gamma-GT Levels Research Articles

Type 1 autoimmune hepatitis: patterns of clinical presentation and differential diagnosis of the 'acute' type

Autoimmune hepatitis (AIH) has three different presentations: chronic, acute and asymptomatic. To evaluate AIH presentation in Italian patients and investigate criteria that differentiate between acute-type AIH and acute viral hepatitis. Prospective observational study. Eighty-six consecutive patients with type 1 AIH and 41 with acute viral hepatitis (controls) were studied. 'Acute' AIH was defined as recent-onset (<30 days) symptoms (jaundice and/or fatigue and/or fever) with marked alterations in serum liver tests; the 'asymptomatic' pattern as the occasional detection of liver abnormalities, and the 'chronic' pattern as the presence of signs and/or symptoms of long-lasting liver disease. Of 86 AIH patients, 59 (68%) presented with the chronic pattern, 22 (26%) with the acute pattern, and 5 (6%) were asymptomatic. 'Acute' patients had higher AST, ALT and bilirubin serum levels (p < 0.0001). No differences were detected with respect to age and serum levels of alkaline phosphatase, gamma-GT, albumin or gamma-globulin. All three groups had similar prevalences of moderate/severe (vs. mild) histological findings and liver cirrhosis. When compared with controls with acute viral hepatitis, 'acute' AIH patients were more often female (82% vs. 24%, p < 0.0001) and had higher serum gamma-globulin levels (26.9 vs. 13.4 g/l, p < 0.0001) and AST/ALT ratio (1.20 vs. 0.61, p < 0.0001). Although in Italy type 1 AIH patients usually present with a chronic pattern, some 25% have an acute presentation resembling that of viral hepatitis. 'Acute' AIH and viral hepatitis can be reliably differentiated by simple parameters such as gender, gamma-globulin serum levels and AST/ALT ratio.

Predictors of choledocholithiasis in patients sustaining gallstones

The aim of this study was to identify clinical, biochemical and ultrasonographic predictors of choledocholithiasis in patients sustaining gallstones assessed by cholangiography. In a prospective study, 148 patients were analyzed regarding clinical, biochemical and ultrasonographic data. All patients underwent cholangiography, either preoperative endoscopic or during cholecystectomy. Each variable was compared between the ones who sustained lithiasis in the biliary tree and the others, in order to find out the predictors of choledocholithiasis. Sensibility, specificity, positive predictive value, negative predictive value (NPV) and accuracy were calculated. Spearman correlation, Odds ratio and logistic regression were employed for the statistical analysis, considering p<0.05 as significant. The variables that showed statistical significance were: presence of jaundice, elevated blood serum levels of alkaline phosphatase, g glutamyltransferase (gamma GT), aspartate aminotransferase, alanine aminotransferase, total bilirrubin, and biliary tract dilatation or choledocholithiasis in the ultrasound. The logistic regression presented an equation capable of predicting the probability of choledocholithiasis based in the variables: jaundice, presence of choledocholithiasis in the ultrasound, and blood levels of gamma GT. The best option to exclude the presence of choledocholithiasis was gamma GT, as it held the higher NPV. Every patient with choledocholithiasis in this sample sustained at least one of the preoperative criteria analyzed. Jaundice and choledocholithiasis at the ultrasound were the best predictors of choledocholithiasis; as well as gamma GT was the most reliable factor to exclude this diagnosis.

Inhibition of gamma-glutamyl transpeptidase activity decreases intracellular cysteine levels in cervical carcinoma.

To determine whether gamma-glutamyl transpeptidase (gamma-GT) is involved in the maintenance of elevated cysteine levels in cervical carcinoma. Four cervical carcinoma cell lines were tested in vitro for cysteine accumulation and gamma-GT levels. The highest and lowest gamma-GT-expressing cell lines were used in in vivo experiments to determine the effect of gamma-GT inhibition on cysteine levels. Treatment of a series of cervical carcinoma cell lines with acivicin decreased intracellular cysteine concentrations. Cysteine depletion was evident in Me180 cells which had the greatest levels of gamma-GT activity, and had a more pronounced cysteine decrease in medium with glutathione and cysteine concentrations simulating the in vivo situation. Also investigated were the effects of inhibition of gamma-GT activity on intracellular cysteine levels in xenografts grown in severe combined immunodeficient (SCID) mice. With the use of 35 mg/kg of acivicin, gamma-GT activity decreased to basal levels of detection in both tumour types and significant decreases in cysteine levels were seen in the high gamma-GT-expressing tumours (Me180). Thus, inhibition of gamma-GT activity may have therapeutic potential in high-expressing cancers. In tumours and cell lines with elevated levels of gamma-GT activity, inhibition of this enzyme led to decreases of cysteine levels.

Diagnostic and surgical therapeutic features of extrahepatic bile duct carcinoma without jaundice.

To analyze the diagnostic and therapeutic features of extrahepatic bile duct carcinoma (EBDC) without jaundice. Between 1985 and 1999, 101 patients underwent surgery for EBDC in Xiangya Hospital. These patients were divided into two groups: 84 jaundiced patients and 17 non-jaundiced patients according to preoperative serum total bilirubin levels. The clinical manifestations, laboratory findings, location, pathology and surgical resectability of the tumors were compared between the two groups. The laboratory parameters such as hemoglobin, serum albumin ALB, AKP, gamma-GT, and sonography appearance were similar between the two groups, and there was no significant difference in tumor location, pathological type and resectability. However, the number of non-jaundiced patients associated with chololithiasis was significantly greater than that of jaundiced patients (P = 0.008). The presence of jaundice is not a reliable criterion for the prediction of the resectability and the extent of tumor progression in extrahepatic bile duct carcinoma. Decreased levels of blood hemoglobin and serum albumin, elevated levels of AKP and gamma-GT, and /or abnormal sonography may be suggestive. Biopsy of a stenotic or thickened bile duct is strongly recommended for a correct diagnosis before the appearance of jaundice.

Comparison of postoperative hepatic function after laparoscopic versus open gastric bypass

Background Pneumoperitoneum has been shown to reduce hepatic portal blood flow and alter postoperative hepatic transaminases. This study evaluated the changes in hepatic function after laparoscopic and open gastric bypass (GBP). Methods Thirty-six morbidly obese patients were randomly assigned to undergo either laparoscopic (n = 18) or open (n = 18) GBP. Liver function tests—total bilirubin (T Bil), gamma GT (GGT), albumin, alkaline phosphatase (ALP), aspartate transferase (AST), alanine transferase (ALT)—and creatine kinase levels were obtained preoperatively and at 1, 24, 48, and 72 hours postoperatively. Results The two groups were similar in age, sex, and body mass index. Albumin and ALP levels decreased while T Bil and GGT levels remained unchanged from baseline in both groups without significant difference between the two groups. After laparoscopic GBP, ALT and AST transiently increased by sixfold and returned to near baseline levels at 72 hours. After open GBP, ALT and AST transiently increased by fivefold to eightfold and returned to near baseline levels by 72 hours. Creatine kinase level was significantly lower after laparoscopic GBP than after open GBP at 48 and 72 hours postoperatively. There was no postoperative liver failure or mortality in either group. Conclusions Laparoscopic GBP resulted in transient postoperative elevation of hepatic transaminase (ALT, AST) but did not adversely alter hepatic function to any greater extent than open GBP. Creatine kinase levels were lower after laparoscopic GBP reflecting its lesser degree of abdominal wall trauma.

Interleukin-6 release in the hepatic blood outflow during normothermic liver ischaemia in humans.

Liver surgery techniques have consistently improved and normothermic ischaemia of the liver is considered to be a safe procedure to reduce intraoperative haemorrhage. Hepatic failure, however, remains a significant complication. In liver ischaemia-reperfusion injury, cytokines play a key proinflammatory role. Cytokines may be part of the intercellular signalling that leads to recovery or to failure after major surgery. Moreover, they could be potential predictors of the outcome. Modulation of the pattern of cytokine response in the early postsurgery period could represent a new approach to minimise the impact of these procedures. The aim of our study was to analyse the cytokine pattern in the hepatic blood outflow in patients undergoing surgical intervention of partial liver resection with clamping of the hepatic pedicle and liver ischaemia, and to correlate the cytokine behaviour with clinical parameters. We studied eight patients (mean age 55 years) who underwent surgical intervention of liver resection during vascular exclusion of the hepatic pedicle. Patients were monitored for haemodynamic and haematological parameters during the pre-, infra- and postoperative period. IL-I alpha, IL-6, TNF-alpha and IFN-gamma were assayed from peripheral and central vein blood at different times. Blood samples for cytokine assays were also drawn from the supra-hepatic veins after clamping of the porta hepatis. We found a significant increase of the IL-6 levels in the supra-hepatic samples during liver ischaemia, while the trend with IL-1alpha was less clear; IFN-gamma and TNF-alpha were undetectable with the methods used. IL-6 levels appeared to correlate positively with bilirubin and gamma-GT levels and negatively with the degree of acidosis. Our study confirms that during surgical ischaemic stress there is an increase of IL-6 serum levels more relevant in supra-hepatic vein blood. Cytokines could contribute to modulate the inflammatory response to liver ischaemia.

Klinischer Nutzen und diagnostische Bedeutung der Leberbiopsie bei chronisch erhöhten Leberwerten nicht viraler Genese

In the context of increasing non-invasive diagnostic techniques the purpose of the present study was to determine the clinical usefulness and the diagnostic value of percutaneous liver biopsy in patients with chronically elevated liver enzymes of non-viral origin. 100 patients from the outpatient clinic of the department of gastroenterology and hepatology who had a liver biopsy in the years 1996 to 1998 because of chronically elevated alanine-aminotransferase (ALT) and/or gamma-glutamyltransferase (gamma-GT) levels were included. Exclusion criteria were as follows: chronic hepatitis B or C infection, focal liver disease and clinical signs of hepatic decompensation. Retrospectively gained clinical data were independently evaluated by two experienced hepatologists. Initially, both examiners made a preliminary clinical diagnosis prior to knowing results from liver histology. With the results from liver histology both examiners were asked to make a final diagnosis. For each patient, the preliminary clinical diagnoses of both examiners were then correlated with the corresponding final diagnoses. Liver histology led in 71 % respectively 74 % of the patients to confirmation or specification of the clinical diagnosis. Liver biopsy was particularly helpful in differentiating non-decompensated liver cirrhosis, cryptogenic hepatitis, auto-immune hepatitis and biliary diseases. Despite improved non-invasive diagnostic tools including a broad spectrum of serologic tests liver biopsy is often indispensable for differentiating primary liver from biliary diseases and for the early detection of patients with liver cirrhosis.

Serum levels of sex steroid and pituitary hormones in chronic alcoholics and head and neck cancer patients as compared to normal controls

Head and neck squamous cell carcinoma (HNSCC) is diagnosed mainly in male patients (more than 80% of the cases) with a history of smoking and heavy alcohol consumption. However, only a few percent of all alcoholics develop head and neck cancer. to investigate the hormonal status in HNSCC patients as compared to healthy controls and alcoholic persons in order to find changes, if any, characteristic for cancer. The liver function expressed by gamma-GT levels, the hypophysis gonadotrop hormone (FSH, LH, prolactin) and sex steroid hormone serum levels were examined in 130 male HNSCC patients, in 54 men with alcoholic liver disease but without any known cancer and in 56 healthy men as controls. When compared to the healthy controls, both alcoholics and tumor patients had abnormal liver function, testosterone, sex hormone binding globuline and prolactin levels, reflecting the presence of alcoholic liver disease in tumor patients as well. However, abnormally elevated circulating FSH (p<0.005) and LH (p<0.0003) levels were present only in the tumor patients. Sex steroid hormone abnormalities are common among head and neck cancer patients, mainly as results of the chronic alcoholic liver disease. Elevation of FSH and LH levels suggests a potential role of these hormones in the formation of head and neck cancer. The exact role of the hypothalamus-hypophysis-liver axis in the biology of head and neck cancer requires further investigations.

Type I gamma-GT mRNA is expressed in B16 melanoma and levels correlate with pigmentation.

Gamma-glutamyl transpeptidase (gamma-GT), an ectoenzyme involved mainly in glutathione metabolism, is expressed in B16 melanoma cells. B16 melanoma cells under continuous culture conditions show a phenotypic drift from melanotic to amelanotic and re-melanotic stages. We have investigated the regulation of gamma-GT in B16 melanoma cells under such different pigmentary conditions. High levels of gamma-GT messenger RNA (mRNA) and activity were detected in pigmented B16 melanoma cells, whereas in amelanotic B16 melanoma cells the levels were very low. Treatment with lactic acid, a known inhibitor of tyrosinase gene expression, also led to the down-regulation of gamma-GT mRNA and activity. Thus our results indicate that gamma-GT regulation depends on the pigmentation status in pigment cells. We have also assessed the levels of gamma-GT in normal murine melanocytes (melan-a cells). It was seen that melan-a cells express very low levels of gamma-GT. As gamma-GT is known to be regulated in a tissue-specific manner, and is expressed from as many as six promoters giving rise to six different types of mRNAs each having unique 5' ends, we have further investigated the type of gamma-GT mRNA expressed in B16 melanoma and melan-a cells. In this study, we have conclusively demonstrated that type I mRNA transcript of gamma-GT is expressed in B16 melanoma and melan-a cells.

Lamivudine therapy for hepatitis B in renal transplantation

Antiviral therapies are associated with an increased risk of acute rejection in transplant patients. The aim of the present study was to evaluate the efficacy and safety of lamivudine therapy for hepatitis B virus (HBV) infection in renal transplant patients. Six patients were included in this study. They received 150 mg/day of lamivudine during a follow-up period of 24 months. The laboratory tests monitored were HBV DNA, HBsAg, HBeAg, ALT, gamma-GT, serum creatinine and blood cyclosporine levels. The HBV DNA became undetectable in four patients as early as in the third month of treatment. After six months, the viral load was also negative in the other two patients, and remained so until 18 months of follow-up. The medication was well tolerated with no major side effects. Lamivudine was safe and effective in blocking HBV replication in renal transplant patients without any apparent increase in the risk of graft failure for the 24-month period of study.

Prognostic value of serum gamma-glutamyl transferase activity after myocardial infarction.

Serum gamma-glutamyl transferase activity (gamma-GT) is able to catalyse low-density lipoprotein oxidation and has been detected in coronary atherosclerotic plaques. gamma-GT has been documented as an independent risk factor for cardiac mortality in middle-aged men. The purpose of this study is to determine the prognostic value of gamma-GT in patients with coronary artery disease. In a prospective study, gamma-GT and other cardiac risk factors were evaluated in 469 consecutive subjects with angiographically documented coronary artery disease, using mortality and mortality plus non-fatal myocardial infarction as end-points. gamma-GT showed an independent prognostic value beyond known established risk factors in the subgroup of 262 patients with previous myocardial infarction. At a 6-year follow-up, cardiac mortality was 25.2% in patients with gamma-GT >40 U x l(-1)vs 13.9% in those with gamma-GT <40 U x l(-1)(P=0.038). When both cardiac mortality and non-fatal myocardial infarction were considered as end-points, these events were recorded in 32.7% of patients with gamma-GT >40 U x l(-1)and in 20.4% of those with levels <40 U x l(-1)(P=0.031). Excess mortality and non-fatal infarction in patients with high gamma-GT levels were concentrated in the first 2 years of follow-up (P=0.014). The association of gamma-GT values >40 U x l(-1), previous myocardial infarction, and multiple vessel disease identified a subgroup of 168 patients with the highest risk of cardiac events at 6 years (P=0.024). The relationship between gamma-GT levels and cardiac events remained significant after adjustment for cardiac risk factors, and possible confounders, including alcohol consumption. gamma-GT did not show significant prognostic value in the 207 patients without previous myocardial infarction. gamma-GT is an independent cardiac risk factor in ischaemic patients with established coronary atherosclerosis and previous myocardial infarction.

Increased levels of gammaGT suggest the presence of bile duct lesions in patients with chronic hepatitis C: absence of influence of HCV genotype, HCV-RNA serum levels, and HGV infection on this histological damage.

Damage to bile ducts in chronic hepatitis C is a characteristic histological lesion. Moreover, the presence of abnormal levels of gammaGT in these patients is also a common finding. Assessing whether the presence of bile duct lesions is indicated by biochemical abnormalities or whether virological characteristics can influence their development may help in the definition of clinical-histological relationships in chronic hepatitis C. In this study we evaluated the relationships among routine biochemical parameters, serum bile acids, and pi-class glutathione S-transferase levels, and the presence of bile duct lesions in 60 patients with chronic hepatitis C. Furthermore, we assessed whether the presence of bile duct lesion might be related to HCV genotype, HCV-RNA serum levels, and positivity for HGV-RNA. We found that gammaGT was the only parameter related to the presence of bile duct lesions. Although a trend towards higher serum bile acids and pi-class glutathione S-transferase levels was observed in patients with bile duct lesions, this trend did not reach statistical significance. Different HCV genotypes and RNA levels, and HGV-RNA positivity did not seem to influence the presence of bile duct damage. In conclusion we found that gammaGT levels point out the presence of bile duct lesions in patients with chronic hepatitis C. Since we observed a different pattern of alteration of gammaGT, serum bile acids, and pi-class glutathione S-transferase, we suggest that these various biochemical alterations reflect a more complex damage to bile duct structures, which is not likely represented by the common assessment of bile duct lesions. Viral factors such as HCV genotype and RNA levels as well as HGV-RNA positivity are probably not the main cause of this histological damage.

The postoperative course of gamma-glutamyl transpeptidase--a marker of cytomegalovirus (CMV) replication risk?

Cytomegalovirus (CMV) infection is a common complication in the postoperative course of liver transplantation. In order to start early prophylactic therapy, but to avoid unnecessary treatment, or expensive screening, a desirable goal in post-transplant monitoring is to find appropriate markers in standard laboratory diagnostics. In the present study, the results of a 6-week CMV replication monitoring schedule by the pp65 antigenemia assay in 100 liver graft recipients were included. The activities of transaminases, glutamate dehydrogenase and gamma-glutamyl transpeptidase (gamma-GT) were measured by routine laboratory methods. In contrast to the transaminases, the serum activity of gamma-GT increased during the first postoperative week. The maximum levels were 246 +/- 211 U/l in patients without (n = 46) and 140 +/- 89 U/l in patients with early CMV replication (n = 54; p = 0.02). Patients with gamma-GT levels below 200 U/l on the 5th postoperative day (n = 72) had a CMV replication risk of 65%, whereas those patients with gamma-GT levels above this threshold had a risk of 30% (n = 28; p = 0.0007; relative risk = 2.9). These findings provide a routinely usable marker for the identification of patients at an increased risk of CMV replication. It can be considered that these phenomena may be caused by an additional immunosuppressive effect of the CMV virus.

Plasma C3a and C4a levels in liver transplant recipients: a longitudinal study.

Liver transplant patients were enrolled in a study designed to investigate correlations between plasma complement C3a or C4a levels and various postoperative complications. Longitudinal EDTA-plasma levels of C3a and C4a were measured by quantitative radioimmunoassay. Acute rejection gave a characteristic and marked increase in blood C3a, C4a and gamma-glutamyl transferase (gammaGT) levels, which rapidly resolved after high dose steroid treatment. Cytomegalovirus (CMV) infections in two of three patients gave an initial small increase only in C3a levels (i.e., alternative pathway activation) followed approximately 6 weeks later by a marked increase in C4a levels (i.e., classical or lectin pathway activation). In a third patient diagnosed for CMV infection, the complement activation profile was complicated by a coincident minor rejection episode. However, a late stage elevation in C4a was also noted. Two patients experiencing biopsy proven recurrent hepatitis C infections following transplantation exhibited increases in both gammaGT and C4a levels, without a significant increase in the level of C3a. Several hepatitis C and one hepatitis B patient had multiple late activation episodes involving marked elevation in both plasma C3a and C4a levels without detectable increases in the liver enzymes conventionally used to monitor organ function. We also showed that ex vivo activation of complement in EDTA plasma from all transplant patients was abnormally high. The classical or lectin pathway is believed to be responsible for this excessive ex vivo complement activation in the plasma of these patients. Therefore, subclinical rejection episodes and/or viral infections may be effectively detected or monitored by measuring C3a and C4a levels in plasma samples from liver transplant patients. Routine measurement of plasma complement products may provide an early non-invasive mode for detecting infections and also serve to monitor chronic or acute changes in the patient's immune system.

The relationship between alcohol consumption, health indicators and mortality in the German population.

The patterns of total alcohol, beer and wine consumption were evaluated in the German National Health Surveys. The impact of these habits on cardiovascular and all-cause mortality as well as cardiovascular risk factors and liver disease parameters was estimated. Independent representative samples of the German population (15,400 people), and regional samples of the Berlin-Spandau population (2,370 in total), aged 25-69 years, were analysed. The amount and frequency of alcohol consumption was assessed with standardized questionnaires. Biochemical analyses included serum lipids and gamma-glutamyl-transpeptidase (Gamma GT). Multiple analyses of variance were used to determine the relationship between alcohol intake and biochemical parameters. A mortality follow-up of about 7 years was conducted for the Berlin-Spandau population. Proportional hazard models were used to estimate hazard ratios (HR) for all-cause and cardiovascular mortality. Over 80% of men and 55% of women in Germany drink alcohol on a regular base. The majority of the consumers (65% of men, 87% of women) are light (1-20 g/day) or moderate (21-40 g/day) drinkers. Higher serum high density lipoprotein (HDL)-cholesterol and Gamma GT levels were observed with increasing alcohol intake. In light and moderate drinkers no significant relationship was seen with non-HDL-cholesterol, triglycerides, blood pressure and body mass index, compared to teetotallers. Men who consumed 1-20 g alcohol/day had a significantly lower all-cause and cardiovascular mortality. As compared to nondrinkers, the risk was almost 50% lower. The results suggest that light (and possibly moderate) alcohol consumption reduces the risk of cardiovascular and total mortality risk and is favourably related to HDL-cholesterol.

Hypertriglyceridaemia in mild hypertension: impact on cardiovascular and hormonal reactivity under different stress tests.

We investigated the significance of hypertriglyceridaemia (HTG) for associated components of the metabolic syndrome and stress reactivity in subjects with mild hypertension. Seventeen asymptomatic subjects with mild hypertension assessed by 24-h blood pressure (BP) measurement plus HTG (TG >2.3 mmol/l) were recruited and compared with age- and sex-matched subjects with hypertension alone and healthy controls. Cardiovascular and hormonal stress reactivity were tested in a standardised programme consisting of 6 min mental stress, 3 min finger grip and a submaximal bicycle ergometry. The hypertensive patients with HTG exhibited significantly higher fasting insulin, uric acid and gamma-GT levels and lower HDL-cholesterol. The cardiovascular reactivity was similar in all three tests with respect to brachial and peripheral BP in the groups. Peripheral BP during the tests was found to be higher particularly in subjects with hypertension alone. The correlations between BP parameters were disturbed in hypertensives with HTG. Latter group showed significantly higher dopamine, noradrenaline, as well as ACTH levels and an increased ACTH/cortisol ratio. HTG in mild hypertension is indicative for insulin resistance accompanied by a modified vascular reactivity as well as elevated catecholamines and ACTH.

Evaluation by ultrasound of abdominal lymphadenopathy in chronic hepatitis C.

Abdominal ultrasound has shown a frequent association between abdominal lymphadenopathy (LA) and chronic liver disease, but contradictory data have been reported on its relationship with the main parameters of hepatic function. The aim of this study was to correlate the prevalence of LA in patients who were chronic hepatitis-anti-hepatitis C virus positive prospectively followed-up over the last 3 years and its relationship with biochemical and histological data. 136 RIBA II confirmed positive patients with ALT levels >2N were included. None of these had been or was at the time of study on interferon treatment. Ultrasound was performed using a Toshiba SSA 240 A apparatus with a 3.75 MHz convex probe; the operator was unaware of the other results. Diagnosis of chronic hepatitis in all cases was made on biopsy specimens; the histological activity index (HAI) score, according to Knodell, and the grading (G) and staging (S) scores, according to Desmet, were also evaluated. LA was found in 54 out of 136 patients (40%); accordingly, patients were divided into two groups: the LN + ve group included 54 patients (M 33, mean age 48.1+/-11.7 yr) and the LN-ve group included 82 patients (M 69, mean age 45.3+/-11.9 yr). LN + ve patients showed significantly higher serum levels of AST (p < 0.0005), ALT (p < 0.001), gammaGLO (p < 0.05) and gammaGT (p < 0.02) than LN - ve patients. There was a more severe degree of liver disease in LN + ve patients, expressed by the higher HAI (p < 0.002), G (p < 0.002), and S (p < 0.005). The chi2 test for linear association analysis confirmed the trend toward greater histological severity in LN + ve patients (chi2 MH = 10.2; p < 0.002). Logistic regression confirmed the association between the presence of LA and AST (p < 0.02), ALT (p < 0.03), G (p < 0.02), and S (p < 0.02). This study showed a moderate prevalence of LA in chronic hepatitis C, lower than that reported in other studies. LA was associated with serum parameters of cytolysis, and above all, with the severity of histological damage.

A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis.

The progressive familial intrahepatic cholestases (PFIC) are a group of inherited disorders with severe cholestatic liver disease from early infancy. A subgroup characterized by normal serum cholesterol and gamma-glutamyltranspeptidase (gammaGT) levels is genetically heterogeneous with loci on chromosomes 2q (PFIC2) and 18q. The phenotype of the PFIC2-linked group is consistent with defective bile acid transport at the hepatocyte canalicular membrane. The PFIC2 gene has now been identified by mutations in a positional candidate, BSEP, which encodes a liver-specific ATP-binding cassette (ABC) transporter, sister of p-glycoprotein (SPGP). The product of the orthologous rat gene has been shown to be an effective bile acid transporter in vitro. These data provide evidence that SPGP is the human bile salt export pump (BSEP).

Determination of plasma alpha-glutathione S-transferases in patients with HCV-related chronic infection: its significance and possible clinical relevance.

Alpha-glutathione S-transferases (alpha-GST) are the cytoplasmatic class of enzymes responsible for cellular detoxifying processes. We evaluated the plasma alpha-GST activity in relation to chronic infection caused by hepatitis C virus (HCV). Eighteen anti-HCV-negative healthy subjects (controls), 32 anti-HCV-positive subjects with a constant normality of alanine aminotransferases (ALT) and gamma-glutamyl transpeptidase (gamma-GT) levels ("apparently healthy carriers"), and 85 patients with HCV-related chronic liver disease (40 chronic hepatitis, 27 cirrhosis, and 18 with hepatocellular carcinoma) were studied. We assayed plasma alpha-GST in all subjects upon their entry into the study; and every 6 months for 3 years in the control group and in anti-HCV apparently healthy carriers. Alpha-GST values were significantly higher than normal values in 57% of the 21 HCV-RNA-positive apparently healthy carriers and in none of 11 persistently HCV-RNA-negative subjects; the highest increment of alpha-GST was documented in patients with chronic hepatitis. We did not observe correlation among HCV-RNA, histological activity, gamma-GT and ALT or alpha-GST values. Therefore, the increment of plasma alpha-GST indicates a liver involvement even when ALT levels are normal. This may be clinically relevant to "apparently healthy carriers" whose plasma alpha-GST values, when increased, might need further evaluation.

Influence of treatment with aminoglutethimide on plasma and red-blood-cell glutathione status in breast cancer patients.

Elevated cellular glutathione has been associated with resistance to cancer chemotherapy. Treatment with the aromatase inhibitor aminoglutethimide increases the concentration of gamma-glutamyl transpeptidase (gamma-GT) in breast cancer patients. This enzyme catalyzes the first step in the degradation of extracellular glutathione, and the products formed may act as precursors for intracellular glutathione synthesis. Plasma and red-blood-cell glutathione levels were determined in 26 patients suffering from advanced breast cancer before and during treatment with aminoglutethimide (n = 16) or the steroidal aromatase inhibitors exemestane or formestane (n = 10) and in 5 cancer patients receiving dexamethasone. Pretreatment values for gamma-GT in the total patient group (n = 31) correlated negatively with the level of reduced (P < 0.0001), oxidized (P < 0.025), and total glutathione (P < 0.005) in plasma. Plasma gamma-GT levels increased by a mean value of 249% during treatment with aminoglutethimide. The concentration of reduced and oxidized glutathione in plasma decreased to 42.7% (P < 0.0005) and 80.6% (P < 0.005) of their pretreatment levels, respectively. This fall in reduced plasma glutathione correlated negatively with the increase in gamma-GT (P < 0.001). The ratio of oxidized to reduced glutathione increased by 88.9% (P < 0.005), and this increase correlated positively with the increase in gamma-GT (P < 0.005). Treatment with the steroidal aromatase inhibitors (exemestane and formestane) or dexamethasone did not influence the plasma thiol status. We conclude that aminoglutethimide influences plasma glutathione disposition by mechanisms not related to estrogen suppression or due to glucocorticoids given in concert.