Serum gamma-GT Research Articles

Ameliorative potential role of Rosmarinus officinalis extract on toxicity induced by etoposide in male albino rats.

The present work was showed to assess the effect of administration of rosemary extract on etoposide-induced toxicity, injury and proliferation in male rats were investigated. Forty male albino rats were arranged into four equal groups. 1st group, control; 2nd group, etoposide; 3rd group, co-treated rosemary & etoposide; 4th group, rosemary alone. In comparison to the control group, etoposide administration resulted in a significant increase in serum ALT, AST, ALP, total bilirubin, total protein, and gamma GT. In contrast; a significant decrease in albumin level in etoposide group as compared to G1. G3 revealed a significant decrease in AST, ALT, ALP, total protein and total bilirubin levels and a significant rise in albumin level when compared with G2. Serum levels of urea, creatinine, potassium ions, and chloride ions significantly increased; while sodium ions were significantly decreased in G2 when compared with G1. Also, there was an increase of MDA level for etoposide treated group with corresponding control rats. However, there was a remarkable significant decrease in SOD, GPX and CAT levels in G2 as compared to G1. There was a significant increase in serum hydrogen peroxide (H2O2) and Nitric oxide (NO) levels in group treated with etoposide when compared to control group. It was noticeable that administrated by rosemary alone either with etoposide had not any effect on the levels of H2O2 and Nitric oxide. Serum level of T3 and T4 was significantly increased in etoposide-administered rats in comparison with G1. The administration of rosemary, either alone or with etoposide, increased the serum levels of T3 and T4 significantly when compared to control rats. The gene expression analysis showed significant downregulation of hepatic SOD and GPx in (G2) when compared with (G1). The treatment with rosemary extract produced significant upregulation of the antioxidant enzymes mRNA SOD and GPx. MDA gene was increased in (G2) when contrasted with (G1). Treatment of the etoposide- induced rats with rosemary extract delivered significant decrease in MDA gene expression when compared with etoposide group. Rats treated with etoposide showed significant decline in hepatic Nrf2 protein expression, when compared with G1. While, supplementation of Etoposide- administered rats with the rosemary produced a significant elevation in hepatic Nrf2 protein levels. Additionally, the liver histological structure displayed noticeable degeneration and cellular infiltration in liver cells. It is possible to infer that rosemary has a potential role and that it should be researched as a natural component for etoposide-induced toxicity protection.

Association of Gamma-GT Serum and Nerve Conduction Velocity of Nervus Peroneus Motor Vehicles on Diabetic Polyneuropathy Patients

Background and Objectives: Diabetic Polyneuropathy is one of the common complications of diabetesmellitus (DM) and can lead to foot ulcers or amputation. The pathophysiology of Diabetic Polyneuropathyincludes several factors such as metabolic, vascular, autoimmune, oxidative stress and neurohormonalgrowth-factor deficiency. The recent studies have suggested the use of serum gammaglutamyl transferase(GGT) as an early marker of oxidative stress. Therefore, we investigated whether serum GGT may be usefulin predicting Diabetic Polyneuropathy.Methods: The study was conducted in patients with diabetic polyneuropathy who meet the criteria forinclusion and exclusion in neurological outpatient clinic and EMG room departments of NeurologyDr.Soetomo General Hospital Surabaya consecutively started in June 2014 to April 2015.Result: We obtained 20 study subjects (8 subjects with increased serum levels of gamma GT and 12 subjectswith normal serum levels of gamma GT). There was statistically no significant between serum levels ofgamma GT with motoric nerve conduction velocity (NCV) of peroneal nerve (p = 0.582 ; Odds ratio 0.600).Conclusion: There was no relationship between elevated levels of serum gamma GT with decreased motornerve conductivity velocity peroneal nerve in patients with diabetic polyneuropathy.

Serum levels of gamma-glutamyltransferase predict outcome in heart failure with preserved ejection fraction

Previous studies suggested an association between heart failure (HF) and hepatic disorders. Liver function parameters have been shown to predict outcome in HF with reduced ejection fraction, but their impact in HF with preserved ejection fraction (HFpEF) has not yet been investigated. Between January 2011 and February 2017, 274 patients with confirmed HFpEF were enrolled (age 71.3 ± 8.4 years, 69.3% female) in a prospective registry. During a median follow-up of 21.5 ± 18.6 months, 97 patients (35.4%) reached the combined endpoint defined as hospitalization due to HF and/ or death from any cause. By multivariable cox regression, serum gamma-glutamyltransferase (GT) was independently associated with outcome (Hazard Ratio (HR) 1.002, p = 0.004) along with N-terminal pro brain natriuretic peptide (HR 2.213, p = 0.001) and hemoglobin (HR 0.840, p = 0.006). Kaplan-Meier analysis showed that patients with serum gamma-GT levels above a median of 36 U/L had significantly more events as compared to the remainder of the group (log-rank p = 0.012). By multivariable logistic regression, higher early mitral inflow velocity/ mitral peak velocity of late filling (Odds Ratio (OR) 2.173, p = 0.024), higher right atrial (RA) pressure (OR 1.139, p < 0.001) and larger RA diameter (OR 1.070, p = 0.001) were independently associated with serum gamma-GT > 36 U/L. Serum levels of gamma-GT are associated with both left and right-sided cardiac alterations and may serve as a simple tool for risk prediction in HFpEF, especially when further diagnostic modalities are not available.

Elevated systemic zonula occludens 1 is positively correlated with inflammation in cirrhosis

Background/AimIt has been well established that disruption of the intestinal barrier function and increased intestinal permeability contribute to endotoxemia and associated liver injury in patients with cirrhosis. However, the relationship between systemic inflammation and tight junction protein in cirrhosis remain unidentified. The aim of this study was to assess and compare the blood concentrations of ZO-1 with systemic hsCRP in patients with cirrhosis and healthy individuals. Methods: 30 cirrhotic patients and 30 healthy individuals were enrolled in the study. Blood ZO-1 and hsCRP were measured by ELISA and biochemical parameters by AU680 Beckman Coulter (USA) autoanalyser. Results: The serum ALT, AST, bilirubin, gamma GT, ALP and ammonia were significantly (P < 0.0001) elevated whilst serum albumin concentration was decreased in cirrhotic patients when compared to healthy individuals. Systemic tight junction protein ZO-1 concentration [590.0 ± 32.79 vs. 349.9 ± 18.76 pg/ml, respectively; P < 0.0001] and hsCRP [10.50 ± 1.05 vs 5.31 ± 0.65 mg/L, respectively; P < 0.001] were significantly elevated in patients with cirrhosis compared to controls. Significant positive correlation was found between increased ZO-1 and hsCRP (r = 0.2680 P < 0.01). Conclusion: Our results suggested that increased systemic ZO-1 concentration was associated with inflammation in cirrhosis. Thus, elevated blood ZO-1 levels could be a prognostic marker of cirrhotic patients with intestinal TJ disruption on the background of inflammation.

Serum Gamma-Glutamyl Transferase Activity as a Potential Novel Cardiovascular Biomarker in COPD.

Gamma-glutamyl transferase (gamma-GT) is an enzyme present in the cell membranes, which is used as a new biomarker in prediction of inflammation, myocardial infarction, stroke, and cardiac death. The objective of this study was to investigate the relationship between serum levels of gamma-GT and cardiovascular disease in subjects with COPD and the correlation between serum gamma-GT level and degree of the limitation of air flow in COPD. A total of 70 subjects (46.1%) with Global Initiative for Chronic Obstructive Lung Disease (GOLD) A-B and normal function of the liver and biliary tract (mean age [IQR] 59 [51.75-70] y; 77.1% men) and 82 subjects (53.9%) with GOLD C-D (mean age [IQR] 59 [56-66] y; 79.3% men) participated. Serum levels of gamma-GT and C-reactive protein were measured and compared between the 2 groups. The serum level of gamma-GT was found to be significantly (P < .001) higher in the GOLD stage C and D group than in the GOLD stage A and B group. Mean values of C-reactive protein, aspartate aminotransferase, and alanine aminotransferase did not differ significantly between the 2 groups. The prevalence of cardiovascular disease was statistically significantly higher in subjects in the GOLD stage C and D group than in the GOLD stage A and B group (P < .001). The serum level of gamma-GT was higher in subjects with COPD with coexisting cardiovascular disease than in those without cardiovascular disease (64 units/L [interquartile range 57-72.5] vs 17.5 units/L [interquartile range 10-25]). Our results demonstrate that serum levels of gamma-GT may be helpful in grading the severity of COPD as the marker of oxidative stress, and there is a strong correlation between high serum levels of gamma-GT and cardiovascular events in subjects with COPD.

Baseline gamma-GT levels within the normal range predict high virologic response rates in treatment-naïve patients undergoing boceprevir triple therapy for HCV genotype 1 (G1) infection

Background: A considerable number of patients (pts) with chronic HCV G1 infection will present with elevated serum gamma-GT levels. However, the impact of gamma-GT elevation on virologic response to boceprevir triple therapy has not been investigated until yet and was therefore the aim of the present interim analysis of the German NOVUS observational study.

Effect of L-ornithine L-aspartate granules in treating chronic liver disease in patients with high-level serum gamma-glutamyltransferase

To explore the clinical effect of L-ornithine L-aspartate (LOLA) granules in treating chronic liver disease in patients with high-level serum gamma-glutamyltransferase (G-GT) using a 24-week treatment course. Two-hundred patients with chronic liver disease and above normal G-GT were given a 12-week course of LOLA granules (9 g/d) and then classified into the following three groups according to the change in serum Gamma-GT:group I:patients with Gamma-GT level returned to normal;group II:patients with serum Gamma-GT level that was reduced during the treatment; group III:patients with serum Gamma-GT level that did not decrease or that increased to a higher level than at start of treatment.After the 12-week treatment course, the patients in group I were divided into three subgroups for receipt of a control drug (compound glycyrrhizin, 50mg/d) or an additional 12-week course of Gamma-GT at a reduced dose (LOLA granules 3 g/d) or at the original dose; groups II and III were maintained on the initial dose for an additional 12 weeks.The groups were reassessed at the end of the second 12-week course (at the end of week 24 of the study's observation period).Count data were compared using the x2 test and measurement data were compared using the t-test. In group I, the serum Gamma-GT level was 90.9% at the end of the first 12-week course and dropped to a mean level of 52.2% for both of the subgroups that received the reduced and original dose after the additional 12 weeks of LOLA granules treatment; the difference from week 12 to week 24 was significant (x2=8.213, P less than 0.05).The 24-week change in serum Gamma-GT levels for the group I reduced and original dose subgroups vs.the control subgroup were also significantly different from those seen in groups II and III (P less than 0.05).The percentage of patients in group I who achieved normal level serum Gamma-GT after 24 weeks of treatment (78.6%) was significantly higher than that for the control group (vs.55.0%, x2=11.452, P less than 0.05).When the patients in group 1 who had received the 12 additional weeks of LOLA granules treatment were measured again at two weeks after the treatments had been discontinued (end of week 26), the percentage of patients with normal serum Gamma-GT level was 92.7%, with only three cases showing obviously abnormal levels; in contrast, the group I patients in the control group of the second 12-week study period had on 66.7% of patients with normal-level serum Gamma-GT.The difference in change between the treated groups (both reduced and original dose) and the control group was significant (x2=14.964, P less than 0.05). Patients whose serumGamma-GT levels returned to normal after receipt of LOLA granules for 12 weeks benefitted from an additional 12 weeks of consolidation treatment, and those given the treatment at the original dose benefitted most.Compared with the compound glycyrrhizin, LOLA granules provided a better maintenance of resolved Gamma-GT level.Therefore, the effect of LOLA appears to be reliable and stable as well as safe for clinical use.

Effect of Troglitazone on Serum γ-Glutamyltransferase Activity and Plasma t-PA/PAI-1 Complex in Type 2 Diabetic Patients

This study was conducted to determine whether troglitazone (CAS 97322-87-7, Noscal), a thiazolidinedione with alpha-tocopherol in the side chain, had an antioxidant effect in patients with Type 2 diabetes. In 46 Type 2 diabetic outpatients aged 64 +/- 7 years (male/female: 33/13), with a body mass index of 23.4 +/-2.8 kg/m2, a 2-year prospective study was performed. Patients were given troglitazone tablet (200 mg) twice a day. After treatment for 4 months, troglitazone was withheld for one month (washout period). Then troglitazone was resumed for a further 19 months. The study was completed in 28 patients. In 18 patients, it was not completed because of side effects in 4 female patients and because of withdrawal of troglitazone from the Japanese market in 14 patients. Fasting plasma glucose was decreased by troglitazone treatment from 170.2 +/- 38.2 mg/dl to 151.6 +/- 34.5 mg/dl (ANOVA: F = 8.054, p < 0.001). Washout caused it to return to the pre-treatment level (170.9 +/- 38.0 mg/dl), but it decreased again to 145.4 +/- 33.4 mg/dl with the resumption of treatment (F = 3.845, p < 0.001). Glycated hemoglobin was decreased by treatment from 8.2 +/- 1.6 % to 7.9 +/- 1.6 % (F = 7.558, D < 0.001). Washout caused it to return to the pre-treatment level (8.0 +/- 1.6 %), but it decreased again to 7.6 +/- 1.2 % with the resumption of treatment (F = 1.985, p = 0.041). Fasting serum immunoreactive insulin was decreased by treatment from 5.5 +/- 3.4 pU/ml to 4.0 +/- 2.2 pU/ml (F = 9.098, p < 0.001). Washout caused it to return to near the pre-treatment level (4.6 +/- 2.4 pU/ml). After resumption of treatment, it remained unchanged. Serum n-glutamyltransferase (gamma-GT) activity was decreased by treatment from 37.5 +/- 25.7 U/I to 25.6 +/- 12.3 U/I (F = 19.406, p < 0.001). Washout caused it to return to the pre-treatment level (36.5 +/- 25.1 U/I), but it decreased again to 24.2 +/- 10.1 U/l with the resumption of treatment (F = 7.931, p < 0.001). Plasma tissue plasminogen activator(t-PA)/plasminogen activator inhibitor-1 (PAI-1) complex was decreased by treatment from 21.7 + 8.6 ng/ml to 19.0 +/- 6.6 ng/ml (F = 8.784, p < 0.001). Washout caused it to return to the pretreatment level (21.9 +/- 7.4 ng/ml), but it decreased again to 14.3 +/- 4.3 ng/ml after the resumption of treatment (F = 12.341, p < 0.001). Decreases in serum gamma-GT activity and plasma t-PA/PAI-1 complex were closely related with antioxidant action of troglitazone.

Oral supplementation with l-aspartate and l-glutamate inhibits atherogenesis and fatty liver disease in cholesterol-fed rabbit

Previous studies have shown that dietary supplementation with L-aspartate and L-glutamate inhibits fatty streak initiation in cholesterol-fed rabbit. The present study investigates the role of dicarboxylic amino acids on the progression of fatty streaks and the development of fatty liver disease, which were caused in New Zealand White rabbits after a 0.5% w/w cholesterol diet for 7 weeks. A group of animals additionally received a combination of 12.5 mM L-aspartate and 12.5 mM L-glutamate per day through drinking water. Total cholesterol (TC), high-density lipoproteins cholesterol (HDLC), non-HDLC and triacylglycerol (TAG) concentrations were measured in plasma. Serum gamma-glutamyl transferase (gamma-GT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were also determined. At the end of dietary intervention, animals were sacrificed. Aortic, hepatic and brain lesions were evaluated after staining with hematoxylin and eosin. Supplementation with dicarboxylic amino acids inhibited the progression of aortic intima thickness (P < 0.05) and the development of liver lesions (P < 0.05). TC, non-HDLC and TAG were similarly increased in both cholesterol-fed groups. Serum gamma-GT and AST activities elevated during the study in all cholesterol-fed animals but the elevation of gamma-GT was milder and significantly lower in rabbits treated with L-aspartate and L-glutamate (P < 0.05). ALT activity was not affected by cholesterol feeding. In conclusion, oral supplementation with L-aspartate and L-glutamate inhibits the progression of atherogenesis and the development of fatty liver disease in the animal model of cholesterol-fed rabbit. The beneficial effects of dicarboxylic amino acids reflect the limited elevation of serum gamma-GT activity.

Synergism between smoking and alcohol consumption with respect to serum gamma‐glutamyltransferase†‡

There is increasing evidence that serum levels of the liver enzyme gamma-glutamyltransferase (gamma-GT) are an important predictor of incidence and mortality of various diseases. Apart from alcohol consumption, body mass index and smoking have been found to be associated with serum levels, but little is known about potential interactions of these factors. The aim of this study was to assess the individual and joint impact of alcohol consumption and smoking on levels of gamma-GT, with particular attention to potential differences by sex. The study was based on data of 8465 subjects aged 50 to 74 years, obtained at baseline examination of the ESTHER study, a large population-based cohort study in Germany. Exposure-outcome relationships were assessed in women and men, adjusting for potential confounders by multiple regression. In both sexes, moderate to heavy alcohol consumption (100+ g/week) was associated with 1.7-fold increased odds of elevated gamma-GT (>50 IU/L) in reference to nonsmoking alcohol abstainers, whereas smoking by itself was unrelated to gamma-GT. However, when moderate to heavy alcohol consumption was present in combination with heavy smoking, the odds ratios (95% CI) increased to 2.9 (1.1-7.6) in women and to 3.8 (2.2-6.6) in men (test for interaction between alcohol consumption and smoking: P(females) = 0.12, P(males) = 0.0017). Our results support the notion of a detrimental interaction between cigarette smoking and alcohol consumption as determinants of elevated serum gamma-GT, especially in men.

Pseudodeficiency of glutamine in infant liver disease

Gamma-glutamyltransferase (gamma-GT) is an early marker for cholestasis and has the capability of glutamine-deamidation. Two infants with elevated serum gamma-GT had a decreased serum glutamine. A time course of glutamine and glutamate concentration changes was performed. This revealed a time dependent decrease of glutamine far below the normal lower limit while glutamate increased above the normal upper limit. In conclusion, increased in vitro gamma-GT can cause pseudodeficiency of glutamine. To avoid pitfalls, physicians should inform the laboratory on accompanying pathologies.

Antiangiogenic effect of Lygodium flexuosum against N-nitrosodiethylamine-induced hepatotoxicity in rats

The antiangiogenic effect of Lygodium flexuosum extract was evaluated in Wistar rats intoxicated with N-nitrosodiethylamine (NDEA) in preventive and curative models. In preventive groups, NDEA was administered for 20 weeks. Daily doses of L. flexuosumn-hexane extract (200mg/kg) started 1 week before the onset of NDEA intoxication and continued for 20 weeks. In curative animals, NDEA was administered for 20 weeks followed by treatment with the n-hexane extract of L. flexuosum for 28 days. Rats intoxicated with NDEA had elevated levels of serum gamma-GT, AST, ALT, LDH levels and hepatic MDA and decreased levels of hepatic GSH. When treated with L. flexuosum extract had normal levels of gamma-GT, AST, ALT, LDH levels, hepatic MDA and GSH. NDEA administered rat liver showed an overexpressed levels of angiopoietins 1 (Ang-1) and 2 (Ang-2) and its receptor Tie-2 mRNA. L. flexuosum extract treatment significantly (p<or=0.05) reduced the levels of Ang-1 and Ang-2 and Tie-2 in rat livers evidenced by RT-PCR. Immunohistochemical analysis showed that vascular endothelial growth factor (VEGF) was overexpressed and localized around periportal area of liver sections intoxicated with NDEA and its overexpression was effectively reduced by the treatment with L. flexuosum extract. Histopathological observations also substantiated NDEA-induced hepatotoxicity and the effect was significantly (p<or=0.05) reduced by L. flexuosum extract treatment. Thus, L. flexuosum extract at a dose of 200mg/kg effectively reversed the hepatotoxicity induced by N-nitrosodiethylamine in both experimental models.

Selective nuclear factor κ‐B inhibitors, pyrolidium dithiocarbamate and sulfasalazine, prevent the nephrotoxicity induced by gentamicin

To investigate the effect of selective nuclear factor kappa-B (NFkappa-B) inhibitors, pyrolidium dithiocarbamate (PD) and sulfasalazine (SZ) on renal tubular necrosis and inducible nitric oxide synthase (iNOS) and NFkappa-B expression induced by gentamicin in rats. In all, 48 adult male Sprague-Dawley rats were divided into six equal groups; group 1, control; group 2, injected with gentamicin for 10 days (100 mg/kg/day, intraperitoneal, i.p.); group 3, injected with gentamicin plus PD (100 mg/kg/day, i.p.); group 4, injected with gentamicin plus SZ (75 mg/kg/day, i.p.); group 5, injected with gentamicin plus distilled water (vehicle for PD); and group 6, injected with gentamicin plus ammonium hydroxide (75 mg/day, 1 m, vehicle for SZ) for 10 days. At 24 h after the last injection, rats were killed and the renal cortex separated from the medulla. A small sample was fixed in formaldehyde solution for histological and immunohistochemical examination. Blood samples were also taken to assess the serum levels of urea, creatinine, Na(+), K(+) and gamma-glutamyl transpeptidase (GT). Crude extracts of the cortex were used to determine reduced glutathione (GSH-Px), NO and malondialdehyde (MDA). Immunohistochemically, iNOS and the active subunit of NFkappaB, P65, were evaluated using mouse monoclonal antibodies. On haematoxylin and eosin staining, compared with the controls rats, gentamicin caused widespread tubular necrosis (grade 3 and 4) but in group 3 and 4 there was a marked reduction in the extent of tubular damage. Immunohistochemically there was more marked staining for iNOS and P65 expression in rats given gentamicin than in the control and group 3 and 4 (P < 0.001). In groups 3 and 4 iNOS and P65 expression were significantly less than in rats given only gentamicin. There was no significant difference in serum levels of Na(+), K(+), blood urea nitrogen and creatinine. Compared with control rats, gentamicin caused hyperproteinuria, a marked increase in levels of serum gamma-GT, MDA and NO, and a decrease in GSH-Px (P < 0.001). These results indicate that gentamicin induces iNOS expression through activation of NFkappa-B (P65). It is possible to prevent gentamicin-induced nephrotoxicity using selective NFkappa-B inhibitors.

Genetic cholestasis, causes and consequences for hepatobiliary transport.

Bile salts take part in an efficient enterohepatic circulation in which most of the secreted bile salts are reclaimed by absorption in the terminal ileum. In the liver, the sodium-dependent taurocholate transporter at the basolateral (sinusoidal) membrane and the bile salt export pump at the canalicular membrane mediate hepatic uptake and hepatobiliary secretion of bile salts. Canalicular secretion is the driving force for the enterohepatic cycling of bile salts and most genetic diseases are caused by defects of canalicular secretion. Impairment of bile flow leads to adaptive changes in the expression of transporter proteins and enzymes of the cytochrome P-450 system involved in the metabolism of cholesterol and bile acids. Bile salts act as ligands for transcription factors. As such, they stimulate or inhibit the transcription of genes encoding transporters and enzymes involved in their own metabolism. Together these changes appear to serve mainly a hepatoprotective function. Progressive familial intrahepatic cholestasis (PFIC) results from mutations in various genes encoding hepatobiliary transport proteins. Mutations in the FIC1 gene cause relapsing or permanent cholestasis. The relapsing type of cholestasis is called benign recurrent intrahepatic cholestasis, the permanent type of cholestasis PFIC type 1. PFIC type 2 results from mutations in the bile salt export pump (BSEP) gene. This is associated with permanent cholestasis since birth. Serum gamma-glutamyltransferase (gamma-GT) activity is low to normal in PFIC types 1 and 2. Bile diversion procedures, causing a decreased bile salt pool, have a beneficial effect in a number of patients with these diseases. However, liver transplantation is often necessary. PFIC type 3 is caused by mutations in the MDR3 gene. MDR3 is a phospholipid translocator in the canalicular membrane. Because of the inability to secrete phospholipids, patients with PFIC type 3 produce bile acid-rich toxic bile that damages the intrahepatic bile ducts. Serum gamma-GT activity is elevated in these patients. Ursodeoxycholic acid therapy is useful for patients with a partial defect. Liver transplantation is a more definitive therapy for these patients.

Serum gamma-glutamyl transpeptidase activity and bile acids in normal Taiwanese infants.

To facilitate making a diagnosis of cholestatic liver disease in Taiwan, we have established reference ranges for serum gamma-glutamyl transpeptidase (gamma-GT) activity and bile acids in normal Taiwanese infants. The serum level of gamma-GT activity was assayed in 90 normal Taiwanese infants and children aged between 2 days and 2 years old. These data were analyzed in twenty-three 0-3-month-old, twenty-four 4-6-month-old, and forty-three 7-24-month-old infants. The mean values of serum gamma-GT activity were 47.4 +/- 26.6, 21.5 +/- 7.3, and 14.0 +/- 3.2 IU/L for the respective age groups. The highest reference gamma-GT values were 99.5, 35.8, and 20.3 IU/L for the respective age groups. The mean values of serum gamma-GT activity were highest in infants younger than 3 months, and these gradually decreased to the adult level with age (p < 0.01). Serum bile acids were measured in 24 premature and 56 full-term infants. The mean values of serum bile acids were 34.5 +/- 34.5 mumol/L in preterm infants and 18.7 +/- 21.9 mumol/L in full-term babies. The bile acid levels of preterm infants were higher than those in full-term babies (p < 0.01).

Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy with serious consequences for the mother and fetus. Two pedigrees have been reported with ICP in the mothers of children with a subtype of autosomal recessive progressive familial intrahepatic cholestasis (PFIC) with raised serum gamma-glutamyl transpeptidase (gamma-GT). Affected children have homozygous mutations in the MDR3 gene (also called ABCB4 ), and heterozygous mothers have ICP. More frequently, however, ICP occurs in women with no known family history of PFIC and the genetic basis of this disorder is unknown. We investigated eight women with ICP and raised serum gamma-GT, but with no known family history of PFIC. DNA sequence analysis revealed a C to A transversion in codon 546 in exon 14 of MDR3 in one patient, which results in the missense substitution of the wild-type alanine with an aspartic acid. We performed functional studies of this mutation introduced into MDR1, a closely related homologue of MDR3. Fluorescence activated cell sorting (FACS) and western analysis indicated that this missense mutation causes disruption of protein trafficking with a subsequent lack of functional protein at the cell surface. The demonstration of a heterozygous missense mutation in the MDR3 gene in a patient with ICP with no known family history of PFIC, analysed by functional studies, is a novel finding. This shows that MDR3 mutations are responsible for the additional phenotype of ICP in a subgroup of women with raised gamma-GT.

A New UV Method for Serum -Glutamyltransferase Assay Using Recombinant 4-Aminobenzoate Hydroxylase as a Coupling Enzyme

4-aminobenzoate hydroxylase (4ABH) is a flavin-dependent monooxygenase that catalyzes the decarboxylative hydroxylation of 4-aminobenzoate to 4-hydroxyaniline. For use as a clinical reagent, the gene encoding 4ABH from Agaricus bisporus was cloned by the RACE method. Also, the cDNA encoding 4ABH was expressed in Escherichia coli cells as a fusion protein with glutathione S-transferase (GST). The expressed GST-4ABH fusion protein (recombinant 4ABH) in the soluble fraction exhibits decarboxylative hydroxylation and additional NADH oxidation activities.We investigated a new ultraviolet spectrometric method for determining serum gamma-glutamyltransferase (gamma-GT) using recombinant 4ABH as a coupling enzyme. The principle of the method is as follows. Using gamma-glutamyl-3-choloro-4-aminobenzoate (L-gamma-glu-PAClBA) and glycylglycine as the donor and acceptor substrates, 3-choloro-4-aminobenzoate (PAClBA) is formed by the catalysis of serum gamma-GT. PAClBA is stoichiometrically converted to 3-choloro-4-hydroxyaniline (PHClA) and NAD(+) by 4ABH and NADH. However, NADH oxidation results in a high reagent blank, which is considered as a drawback for use as a clinical reagent. Using recombinant 4ABH, we examined the effects of pH and detergents on these two activities, and found that several detergents suppress the additional NADH oxidation activity with little or no effect on hydroxylation activity. The results indicate a promising approach to establishing an ultraviolet spectrophotometric method for determining serum gamma-GT activity using L-gamma-glu-PAClBA as the donor substrate and recombinant 4ABH as a coupling enzyme.

Conventional and quantitative liver function tests after hepatic transplantation: a prospective long-term follow-up.

In long-term survivors of liver transplantation, hepatic function is obviously of vital importance. Therefore, we prospectively performed conventional and quantitative liver function tests in patients who had survived a first transplantation for at least 4 years. Compared to 6 months after transplantation, serum bilirubin concentration and gamma GT activity were significantly lower after 3, 4, and 5 years (bilirubin 1.2 +/- 0.2 mg/dl at 6 months vs 1.0 +/- 0.1, 1.0 +/- 0.2, and 0.8 +/- 0.1 mg/dl respectively; gamma GT 106 +/- 0 33 U/l at 6 months vs 56 +/- 17, 67 +/- 35, 39 +/- 10 U/l respectively). At these points in time, blood levels of cyclosporin A were also significantly lower. Other parameters of liver cell function and liver cell integrity (AP, AST, ALT, GLDH, total protein, thromboplastin time, partial thromboplastin time) were unchanged over time. Serial quantitative liver function tests (indocyanine green half-life, galactose elimination capacity, lidocaine half-life, and MEGX formation) also remained stable. Thus, we conclude that hepatic function remains stable in long-term survivors of liver transplantation for at least several years.

Body composition, cardiovascular risk factors and liver function in long-term androgenic-anabolic steroids using bodybuilders three months after drug withdrawal.

The purpose of this study was to investigate in a cross-sectional design body composition, muscle fiber characteristics, cardiovascular risk factors and liver enzymes in long-term androgenic-anabolic steroids (AAS) using bodybuilders three months after drug withdrawal (AAS group; n = 16) and in non-users (CO group; n = 12). Training and dietary data were collected in all subjects. Anthropometry included weight, height, 8 skinfolds and 11 circumferences. Percentage fat (%FAT), fat mass (FM) and lean body mass (LBM) were calculated. In a muscle biopsy from the vastus lateralis muscle water content, fiber type distribution and diameters of fiber type I and type II were determined. Age, height, training characteristics, nutrition, skinfolds, %FAT and FM did not differ between the groups. The AAS group had greater BW and LBM, and larger circumferences of thorax, waist, upper arm and thigh than the CO group. Muscle biopsy data were comparable, except for muscle fiber diameter of type I which was larger in the AAS group. No differences in serum values of total cholesterol, HDL-cholesterol and triglycerides, nor in systolic and diastolic blood pressure were observed. In both groups serum alkaline phosphatase and gamma GT were within the normal range. This study suggests that in long term AAS using body-builders, after a three months AAS free period, BW is greater than in non drug users. This is reflected in larger LBM, circumferences and diameter of muscle fiber type I. In addition, no differences in fat mass, blood pressure, lipoprotein profiles and liver enzymes exist between AAS users three months after interrupted drug use and their non drug using counterparts.

Preferential virological response to interferon-alpha 2a in patients with chronic hepatitis C infected by virus genotype 3a and exhibiting a low gamma-GT/ALT ratio.

Hepatitis C virus infection causes acute and often chronic hepatitis. Therapy with interferon-alpha has been shown to induce remission of the inflammatory process within the liver and also elimination of the virus. However, only about 50% of treated patients respond in terms of at least a transient disappearance of viral RNA from the circulation below the limit of detection. In order to find prognostic factors for responsiveness, patients with chronic hepatitis C virus infection were analyzed for virus genotype and pretreatment biochemical liver parameters including serum AST, ALT, and gamma-GT activities. Whereas the initial biochemical response to interferon-alpha 2a was found not to be related to virus genotype, the initial virological response was found to be closely related to infection by genotype 3a and to a low pretreatment ratio of serum gamma-GT/ALT activity. These data confirm and extend the importance of virus genotype for responsiveness to interferon-alpha therapy and introduce an additional, host-specific parameter with a potential predictive value, namely the pretreatment ratio of serum gamma-GT/ALT activity.