Diagnostic Value of Serum γ-Glutamyl Transferase Isoenzyme for Hepatocellular Carcinoma: A 10-Year Study

Serum gamma-glutamyl transferase (GGT) was separated into nine to 11 isoenzyme bands (designated as GGT I-XI) by vertical slab electrophoresis on polyacrylamide gradient gel. The diagnostic value of GGT isoenzyme II (GGT II) for hepatocellular carcinoma (HCC) was studied, and the results were as follows: 1) GGT II was positive in 90% of 90 cases of HCC, and negative in most patients with acute and chronic viral hepatitis, extrahepatic tumors, in pregnant women, and in healthy controls; 2) the positive rate of GGT II assay was higher than that of alkaline phosphatase isoenzyme I (ALP I), alpha-fetoprotein (AFP), and alpha 1-antitrypsin (AAT) in 101 cases of HCC. In cases in which the AFP was greater than 50 ng/ml or less than 50 ng/ml, the positive rates of GGT II were 70.8% and 75-100%, respectively; 3) of 14 cases of small-size HCC, the positive rate of GGT II was 78.6%, which was higher than that of AFP (50%), AAT (28.6%), and ALP I (0%); 4) of 62 cases that were false-positive for GGT II assay, 24.2% developed into HCC during a follow-up of 2.1-20 months. In subjects with persistent and recurrent positivity of GGT II, 86.7% and 22.2%, respectively, developed HCC. No patient with temporal positivity of GGT II developed HCC. The results show that GGT II can be applied as an additional marker for HCC, and is valuable not only for the diagnosis of clinical HCC, but for the detection of small or subclinical HCC. Periodic follow-up with assay of GGT II in patients at high risk for HCC may predict the development of hepatoma.     

Alcohol-induced Enhancement of Intestinal γ-Glutamyl Transpeptidase Activity in Rats and Humans: A Possible Role in Increased Serum γ-Glutamyl Transpeptidase Activity in Alcoholics

It is a well-known phenomenon that serum gamma-glutamyltranspeptidase (gamma-GTP, EC 2.3.2.2.) activity is increased after chronic consumption of ethanol, and gamma-GTP has been, therefore, widely used as a sensitive marker for detection of alcoholism and its related liver disease. However, the precise mechanisms whereby the chronic ethanol consumption leads to an increase in serum gamma-GTP activity are not fully understood. In the present study, we investigated the relationship between the intestinal and serum gamma-GTP activities after chronic ethanol consumption both in rats and humans. Chronic ethanol feeding to rats resulted in a significant increase in serum gamma-GTP activity associated with a significant increment of the intestinal gamma-GTP activity. The histochemical staining of gamma-GTP in the mucosa of the small intestine of these animals demonstrated enhanced gamma-GTP activity at the microvilli of the brush border membrane, lamina propria of the mucosa, and endoplasmic reticulum of the intestinal epithelial cell. The augmented activity in the lamina propria was mainly localized at the submucosal lymphatics. Histology of the small intestine of human alcoholics was, more or less, similar to those observed in alcoholic rats. We further investigated the gamma-GTP activity in the mesenteric lymph using the animal model of lymphorrhea, and found that the gamma-GTP activity was increased by 83% when expressed per unit of lymph in the ethanol-fed rat, accompanied by a marked decrease of serum gamma-GTP activity, suggesting a close relationship between the serum and the intestinal gamma-GTP via the lymphatic channel.(ABSTRACT TRUNCATED AT 250 WORDS)     

Correlation Between Insulin Resistance and γ-Glutamyl Transpeptidase Sensitivity in Light Drinkers

Background: Our previous studies suggested that serum γ-glutamyl transpeptidase (GGTP) level was correlated with insulin resistance level estimated by the homeostasis model assessment in teetotalers and occasional drinkers. In the surveys, strong correlation between GGTP and triglyceride also was observed. This study examined whether the correlation held true for regular drinkers.
Methods: Seven hundred and seventeen male subjects in annual health checkups were divided into three groups according to their drinking styles and further divided into four subgroups according to their serum GGTP levels. In the other surveys, they were ranked by their amount of ethanol consumption. The correlation between GGTP and insulin resistance level was studied in each group.
Results: Single regression analysis and analysis of variance showed that GGTP level was significantly correlated with insulin resistance level as determined by the homeostasis model assessment, as well as with triglyceride level regardless of subjects' drinking styles. The associations were confirmed by multiple regression analyses in which age, levels of uric acid, total cholesterol, high-density lipoprotein cholesterol, and body mass index were adjusted, at least in nondrinkers or light drinkers. However, the multiple regression analyses indicated that the association between GGTP and insulin resistance level was not significant in subjects who take ethanol more than five times per week. The studies according to the amount of subjects' ethanol consumption indicated that the association between GGTP and insulin resistance was significant in the subjects who take ethanol up to 280 g/week.
Conclusion: Individual variation in insulin resistance status may contribute to individual variations of sensitivity of GGTP to ethanol intake, at least in light drinkers.     

γ-Glutamyl Transpeptidase Activity in Liver of Alcoholics and Its Histochemical Localization

The activity and the histochemical localization of gamma-GTP in the liver of chronic alcoholics were investigated. Mean serum gamma-GTP activity in alcoholics was 542.5 +/- 337.9 milliunits/ml, and that of patients with nonalcoholic liver disease was 34.3 +/- 22.6 milliunits/ml. Hepatic gamma-GTP activity in alcoholics was significantly increased compared to that in control patients (15.62 +/- 9.29 versus 4.04 +/- 2.67 units/g of liver; p less than 0.001). A significant correlation was observed between hepatic and serum gamma-GTP activity. Light microscopically, a marked gamma-GTP activity was found in the bile canaliculi and a diffuse activity in the cytoplasm in alcoholic livers. By contrast, in the livers of nonalcoholic patients, only slight activity was observed in the bile canaliculi. The electron micrographs showed the enzyme was localized in the microvilli of both the bile canalicular and plasma membranes and the endoplasmic reticulum near the mitochondria in alcoholics. But a very low activity was demonstrated in the plasma membranes in the livers of nonalcoholic patients.     

Testosterone in Chronic Alcoholic Men

Reduced testosterone levels in chronic alcoholic men may be associated with the age, alcohol consumption history, severity of liver injury, and nutritional status of these patients. In this study, total testosterone levels were measured in 163 alcoholic men upon admission to an alcohol treatment program (ATP) and at 3 months follow-up. Values of testosterone below the clinical normal range were found in over 17% of the subjects, a finding significantly predicted by age, alcohol consumption and liver injury tests. Follow-up at 3 months further demonstrated that abnormally low testosterone values significantly increased in men who remained abstinent as compared to those who continued to drink.     

Association Between γ-Glutamyl Transpeptidase Activity and Status of Disorders Constituting Insulin Resistance Syndrome

Background: Serum γ-glutamyl transferase (γGTP) activity is a well-established marker of alcohol consumption. However, recently, a correlation between serum γGTP activity and insulin resistance status has been demonstrated.
Methods: To determine whether serum γGTP activity could be associated with the status of various disorders caused by increased insulin resistance levels, namely, insulin resistance syndrome, a cross-sectional study for 11,884 Japanese men was performed. They were divided into three groups by their age, and associations between γGTP and various indexes of insulin resistance syndrome were studied by multiple logistic regression analysis in which subjects' drinking styles were corrected for in each age bracket.
Results: Consuming ethanol more than 40 g/day, body mass index more than 25.9 kg/m², and triglyceride levels more than 150 mg/dl were significant risk factors accounting for increased γGTP activity (more than 78 IU/liters) irrespective of age. In addition, when subjects of 40 to 59 years old were selectively studied, hypertension, hypercholesteremia, hyperuricemia, and increased glycohemoglobin A1C levels were also significant risk factors for increased γGTP activity.
Conclusions: There are significant associations between γGTP and the status of insulin resistance syndrome. In addition to excessive alcohol consumption, the status of insulin resistance syndrome could affect subjects' γGTP activities.     

Usefulness of Carbohydrate-Deficient Transferrin in Alcoholic Patients with Normal γ-Glutamyltranspeptidase

The biological diagnosis of alcoholism is conducted routinely by assay of γ-glutamyltranspeptidase (GGT) and mean corpuscular volume (MCV). However, their low specificity and sensitivity have prompted research to find other more reliable parameters. Stibler showed an increase in desialylated transferrin [carbohydrate-deficient transferrin (CDT)] in alcoholic patients. The normal value of the serum CDT concentration is under 60 mg/liter; a value between 60 and 100 mg/liter indicates probable alcoholism, and a value >100 mg/liter indicates a very high probability of alcoholism (specificity: 99%). Its sensitivity ranges from 60 to 91%, and its specificity ranges from 92 to 100%. Its half-life is 17 ± 4 days. CDT is thus a useful laboratory marker, but its assay is costlier and more complex than that of GGT. This study concerns 31 alcohol-dependent patients as defined by DSM-IV, with GGT levels in the normal range. It evaluates CDT at day 0 and its time course after 15 days withdrawal. GGT and MCV were assayed concomitantly. Remarkably, the results show a sensitivity of 83.9 (26 positives of 31) in this particular population and a specificity of 92.2. The fall in CDT after 15 days withdrawal was 36%. CDT is thus a particularly useful marker for the diagnosis and follow-up of alcoholics with normal GGT levels.     

Elevated Basal and Abnormal Thyrotropin-Releasing Hormone-Induced Thyroid-Stimulating Hormone Secretion in Chronic Alcoholic Men with Liver Disease

Basal levels of serum thyroid-stimulating hormone (TSH). T₃, T₄, free T₃ and free T₄ were measured in 40 chronic alcoholic men and in 31 normal volunteers. Their serum TSH responses to provocative thyrotropin-releasing hormone (TRH) stimulation were then examined serially: in chronic alcoholics, every 5 days for a total of 3 studies; in 25 of the normal volunteers, before and 72 hr after daily ingestion of ethanol (2 cc/kg/day). Basal serum TSH levels were increased in the alcoholic men (3.5 ± 0.2 μU/ml) (mean ± SEM) compared to those of the normal controls (1.7 ± 0.1) (p < 0.01). Both basal serum T₃ and T₄ levels (T₃, 0.89 ± 0.10 ng/ml; T₄, 7.0 ± 0.4 μg/dl) were reduced in the alcoholic men when compared to those of the normal controls (T₃,1.20 ± 0.03 ng/ml; T₄, 8.6 ± 0.3 μg/dl) (p < 0.01 and p < 0.05, respectively). Basal serum free T₃ levels were reduced in the alcoholic men (169 ± 22 pg/dl) compared to the normal controls (380 ± 18) (p < 0.01). In contrast, basal serum free T₄ levels were increased in the alcoholics (4.0 ± 0.2 ng/dl) compared to those of the normal controls (2.9 ± 0.1) (p < 0.01). In response to TRH, the serum TSH levels of the alcoholic men achieved a peak of 13.5 ± 0.9 μU/ml compared to 14.9 ± 0.9 for the normal controls (no significant difference). Despite better nutrition and alcohol abstinence associated with hospitalization for 10 days, no improvement in either the basal levels of TSH, T₃, and T₄ or the TSH responses to provocative TRH was observed in the alcoholic men studied. In normal volunteers, ethanol had no effect on the basal or TRH-stimulated levels of serum TSH and thyroid hormones.     

Indicators of Alcohol Consumption: Comparisons Between a Questionnaire (Mm-MAST), Interviews and Serum γ-Glutamyl Transferase (GGT) in a Health Survey of Middle-aged Males

A questionnaire consisting of nine questions about drinking habits was used in a preventive programme for middle-aged males in Malmo. With a cut-off point of two yes-answers to the questions, 66% of a group of heavy drinkers, 73 % of all registered alcoholics and 90% of not previously identified alcoholics were identified. Serum γ-glutamyltransferase (GGT), used as an indicator of heavy alcohol consumption in the screening, was a poor instrument for the detection of alcoholism in the same population, assigning correctly only 35%. In combination, the two tests identified 82% of all registered alcoholics, and 97% of the alcoholics who were registered in the period following the screening investigation. Thus Mm-MAST is a useful screening test for alcoholism in medical screening examinations and may successfully be used in combination with biochemical tests.     

Relationship between γ-Glutamyl Transpeptidase and Mean Urinary Alcohol Levels in Alcoholics While Drinking and after Alcohol Withdrawal

In 42 patients with alcoholic liver disease in whom daily urinary ethanol concentrations were measured for 3 months, after an abstinence of at least 1 month, serum gamma-glutamyl transpeptidase (GGT) activity was found to correlate (r = 0.69; p less than 0.0001) with mean urinary alcohol levels. The half-life of serum GGT decay in 32 patients who remained abstinent for an 8-week period was calculated to be 26 days. This prolonged half-life can result in high serum GGT levels in patients abstinent for prolonged periods, in whom serum GGT baselines before abstinence were very high. Individual variations in serum GGT levels should be interpreted in relation to continued alcohol consumption, keeping in mind the long half-life for this enzyme in these patients.     

Effect of Diazepam on Plasma γ-Aminobutyric Acid in Sons of Alcoholic Fathers

A subgroup of abstinent alcoholics display low levels of plasma γ-aminobutyric acid (GABA). Two previous studies of plasma GABA in sons of alcoholic fathers (SOAs) have yielded conflicting results. The aim of the current study was to measure plasma GABA both at baseline and after challenge with diazepam, a GABA_A receptor agonist, in a group of SOAs already shown to display decreased eye movement, memory, and sedative effects of diazepam. Twenty-seven SOAs and 23 male control subjects received four logarithmically increasing doses of diazepam or placebo in randomized order on 2 days at least 1 week apart. Plasma GABA was measured at baseline and after the last dose. There were no significant differences between SOAs and controls in baseline plasma GABA levels. In the whole sample, there were significant correlations between baseline plasma GABA and both high novelty-seeking and low-harm avoidance scores on the Tridimensional Personality Questionnaire. Both SOAs and controls displayed decreases in plasma GABA over time on both testing days, but there was no effect of diazepam on plasma GABA and no significant difference between groups in plasma GABA response to diazepam. These results suggest that neither low plasma GABA at baseline nor altered plasma GABA response to diazepam is associated with increased genetic risk for alcoholism.     

Elevated Interleukin-6 and γ-Globulin during Interferon Therapy of Hepatitis B

A 49-yr-old man with chronic hepatitis B manifested hypergammaglobulinemia, lympbadenopathy, and a high serum interleukin-6 level following treatment with recombinant human α-interferon. One month later, when the patient was treated with natural β-interferon, serum levels of interleukin-6 and γ-globulin increased again. The serum γ-globulin decreased to the pretreatment level after discontinuation of interferon therapy. The serum alanine aminotransferase level remained normal for 6 months. In this case, hypergammaglobulinemia and lymphadenopathy, as well as the elevated serum interleukin-6 level, were considered to be signs of highly enhanced humoral immunity related to α- and β-interferon therapy.     

Immunohistochemical Study of T Cell Receptor γδ Cells in Chronic Liver Disease

The distribution and phenotypic characterization of T cell receptor (TCR) gamma delta cells in human liver tissue was investigated immunohistochemically at light and electron microscopic levels. In chronic liver disease, there was a significant increase in the number of TCR gamma delta cells and in the percentage of TCR gamma delta cells to CD3+ cells in the portal areas and hepatic sinusoids. Hepatic TCR gamma delta cells were classified as small or large gamma delta cells. Large gamma delta cells were increased in chronic liver disease, whereas both small and large gamma delta cells were increased in the portal areas and hepatic sinusoids in liver cirrhosis. The increased TCR gamma delta cells were of the BB3+ (peripheral) type, indicating that TCR gamma delta cells in the liver were of the same lineage as those in the peripheral blood. In addition, the majority of the TCR gamma delta cells in the portal areas of liver cirrhosis patients were CD4- and CD8- (double negative). Immunoelectron microscopy showed that the large gamma delta cells were lymphoblastoid and contained multivesicles. The present study clearly demonstrated that there are two types of TCR gamma delta cells, and that these cells were significantly increased in the livers of patients with chronic liver disease. This suggests that they may be involved in regulation of the immune response and hepatocellular damage in chronic liver disease.     

Nighttime Hypoxemia Is Increased in Abstaining Chronic Alcoholic Men

Previously we reported that abstaining chronic alcoholic men demonstrated significantly more nighttime hypoxemia than a control group. Here, we report a replication employing a larger sample of abstaining chronic alcoholics and a more appropriate control group than that used in the previous study. Forty-seven males, 48.4 +/- 1.7 years of age (mean +/- SEM), reporting 24.8 +/- 1.5 years of heavy alcohol use, comprised the abstaining alcohol group. Thirty-five age- and weight-matched males, 50.3 +/- 1.7 years were the control group. The alcohol group had significantly more nighttime oxygen desaturations below 90% than did the control group (16.9 +/- 3.3 vs. 6.2 +/- 1.4, F = 7.8, p less than 0.01), with significantly higher percentages of individuals in the alcohol group manifesting more than 10 or 20 oxygen desaturations below 90%. Regression analyses within the alcohol group revealed that severity of alcohol abuse, but not age, body mass index, days abstinent, or smoking significantly predicted levels of nighttime hypoxemia. These results confirm our original observation of increased nighttime hypoxemia in abstaining chronic alcoholic men and suggest that long-term alcohol abuse may be a risk factor for development of sleep apnea.     

Further Evidence for a Continuum-of-Impairment Encompassing Male Alcoholic Korsakoff Patients and Chronic Alcoholic Men

A battery of challenging tests was used to assess learning ability and short-term memory in groups of detoxified chronic alcoholics with and without complaints of memory impairment, alcoholic Korsakoff patients, and nonalcoholic controls. While alcoholics without memory complaints did not differ from controls on standardized clinical memory tests, their performance was significantly impaired on our more demanding experimental tests. In contrast, the performance of alcoholics reporting memory complaints was impaired, relative to the other alcoholics, on both clinical and experimental memory tests, overlapping that of the alcoholic Korsakoff patients. These results are consonant with Ryback's continuum-of-impairment hvnothesis.     

Haemolytic Disease of the Newborn and Chronic Anaemia Induced by γβ Thalassaemia in a Dutch Family

Summary. Severe haemolytic anaemia with hyperbilirubinaemia and erythroblastaemia was observed in nine newborn infants belonging to one large family. One infant was still-born, two died shortly after birth, five recovered after receiving one or more exchange transfusions and one improved without transfusional therapy. In four out of six newborns whose bilirubin levels were determined, a mixed hyperbilirubinaemia was found with high concentrations of both free and conjugated bilirubin. At the end of the first year of life the surviving children, although in satisfactory general condition, showed a mild microcytic hypochromic anaemia with decreased red cell osmotic fragility and morphological abnormalities of the erythrocytes consisting of microcytosis, anisopoikilocytosis and target cells. The serum iron levels were normal. The same haematological picture was also present in those parents of the affected children that are members of this family; these adults had normal levels of Hbs A₂ and F. Incorporation of [3H]leucine into the globin chains of two adults with this syndrome revealed a reduced β-chain synthesis (β/α ratio of 0.49 and 0.53, respectively). In the two infants available for this investigation, reduced γ-chain production was found shortly after birth. In parallel with the switch from fetal to adult haemoglobin, the deficient γ-chain production was replaced by a similar reduction of β-chain synthesis. These results suggested, therefore, a combined deficiency of γ and β-chain production. The normal levels of Hb A₂ were compatible with a defective δ-chain synthesis as well. Analysis with restriction enzymes had shown previously a large deletion, comprising γ and δ genes, in one of the chromosomes of the affected individuals. The same procedure had established that, in spite of the defective β-chain production, the β-globin structural gene is intact.     

The Effect of Drinking Intensity and Frequency on Serum Carbohydrate-Deficient Transferrin and γ- Glutamyl Transferase Levels in Outpatient Alcoholics

Whereas heavy alcohol consumption is known to elevate serum carbohydrate-deficient transferrin (CDT) and γ-glutamyl transferase (GGT) levels, the contribution of drinking pattern to these effects is not completely understood. We present data on 423 men and 146 women evaluated 1 year after treatment in a large-scale alcoholism treatment study (Project MATCH). Relationships between drinking frequency (number of days drinking), intensity (drinks per drinking day), and blood levels of CDT and GGT were analyzed by using response surface regression models and thin-plate spline-smoothing techniques. Both models indicated differences between CDT- and GGT-drinking pattern relationships in men and, also, a difference between men and women in CDT drinking-pattern relationships. For men, CDT levels appeared to respond primarily to frequency of drinking, whereas GGT was influenced primarily by drinking intensity. For women, both CDT and GGT were influenced more by drinks per drinking day (intensity) than by number of days drinking (frequency). The data confirm both the independent nature of these biological markers of alcohol consumption and gender differences in alcohol-induced CDT response reported previously.     

Elevated serum interferon γ and interleukin-6 in patients with necrotizing lymphadenitis (Kikuchi's disease)

We investigated serum levels of interferon α, interferon γ, tumour necrosis factor α, interleukin-2 (IL-2) and interleukin-6 (IL-6) in patients with necrotizing lymphadenitis (Kikuchi's disease) (NL). Four male patients, diagnosed as having NL following biopsy of the affected lymph nodes and by the clinical course, were included in this study. All four patients had higher than normal serum interferon γ and IL-6 levels during the acute phase, which returned to normal levels during the convalescent phase. Interferon α, tumour necrosis factor α and IL-2 were, however, within the normal ranges. Our findings indicate the possibility that interferon γ and IL-6 may play an important role in the pathogenesis of NL.     

Diagnostic Value of Serum γ-Glutamyl-Transferase Activity and Mean Corpuscular Volume in Alcoholic Patients with or without Cirrhosis

In an attempt to assess the diagnostic values of serum gamma-glutamyltransferase (GGT) and mean corpuscular volume (MCV) variations as markers of liver disease and of abstinence in alcoholic patients, we compared 174 patients with alcoholic cirrhosis, 175 with noncirrhotic alcoholic liver disease and 67 patients with nonalcoholic cirrhosis. GGT and MCV values were checked three times, the day of admission, 7 days later, and on the last sample available during follow-up (1 to 12 months), and were compared according to the liver disease and abstinence. A decrease of GGT activity during the 1st week of hospitalization was noted in alcoholics with (-9 IU/liter) or without (-13 IU/liter) cirrhosis and not in nonalcoholic cirrhosis (+8 IU/liter), without MCV variations. During follow-up, median GGT activity was strikingly different in abstinent patients with (27 IU/liter) or without (21 IU/liter) cirrhosis and in nonabstinent patients (99 IU/liter and 123 IU/liter, respectively) (p less than 0.001). MCV decrease was noted in alcoholics whatever their abstinence or not, contrasting with the absence of decrease in nonalcoholic patients. For the diagnosis of alcoholism in cirrhotic patients, the positive predictive value (PPV) of a GGT or a MCV decrease during the 1st week of hospitalization was 0.82 and 0.78, respectively, and the negative predictive value (NPV) was 0.33 and 0.70, respectively. For abstinence during follow-up, the PPV of a GGT activity less than 50 IU/liter was 0.92 and the NPV was 0.65.(ABSTRACT TRUNCATED AT 250 WORDS)