compared with the “hepatic” (Mann-Whitney-U P = .011) and “others” (Mann-Whitney-U P = .001) groups, the GGT levels were significantly higher in the “biliary” group. ALT levels of the “hepatic” group were higher than those of the “others” group. (Mann-Whitney-U P = .044) (Table 2).

Table 2.

Mean Values of Parameters Within Groups Generally

	Causes of GGT elevation
	Hepatic		Biliary		Others
Parameter	n		n		n
GGT	45	129.7 ± 134.3	15	180.9 ± 118.17	40	107.2 ± 86.7
ALT	45	115.9 ± 205.6	15	88.8 ± 95.8	40	50.8 ± 43.7
ALP	45	327.7 ± 385.7	15	301.6 ± 156.5	40	229.5 ± 110.7
GGT/ALT	45	2.5 ± 2.2	15	6.9 ± 10.4	40	3.6 ± 5.6
ALP/GGT	45	3.8 ± 6.9	15	2.2 ± 1.9	40	2.6 ± 1.4

Distribution of Group Parameters According To Gender

There were no statistically significant gender differences among the groups (Chi-square P = .825). When the differences in the parameters for genders in each group were considered, the ALT levels of the females were significantly higher than those of the males in the “hepatic” group (Mann-Whitney-U P = .049). Similarly, the GGT levels of the females were higher than those of the males in the “biliary” group (Mann-Whitney-U P = .049). The ALP/GGT ratio was significantly higher in the females in the “others” group (Mann-Whitney-U P = .026). The ALT levels of the males of the “hepatic” group were also higher than those of the “others” group (P = .025), whereas the GGT/ALT ratio of the males in the “others” group was higher than that of the “hepatic” group (P = .016). The GGT (P = 0.005) and ALP (P = .026) levels of the females in the “biliary” group were higher than those in the “others” group (Table 3).

Table 3.

Mean Values of Parameters Within Gender Groups

	Causes of GGT elevation
	Hepatic			Biliary		Others
Parameter		n		n		n
GGT	Men	25	121.9 ± 129.3	7	121.5 ± 31.8	22	118.7 ± 107
	Women	20	138.5 ± 143	8	233 ± 143	18	93 ± 52
ALT	Men	25	101.9 ± 175	7	71.5 ± 58	22	48.6 ± 46.7
	Women	20	133.3 ± 242	8	104 ± 122	18	53.4 ± 41
ALP	Men	25	358.7 ± 475.2	7	223 ± 192.6	22	202.3 ± 101.8
	Women	20	289 ± 237.4	8	370.5 ± 74.7	18	262.7 ± 114.8
GGT/ALT	Men	25	2 ± 1.7	7	7.2 ± 12.2	22	4.2 ± 7.2
	Women	20	3.2 ± 2.6	8	6.5 ± 9.3	18	2.9 ± 2.8
ALP/GGT	Men	25	4.6 ± 9.2	7	2.2 ± 2.6	22	2.1 ± 1.4
	Women	20	2.8 ± 1.5	8	2.1 ± 1.2	18	3 ± 1.3

Correlations Between Parameters

The correlations among all the parameters of the groups were evaluated through multivariate analysis. In general, there were negative correlations between age and ALT (Pearson correlation = -0.555; P < .001; n = 100), between age and ALP (Pearson correlation = -0.345; P = .001), and between ALP/GGT ratios (Pearson correlation = -0.274; P = .006). However, age and GGT/ALT ratio (Pearson correlation = 0.261; P = .009), GGT and ALT (Pearson correlation = 0.204; P = .042), and ALP and ALT (Pearson correlation = 0.718; P = .001) were positively correlated.

Among hepatic etiologies, age and ALT (Pearson correlation = -0.769; P = .001; n = 45), age and ALP (Pearson correlation = -0.582; P = .001), and ALP/GGT ratio (Pearson correlation = -0.383; P = .009) were negatively correlated. ALP and ALT (Pearson correlation = 0.807; P = .001) and age and GGT/ALT ratio (Pearson correlation = 0.388, P = .008) had positive correlations.

Among biliary etiologies, no statistically significant correlation was found.

Among the “others” group, while there was a negative correlation between age and ALT (Pearson correlation = -0.411; P = .008; n = 40), a positive correlation was found between GGT and ALT (Pearson correlation = 0.445, P = .004).

Discussion

Despite previous studies reporting hepatobiliary etiologies to be less prevalent, the higher prevalence of hepatobiliary etiologies in this study was attributed to the local characteristics of the study population, and among these etiologies, “nonalcoholic steatohepatitis” alone comprised 30% of the total. While less prevalent than hepatic etiologies, “biliary” etiologies were the leading etiology for the patient group aged 60 years or older. The wide range of etiologies for GGT elevation defined in the study was noteworthy. Considering this evaluation, in the presence of high GGT levels, various systemic pathologies should be kept in mind that would help avoid redundant tests and expenses. A detailed history of the patient and a clear understanding of the condition are essential in determining the underlying etiology. In some cases with milder elevations of GGT, the problem may be overcome with some simple applications such as withdrawal of some drugs and follow-up.

The levels of elevated GGT resulting from the etiologies of “biliary” origin were higher than those of all the other groups, which was most marked among women. This could be accounted for by their being secondary to the role of female hormones in biliary events. Thus, in the presence of relatively high GGT levels, in addition to the evaluations of other enzymes, biliary events should also be considered. The contribution of sexual hormones of females into biliary pathology is particularly noteworthy in hepatobiliary events (eg, intrahepatic cholestasis of pregnancy) during pregnancy that may resolve afterwards.

ALP levels were high in 80% of the “biliary” group, which indicates that GGT may be more sensitive than ALP to biliary events. Therefore, in the cases with probable biliary pathology, GGT tests should be given importance.

Reduced ALT and ALP levels with age can be due to the impaired response of aging metabolism to pathology. Consequently, ALT and ALP levels of older individuals may not be as high as expected. In fact, they may even be within the reference values, which may distract clinicians from the actual diagnosis. However, excessive enzymatic response to the extent of impairing the correlation may account for the absence of this condition in biliary events.

The negative correlation between age and ALP/GGT ratio and the positive correlation between age and GGT/ALT ratio were the other striking results of the study. A decrease in the response of ALT and ALP with age but not in GGT is the reason for these results. Thus, in the evaluations of the enzymes of the aged, GGT evaluation should have the priority.

Conclusion

In conclusion, a wide range of etiologies of high GGT levels compels a comprehensive investigation to determine the pathology. GGT is highly sensitive to biliary events. However, unlike GGT, other hepatobiliary enzymes decrease with age.

ALP, alkaline phosphatase; ALT, alanine aminotransferase

GGT, gamma glutamyltransferase; ALP, alkaline phosphatase; ALT, alanine aminotransferase

GGT, gamma glutamyltransferase; ALP, alkaline phosphatase; ALT, alanine aminotransferase