Elsevier

Journal of Hepatology

Volume 37, Issue 5, November 2002, Pages 601-605
Journal of Hepatology

Hepatic oxidative alterations in patients with extra-hepatic cholestasis. Effect of surgical drainage

https://doi.org/10.1016/S0168-8278(02)00234-9Get rights and content

Abstract

Background/Aims: The mechanisms of liver injury in conditions of biliary obstruction are poorly understood. Hepatic oxidative injury has been observed in experimental models of cholestasis. Little is known in humans. This study aimed to gain more insights into the hepatic redox status in human cholestasis.

Methods: Liver concentrations of total glutathione, protein sulfhydryls and malondialdehyde (end-product of lipid peroxidation) were measured in hepatic specimens of 12 patients with obstructive jaundice before and after the application of an external biliary drainage and in six control subjects.

Results: Compared to control subjects, biliary obstructed patients showed significantly (P<0.001) lower concentrations of hepatic glutathione and protein sulfhydryls, and higher (P<0.001) levels of malondialdehyde, in the presence of comparable protein concentrations. Two-weeks after the application of external biliary drainage, cholestatic indices were significantly improved and the observed changes in glutathione, protein sulfhydryls and malondialdehyde levels, significantly decreased.

Conclusions: This study shows that cholestasis is associated with a decreased protein and non-protein sulfhydryl content in the liver and with an increased lipid peroxidation. These alterations reversed almost completely after biliary drainage, indicating the cholestasis itself as the determining factor for the redox status impairment observed in the liver of patients with extra-hepatic biliary obstruction.

Introduction

Cholestatic liver diseases are characterized by accumulation of hepatotoxic substances, mitochondrial dysfunction and impairment of liver antioxidant defense [1], [2], [3]. The storage of hydrophobic bile acids has been indicated as the main cause of hepatotoxicity with alteration of some important cell functions, such as the mitochondrial energy production [4]. Both mitochondrial metabolism impairment and hydrophobic bile acids accumulation are associated with increased production of oxygen free radical species and development of oxidative damage [5], [6].

Studies conducted in rats with bile duct ligation and transection (BDL), a widely used experimental model of extra-hepatic cholestasis, have shown that the hepatic concentration of reduced glutathione (GSH), the main intracellular detoxifying system, progressively decreases with ongoing cholestasis [7]. In these conditions, the mitochondrial GSH content was found lower and the level of oxidized compounds higher in association with an impaired trans-membrane exchange [7].

Moreover, inflammation-related oxidative stress has been noticed to affect the hepatic secretory function in long-standing biliary obstruction [8]. The involvement of the inflammatory process in this context is supported by the evidence of increased levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in plasma and of phospholipase A2 in bile of patients with biliary obstructive diseases [9]. The consequent oxidative stress is highlighted by the enhanced concentrations of malondialdehyde (MDA) in the bile of these patients [9]. These mechanisms are supposed to play a stimulatory effect on the expression of canalicular membrane transporter proteins in hepatocyte [9] and for the intracellular impairment of protein metabolism in cholestatic conditions [5].

GSH itself is known to play an important role in the mechanisms governing bile formation; in fact, bile salt independent bile flow is related in part to the rate of GSH secretion [10]. GSH is also known to play a regulatory role in the hepato-biliary transport of toxic organic compounds [11], [12]. Accordingly, significant variations of hepatocellular GSH concentration have important repercussions on the regulation of bile formation and secretion [10].

Cholestasis is associated with a decreased secretion of GSH which affects the thiol-dependent bile flow [13]. Therefore, it is conceivable that the underlying biochemical alterations leading to liver cell injury, observed in experimental cholestasis, may be triggered by the cholestatic process itself. However, no information is at present available on the hepatocellular redox status in patients with obstructive cholestasis. Investigations in these patients may finally define whether hepatic oxidative alterations occur also in humans and whether they are reversible with the obstruction removal.

To address these questions, hepatic redox parameters were assessed in liver specimens obtained from subjects with extra-hepatic biliary obstruction of recent onset before and after the application of a surgical drainage.

Section snippets

Patients and methods

Twelve consecutive patients (age 40–65 years, 8 females), admitted to the Surgery Department because of an obstructive jaundice of recent onset (less than 2 weeks), were considered for the study (Table 1). Patients underwent percutaneous application of an external biliary drainage since they were not eligible for deconstructive surgery. Patients were subjected to ultrasound-guided percutaneous liver biopsy before drainage application and 2 weeks later. Liver specimens were also obtained during

Results

As reported in Table 1, compared to control subjects, patients affected by extra-hepatic cholestasis showed ten times higher values of serum bilirubin, mostly conjugated (90%). In these patients, blood transaminase levels were eightfold and the alkaline phosphatase values six times higher.

Compared to normal livers, the tissue samples obtained from biliary obstructed patients showed a significant decreased concentration of GSH (3.34±0.12 vs. 5.12±0.12 μmol/g liver, P<0.001) (Fig. 1). The PSH

Discussion

The fast development of progressive organ failure in patients with extra-hepatic biliary obstruction is most likely related to the reduced detoxification capacity of the liver, which is associated with increased retention of toxic hydrophobic bile acids and with an impaired antioxidant protection [1], [7], [17]. The application of a percutaneous biliary drainage is a successful option to reduce hyperbilirubinemia and to lessen liver injury when the patient is not eligible for major surgery.

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