Increased serum phospholipase A2 activity in advanced chronic liver disease as an expression of the acute phase response.

Phospholipase A2 (PLA2) modifications were investigated in patients with acute and chronic liver diseases, PLA2 variations were related to indices of liver function as well as to parameters of the acute phase response. Serum PLA2 activity modifications were fluorimetrically measured in 105 patients affected by acute and chronic liver diseases or extra-hepatic diseases. One-way ANOVA demonstrated a significant difference among groups (F = 4.53, P < 0.001); Bonferroni's test for pairwise comparisons showed that patients with hepatocellular carcinoma had higher mean values than subjects with benign extra-hepatic diseases (P < 0.01) and mild chronic liver disease (P < 0.05). Multiple regression analysis, performed choosing PLA2 as the dependent variable and blood urea nitrogen, C-reactive protein, alkaline phosphatase and alpha 1-fetoprotein as predictor variables was significant (multiple R = 0.7056, multiple R2 = 0.4978, F = 15.36, P = < 0.0001). The standardized regression coefficients found to be significant were those of C-reactive protein, blood urea nitrogen and alpha 1-fetoprotein. In conclusion, in patients with chronic liver disease, serum PLA2 activity increases parallel to disease severity and accompanies the expression of proteins of the acute phase response that, like PLA2 activity, increase in serum while liver synthesis declines.

CAR-3 and CA 19-9 serum levels in pancreatic cancer: any differences between two epitopes of the same mucin-like glycoprotein?

The aim of this study was to compare the utility of two recently identified tumour markers of pancreatic cancer, CA 19-9 and CAR-3, and to ascertain the roles of some factors influencing both antigens. CA 19-9 and CAR-3 were measured in sera of 18 control subjects, 27 patients with pancreatic cancer, 25 with chronic pancreatitis, and 29 with extra-pancreatic diseases. CA 19-9 and CAR-3 were, respectively, found to be increased in 85 per cent and 44 per cent of patients with pancreatic cancer, 28 per cent and 0 per cent with chronic pancreatitis and 72 per cent and 28 per cent with extra-pancreatic diseases. The ROC curves showed that, for any serum value considered, CA 19-9 is more effective than CAR-3 in discriminating between pancreatic cancer and control subjects and chronic pancreatitis. With the combined use of both antigens the results were no better than those given by CA 19-9 alone. Correlations were found between liver function tests and CA 19-9 levels and between cholestasis indices only and CAR-3 values. Our findings show that CAR-3 is not a sufficiently reliable marker of pancreatic cancer, due to its low sensitivity. Nor does it offer any more information than CA 19-9. Both assays are influenced, at least in part, by the extent of the neoplasia. Cholestasis which can greatly influence a serum glycoproteic marker such as CA 19-9, was found also to affect, to a lesser extent, CAR-3, an epitope on the same mucin molecule.

Intensity of inflammatory damage and serum lipid peroxide concentrations in liver disease.

AIMS: To investigate variations in serum lipid peroxide activities in relation to various clinical entities of liver disease. METHODS: Serum lipid peroxides were measured fluorometrically in eight patients with acute hepatitis, six with liver steatofibrosis, five with chronic persistent hepatitis, 15 with chronic active hepatitis, 28 with liver cirrhosis, 22 with hepatocellular carcinoma; 19 patients with extrahepatic disease (six malignant, 13 benign) were used as controls. RESULTS: Higher serum lipid peroxide concentrations were found in patients with acute hepatitis (4.52 (SEM 0.56)) nmol/ml than in all other groups of patients (p < 0.01). No significant difference was found among the mean values detected in the groups of patients affected by chronic liver disease and extrahepatic diseases. A history of chronic alcohol consumption was not associated with higher lipid peroxide concentrations. A significant correlation (R2 = 0.4538, R = 0.6737, F = 7.617, p = 0.0000) was found between serum lipid peroxides and a set of indices of inflammation (ESR, total leucocyte count, C-reactive protein) and of hepatic function (aspartate aminotransferase (AST) or alkaline phosphatase (ALP) or bilirubin). Of these, bilirubin was the most significant indicator of inflammation. Analysis of covariance showed a significant difference in lipid peroxide values among groups, even when bilirubin was chosen as an independent variable. CONCLUSIONS: Raised serum lipid peroxide concentrations can be found during acute inflammatory liver disease. Acute change in liver function, reflected by high bilirubin concentrations, seems to be more important for intravascular liberation of lipid peroxides than existence of specific aetiological factors or of severe longstanding global liver damage.

Oxygen derived free radicals in patients with chronic pancreatic and other digestive diseases.

To ascertain modifications in the activation products derived from oxygen free radicals in patients with chronic pancreatic and extra-pancreatic diseases, lipid peroxide activity was measured in the sera of 40 control subjects, 28 patients with pancreatic cancer, 49 with chronic pancreatitis, and 53 with extra-pancreatic diseases. In 142 of the subjects, elastase 1, amylase, and pancreatic isoamylase activities were also determined. Increased lipid peroxide activities were found in some patients with both chronic pancreatic and extra-pancreatic diseases. Patients with chronic pancreatitis studied during relapse had higher activities of lipid peroxides than those without active disease. No difference was found between the values in patients with pancreatic cancer with liver metastases and those without. Correlations were found between lipid peroxides and both amylase and pancreatic isoamylase activities; no correlation was detected between lipid peroxides and elastase 1. In benign biliary tract disease a correlation was detected between lipid peroxides and alanine aminotransferase and alkaline phosphatase activities. In all patients, however, a correlation was found between alkaline phosphatase and lipid peroxide activities. It is concluded that activation of oxygen derived free radicals occurs in chronic pancreatic as well as in extra-pancreatic disease; it seems to reflect the degree of inflammation.

Effects of pancreaticobiliary duct obstruction on the exocrine and endocrine rat pancreas.

Experimentally, biliary obstruction can produce morphological and functional changes in the pancreatic gland, whereas pancreatic obstruction may have short-term (hyperamylasemia, pancreatic edema, and lysosomal hydrolase redistribution) or long-term (acinar cell atrophy and interstitial fibrosis) effects. We created a pancreaticobiliary duct obstruction in rats to evaluate (a) exocrine and endocrine anatomobiochemical pancreatic modifications; (b) structural and functional liver alterations; and (c) the relationship, if any, between the alterations found in the two organs. Forty-five male Sprague-Dawley rats were subdivided on the basis of period of obstruction (from 1 to 28 days). In each rat serum we evaluated amylase, cholestatic and cytolytic indices, and glucose. In frozen pancreatic samples we measured insulin, glucagon, and DNA; in the liver the DNA content was determined. Histologically, ductal dilation and proliferation were evaluated for the liver, zymogen granules, and Langerhans' islets, and atrophy for the pancreas. Fibrosis was evaluated for both the liver and the pancreas. Short-term common pancreaticobiliary duct ligation caused an increase in serum amylase levels and mild pancreatic edema. Longer-term obstruction had either similar or different effects on the two organs. In the pancreas it caused fibrosis and exocrine and endocrine atrophy, but not acute pancreatitis. In the liver the main phenomena observed were fibrosis, ductal dilation, and proliferation.

Does acetylsalicylic acid interfere with stimulated pancreatic secretion? An experimental study in the rat.

To evaluate the effect of the prostaglandin inhibitor acetylsalicylic acid (ASA) on rat exocrine pancreas secretion, three groups of rats were administered ASA by infusion: Groups 1-3, 50, 100, and 200 mg/kg body wt, respectively; Group 4 received saline. Twenty minutes later these ASA-pretreated groups were given intraarterial secretin (18 CU/kg) and cholecystokinin (CCK) (18 micrograms/kg). In an additional three groups of seven rats each, saline solution rather than secretin-CCK was given after ASA pretreatment. Pancreatic juice was collected every 10 min by means of a chronic pancreatic fistula. Bicarbonate and protein concentrations were measured and variations in outputs observed. No significant variations were found in the bicarbonate concentrations and outputs of rats with different types of pharmacological treatment, while protein concentrations and outputs were found to vary with time and type of experiment. There was, however, no interaction between these two variables. At lower ASA dosages, the bicarbonate and protein concentrations and outputs of secretin-CCK-stimulated rats were higher than the basal values and the levels of rats without hormonal stimulation. At higher dosages, no difference was found between the two groups. In conclusion, ASA seems to interfere with stimulated pancreatic exocrine secretion of proteins, even when its effect on bicarbonate concentration is factored in, and its effect seems to be present at the highest dosages considered in the study. Among the various hypotheses that may explain this phenomenon, an antagonizing effect of ASA on secretin-CCK action should be the first to be considered.

Beta-cell function in pancreatic adenocarcinoma.

To evaluate beta-cell function in patients with pancreatic cancer, the glucagon stimulation test was performed in seven patients with pancreatic adenocarcinoma, seven patients with type I diabetes mellitus, seven patients with type II diabetes mellitus, and in seven healthy controls. C-peptide serum levels were determined before and after a 1-mg i.v. glucagon injection. Basal C-peptide values were normal or slightly increased in pancreatic cancer and type II diabetic patients and low in type I diabetic patients. Following glucagon stimulation, no significant increase was observed in C-peptide values of type I diabetics and pancreatic cancer patients, whereas significant increases occurred in controls and type II diabetics. It is concluded that the altered beta-cell function found in pancreatic cancer patients may lead to hyperglycemia, which is frequently associated with this tumor type.

An unidentified pancreatic cancer cell product alters some intracellular pathways of glucose metabolism in isolated rat hepatocytes.

In this study we assessed whether conditioned media from a human pancreatic cancer cell line (MIA PaCa 2) can interfere with some intracellular pathways involved in glucose metabolism in isolated rat hepatocytes. The hepatocytes, isolated from Male Wistar rats, were incubated with MIA PaCa 2-conditioned or nonconditioned media. Conditioned and nonconditioned hepatocytes were run for 120 min in the presence or absence of insulin (100 mM) and were sampled at fixed time intervals. Supernatant glucose levels decreased to a similar extent over time in both conditioned and nonconditioned hepatocytes, while lactate levels significantly increased in nonconditioned hepatocytes with respect to conditioned hepatocytes. A pyruvate kinase activity increase was observed only in nonconditioned hepatocytes and was biphasic in nature, since this increased activity was detected both after a few and after 30 min following insulin stimulation. The cyclic AMP level increase was significantly higher in conditioned than in nonconditioned hepatocytes. It appears that MIA PaCa 2 cells produce a factor(s) that may interfere with one of the insulin-mediated intracellular pathways of glucose metabolism, namely, glycolysis. This detrimental effect on glycolysis is supported by the blunted rise in lactate concentration in the medium after the glucose challenge. This substance(s) probably transfers its signal inside the target cells, activating the adenylate cyclase pathway. These results support the hypothesis that pancreatic cancer is the cause rather than the consequence of diabetes mellitus.

Cytokines modulate MIA PaCa 2 and CAPAN-1 adhesion to extracellular matrix proteins.

Variations in cancer cell adhesion to extracellular matrix (ECM) proteins might underlie an enhanced metastatic potential. ECM binding is mediated by cell-adhesion molecules, the membrane expression of which might be influenced by soluble mediators, such as cytokines. The aims of our study were to ascertain whether epidermal growth factor (EGF), transforming growth factor beta1 (TGF-beta1), interleukin 1alpha (IL-1alpha), or interleukin 1beta (IL-1beta) can modify MIA PaCa 2 (pancreatic cancer cell line) and CAPAN-1 (metastatic pancreatic cancer cell line) adhesion to fibronectin, laminin, or type I collagen, and whether these cytokines can shift the membrane expression of the hyaluronic acid receptor (CD44). EGF significantly enhanced MIA PaCa 2, but not CAPAN-1, adhesion to fibronectin, laminin, and type I collagen. TGF-beta1 reduced MIA PaCa 2 adhesion to type I collagen, but enhanced CAPAN-1 adhesion to fibronectin and laminin. IL-1alpha was found to enhance MIA PaCa 2 adhesion to fibronectin, while reducing adhesion to type I collagen, whereas IL-1beta reduced the adhesion to laminin. IL-1alpha enhanced CAPAN-1 adhesion to laminin in a dose-dependent manner; IL-1beta slightly increased the adhesion of these cells to laminin at low dosage, and to type I collagen at high dosage. Both IL-1alpha and IL-1beta reduced CD44 membrane expression of MIA PaCa 2, while TGF-beta1 increased the percentage of CD44-positive CAPAN-1 cells. We suggest that the effects on cell adhesion induced by different cytokines depend on the status of the target pancreatic cancer cell. EGF and, in part, IL-1alpha can favor nonmetastatic pancreatic cancer cell adhesion to ECM, possibly favoring tumor spread. Metastatic cells seem to lose the responsiveness to EGF, while becoming hyperresponsive to IL-1alpha. TGF-beta1 might exert an antidiffusive effect on primary, and a prodiffusive effect on metastatic pancreatic cancer cells. Only IL-1alpha, IL-1beta, and TGF-beta1 seem to influence CD44 membrane expression. All the results presented in this study were obtained in vitro, and in vivo studies are needed to verify whether the studied cytokines can favor or counteract pancreatic cancer spread.

Serum phospholipase A2 activity in chronic pancreatic diseases.

This study was performed to investigate the phospholipase A2 (PLA2) serum activity in patients with chronic pancreatic disease. PLA2, elastase-1, total, and pancreatic isoamylase were evaluated in 40 control subjects, 28 patients with pancreatic cancer, 51 with chronic pancreatitis, and 36 with extrapancreatic diseases, mainly of gastrointestinal origin. Elastase-1, PLA2, and pancreatic isoamylase were increased in 56%, 25%, and 15% of patients with pancreatic cancer, and in 40%, 31%, and 41% of subjects with chronic pancreatitis. All four enzymes gave pathological values in a number of patients with extrapancreatic diseases. We conclude that the diagnostic efficacy of phospholipase A2 in chronic pancreatic disease is similar to that of other well known pancreatic enzymes, with an unsatisfactory sensitivity and specificity.

The pancreatic cancer cell line MIA PaCa2 produces one or more factors able to induce hyperglycemia in SCID mice.

A reduced glucose tolerance or frank diabetes mellitus is a frequent finding in patients with pancreatic cancer. The aim of this study was to verify whether the pancreatic cancer cell line MIA PaCa2 was able to produce any factor which could induce hyperglycemia in SCID (severe complete immunodeficient) mice. MIA PaCa2 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) for 7 days. Twenty-five female SCID mice were used. They were daily i.p. injected with 300 ul of cell culture supernatants (Group T, n = 13) or with 300 ul of DMEM (Group C, n = 12) and followed up for 82 days. Blood glucose levels were significantly higher in Group T than in Group C on days 10 and 25. Intravenous glucose tolerance test, success-fully performed in 9 animals (4 controls and 5 treated), demonstrated a significantly reduced glucose tolerance in Group T compared to Group C mice. At sacrifice, plasma and pancreatic insulin and glucagon levels did not vary between groups. The ratio between pancreatic and plasma insulin was significantly lower in Group T than in Group C. We conclude that: 1. The pancreatic cancer cell line MIA PaCa2 produces one or more soluble factors able to cause hyperglycemia in vivo; 2. this effect is not immunologically mediated, and 3. this/these factor/s could both interfere with the pancreatic beta cells and/or with insulin peripheral action.

Diabetes mellitus in pancreatic cancer follow-up.

The aim of this study was to assess the behavior of fasting serum glucose, C-peptide levels and OGTT in pancreatic cancer follow-up. We studied 49 patients with pancreatic cancer (stage I = 8 pts; II = 16 pts; III = 12 pts; IV = 13 pts). At diagnosis 13/49 patients had fasting serum glucose levels of above 140 mg/dL. Of the remaining 36 pts, 22 underwent OGTT, which indicated diabetes mellitus in 9/22 (41%) and impaired glucose tolerance in 7/22 (32%) cases. C-peptide basal values were within the normal range (0.8-2.0 micrograms/L) in 14/49 (28%), above 2.0 micrograms/L in 6/49 (13%) and below 0.8 micrograms/L in 29/49 (59%) of the cases. No significant correlation was found between tumor stage or size and the presence of diabetes or of a reduced glucose tolerance. Twenty-four patients underwent curative resection (group 1) and 16 palliative resection, while the remaining nine did not undergo surgery (group 2). Group 1 and 2 patients had a follow-up of 2 to 40 months (mean = 14 months) and from 1 to 7.5 months (mean = 3.5 months) respectively. In group 1 patients no significant difference was found between pre- and post-operative fasting serum glucose levels. However, in 11/15 (73%) patients who underwent OGTT before and after surgery, an improvement in glucose tolerance was observed after tumor resection. In group 2 patients, a significant increase in fasting serum glucose levels was found during follow-up. In neither of the groups studied were significant variations found in C-peptide levels during the follow-up, although a slight increase was observed in patients who did not undergo surgery. In conclusion, the reduced glucose tolerance or frank diabetes mellitus, which frequently occurs during the onset of pancreatic cancer, does not seem to be related to tumor stage or size. Curative resection ameliorates glucose intolerance, while tumor persistence can enhance serum glucose levels.

C-peptide pattern in patients with pancreatic cancer.

The pathogenetic mechanism underlying glucose intolerance in pancreatic cancer is still unclear. We studied the pattern of three glucose regulating hormones (C-peptide, glucagon and GH) in pancreatic cancer patients with (N = 34) and without (N = 8) hyperglycemia, and compared the findings made with those from subjects with other hyperglycemic conditions of well-known origin [type I diabetes mellitus (8 cases) and diabetes mellitus secondary to chronic pancreatitis (13 cases) or liver cirrhosis (4 cases)]. In hyperglycemic pancreatic cancer patients, C-peptide was absent in 26% of the cases, reduced in 24%, elevated in 29% and within the normal range in the remaining 21%. In normoglycemic pancreatic cancer this hormone was reduced in two cases (25%) and within the normal range in all the others. GH was within the normal range in all cases: glucagon was below the normal range in some hyperglycemic pancreatic cancer patients (41%) or within the normal range in all the remaining patients. No correlations were found between the three hormones when findings from subjects were considered all together. However, in pancreatic cancer C-peptide and glucagon presented consensual variations. C-peptide, glucagon and GH levels were not related to tumor volume; glucagon was found to be associated with liver metastases. C-peptide was correlated with serum ALT and ALP. We may conclude that hyperglycemia associated with pancreatic cancer may be caused by different mechanisms. In some cases a reduced secretion of both insulin and glucagon was observed, as occurs in chronic pancreatitis. In the majority of patients, beta cell function appears normal, and the hyperglycemic state may depend on an altered peripheral sensitivity to insulin due to the pancreatic pathology itself or to consensual liver involvement.

Tumor markers in the diagnosis, monitoring and therapy of pancreatic cancer: state of the art.

The present review focuses on the utility of serum tumor markers in screening, diagnosis, prognosis and monitoring of pancreatic cancer. Serum determination of all tumor markers studied offers no help in screening or early diagnosis of pancreatic cancer. For diagnosis, blood group-related antigens, in particular CA 19-9, are considered the best indicators of this neoplasm. However, as occurs with other glycoproteic tumor markers, the circulating levels of CA 19-9 are significantly influenced by jaundice, probably because its liver metabolism is reduced. Therefore, the finding of elevated CA 19-9 levels in jaundiced patients has to be evaluated with caution. Since pancreatic cancer recurrences are not susceptible to treatment, the clinical role of widespread use of tumor marker determination in follow-up programs is limited and calls for a critical evaluation.

Hepatic changes and serum ferritin in pancreatic cancer and other gastrointestinal diseases: the role of cholestasis.

Serum ferritin, prealbumin, pseudocholinesterase, alpha-1-antitrypsin and caeruloplasmin were determined in control subjects and patients with pancreatic cancer, chronic pancreatitis or extra-pancreatic disease mainly of gastrointestinal origin, in order to investigate the different hepatic changes which influence serum ferritin in chronic pancreatic and other digestive diseases. Increased circulating ferritin was found in pancreatic cancer and extra-pancreatic disease when compared to controls. Correlations were detected between ferritin and the other proteins investigated and between ferritin and total bilirubin, alkaline phosphatase and alanine aminotransferase. Multiple regression analysis demonstrated that cholestasis accounts for 45% of circulating ferritin, the acute-phase response accounted for 18% and decreased liver function accounted for 11%. We conclude that the increase in serum ferritin in chronic pancreatic and other gastrointestinal diseases largely depends on liver changes, with cholestasis probably playing a primary role.

Comparison of two newly identified tumor markers (CAR-3 and DU-PAN-2) with CA 19-9 in patients with pancreatic cancer.

We compared the diagnostic utility of DU-PAN-2 and CAR-3 with that of CA 19-9 in differentiating pancreatic cancer (23 patients) from chronic pancreatitis (16 patients) and various extra-pancreatic diseases (28 patients) mainly of the upper gastrointestinal and biliary tract. The influence of some pathophysiologic variables on the three markers was also assessed. The sensitivities of the three markers in detecting pancreatic cancer were: CA 19-9, 83%; DU-PAN-2, 56%; and CAR-3, 39%. In patients with chronic pancreatitis and extra-pancreatic diseases, CA 19-9 gave the highest number of false positives. Receiver-operating characteristic curves showed that the ability of CAR-3 to discriminate between pancreatic cancer and other diseases was similar to that of CA 19-9, whereas DU-PAN-2 was a less reliable discriminator. Correlations were found between the behavior of all three markers and that of the cholestasis indices (ALP and GGT). Our findings indicate that DU-PAN-2 and CAR-3 serum determinations do not provide any more information than does CA 19-9 alone. The latter remains the marker of choice in the differential diagnosis of pancreatic cancer, even though it cannot be considered a definitive aid. Serum levels of all three markers increase in the presence of extra-hepatic cholestasis, possibly due to interference with the hepatic clearance of glycoproteins and destruction of ductal biliary epithelium.

[Role of serum markers and or various clinical parameters in the diagnosis of pancreatic carcinoma]. / Ruolo dei marcatori sierici e di alcuni parametri clinici nella diagnosi di carcinoma pancreatico.

This study was performed to ascertain the role of serum markers and simple clinical data in detecting pancreatic cancer and in distinguishing this malignancy from chronic pancreatitis and other gastrointestinal diseases. Serum CA 19-9, tissue polypeptide antigen and carcinoembryonic antigen were measured in 38 control subjects, 37 patients with pancreatic cancer, 39 with chronic pancreatitis and 44 with extra-pancreatic diseases mainly of gastrointestinal origin. Clinical data recorded included age, sex, presence of pancreatic calcifications, weight loss, pain, jaundice, alcohol abuse, diabetes mellitus. Serum markers gave a correct allocation of the subjects in 48.1% of the cases with pancreatic cancer patients correctly predicted in 62.2%. Clinical data correctly diagnosed 74.2% of subjects. Chronic pancreatitis was identified in 84.6% of the cases and pancreatic cancer in 64.9%. The first clinical variables selected were pain and age. The addition of serum markers to clinical data did not enhance accuracy of the results. We conclude that the diagnosis of chronic pancreatic diseases should first be suspected on the basis of accurately recorded simple clinical data; serum markers seem to be only occasionally useful. Since indicative clinical data and serum markers become positive in the advanced phases of pancreatic cancer, early diagnosis of this malignancy still remains an objective to reach.

[Value and limitations of neoplasm markers in the diagnosis of pancreatic carcinoma]. / Valori e limiti dei marcatori di neoplasia nella diagnosi di carcinoma pancreatico.

In the last decades several markers of pancreatic neoplasia have been proposed to obtain a diagnosis as earlier as possible. Prerequisites of a good tumor marker are high sensitivity and specificity. Among the various substances, serum determination of pancreatic enzymes has been found of no utility in early diagnosis of pancreatic cancer, due to its lack in sensitivity and specificity. Similar results with ribonuclease and deoxyribonuclease. Oncofetal antigens (CEA and POA) have been initially considered promising indices; however, further studies showed their limits. In particular CEA is greatly influenced by the presence of hepatic metastases; therefore, serum levels are detectable only in advanced stages. TPA is characterized by a high sensitivity, but lacks in specificity and its use is now avoided. A real progress in the field of tumor markers has been made in the last years with the monoclonal antibody technique: among them CA 19-9 showed a good sensitivity and a satisfactory specificity as regards the diagnosis of pancreatic cancer. However, it cannot be considered as absolute aid, since it is influenced by several factors, as tumor spread, jaundice and liver dysfunction.

Renal functional alterations in extrahepatic cholestasis: can oxidative stress be involved?

Renal function may be compromised by extrahepatic cholestasis. In this context, the nephrotoxic role of bile salts is well known. Recently, however, it has been claimed that other factors, such as lipid peroxides, are involved. We therefore created bile duct ligation in 40 Sprague-Dawley rats. During the follow-up (from 1 to 28 days), significant variations were found in liver histological parameters, but not in renal morphology. Fourteen days after ligation, significant increases were found in serum and urinary thiobarbituric-acid-reactive species and phospholipase A2 (indirect indices of lipid peroxidation), whereas 8-10 days after ligation, a significant decrease was observed in erythrocytic and hepatic GSH levels. The variations in urinary thiobarbituric-acid-reactive species and in phospholipase A2 were not correlated with concomitant variations in the sera. Urinary lipid peroxides were directly correlated with the degree of liver morphological alterations and inversely with circulating GSH. Urinary outputs of lipid peroxides, phospholipase A2 and N-acetyl-glucosaminidase were correlated with each other. These results suggest that there is an imbalance in the oxidative-antioxidant hepatic system in experimental extrahepatic cholestasis. The reduced bioavailability of blood GSH may alter the oxidative equilibrium in other organs, such as the kidney, triggering and favoring the lipoperoxidative cascade.