Catharina Meijer

Elevation of asymmetric dimethylarginine (ADMA) in patients developing hepatic failure after major hepatectomy.

BACKGROUND Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of the arginine-nitric oxide pathway. It is conceivable that its concentration is tightly regulated by urinary excretion and degradation by the enzyme dimethylarginine dimethylaminohydrolase, which is highly expressed in the liver. In rats, we showed a high net hepatic uptake of ADMA. Therefore, we aimed to confirm the role of the liver in humans and hypothesized elevated ADMA levels after major liver resection by a reduction of functional liver mass and injury to the remnant liver. METHODS Patients undergoing a major hepatic resection (HEP, n = 17) or major abdominal surgery (MAS, n = 12) were included and followed in time. In addition, ADMA levels were measured in 4 patients having severe hepatic failure after a liver resection. Plasma ADMA concentration was measured by high-performance liquid chromatography. RESULTS Preoperatively and on days 1, 3, and 5, plasma levels of ADMA were higher in HEP patients when compared with MAS patients. In HEP patients with prolonged (>7 days) hepatic injury, ADMA levels were especially elevated. On the first postoperative day, ADMA significantly correlated to bilirubin concentration (r = .528, p < .05) as a marker of postoperative hepatic function. Besides, in patients with severe hepatic failure, ADMA levels were highly elevated. CONCLUSIONS In the present study, evidence was found for the role of the liver in the elimination of ADMA in humans. Increased levels of ADMA occur in the postoperative course after a major hepatic resection, especially when liver function is severely impaired. Further studies need to assess the role of ADMA in the development of complications after liver surgery.

Bactericidal/Permeability-Increasing Protein Preserves Leukocyte Functions After Major Liver Resection

ObjectiveTo analyze postoperative leukocyte functions in patients undergoing hemihepatectomy, and to assess the effect of treatment with the endotoxin-neutralizing agent bactericidal/permeability-increasing protein (rBPI21). Summary Background DataExtensive liver resection is associated with a high incidence of infectious complications. Because elimination of pathogenic microorganisms occurs mainly by leukocytes, this increased rate of infections is most likely due to an impaired function of these cells. Endotoxin, translocated from the gut into the systemic circulation as a result of increased gut permeability and reduced hepatic clearance function after major liver resection, may play an important role in the impairment of posthepatectomy leukocyte function. MethodsTo investigate whether hemihepatectomy results in impaired leukocyte functions and to determine the role of endotoxin in this process, leukocyte oxidative burst and leukocyte antigen expression were studied in three groups of patients: patients undergoing a hemihepatectomy and receiving rBPI21 treatment, patients undergoing hemihepatectomy and receiving placebo, and as an extra control group patients undergoing other major abdominal surgeries. Blood samples were collected before surgery, 2 hours after surgery, and at days 1, 2, 5, and 7. Phorbol myristate acetate-stimulated oxidative burst was measured using dihydrorhodamine, and leukocyte surface expression of the antigens CD11b, CD16, and CD14 was investigated by indirect immunofluorescence. Both oxidative burst and membrane surface expression were quantified by flow cytometry. An indication of the antiendotoxin effect of rBPI21 treatment was provided by assessment of plasma lipopolysaccharide binding protein (LBP) levels by enzyme-linked immunosorbent assay. ResultsThe oxidative burst in the hemihepatectomized patients receiving placebo and the controls increased 2 hours after surgery, whereas it decreased in the rBPI21-treated patients, resulting in significant differences between the groups. On day 1, neutrophil CD11b expression and monocyte CD14 expression in the rBPI21-treated patients and controls were significantly lower than in the placebo group. At 2 hours, CD16 expression in the placebo-treated patients was significantly higher than in the rBPI21-treated patients and controls. On day 5 and day 7, plasma LBP levels were significantly higher in the placebo-treated patients compared with the rBPI21-treated patients. ConclusionsThe results of this study show that patients undergoing major liver resection have an increased activation of leukocytes compared with those undergoing other major abdominal surgery. This enhanced activation may contribute to the increased risk of infection in these patients. Administration of the endotoxin-neutralizing agent rBPI21 to hemihepatectomy patients was shown to reduce plasma LBP levels, to preserve leukocyte functions partially, and to reduce leukocyte activation to the level of other, nonhepatic abdominal surgery.

Coagulopathy following major liver resection: the effect of rBPI21 and the role of decreased synthesis of regulating proteins by the liver.

This prospective study investigated the role of reduced hepatic synthesis of regulating proteins in coagulopathy after partial hepatectomy (PH) compared with major abdominal surgery (MAS) without involvement of the liver. Furthermore, we studied the effect of rBPI21, an endotoxin-neutralizing agent, on coagulopathy after PH was studied. Compared with MAS, PH resulted in significantly elevated levels of thrombin-antithrombin-III and plasmin-alpha2-antiplasmin complexes. Levels of antithrombin-3, alpha2-antiplasmin, fibrinogen, plasminogen, alpha2-macroglobulin (alpha2-M), and C1-inhibitor remained lower following PH. Treatment with rBPI21 led to significantly lower levels of tissue-type plasminogen activator (t-PA). Post-operative disseminated intravascular coagulation (DIC) was associated with significantly higher bilirubin and t-PA plasma levels and significantly lower levels of alpha2-M. This study indicates that PH induced hepatic failure results in decreased synthesis of hepatic regulating plasma proteins and subsequent activation of coagulation and fibrinolysis. Prevention of t-PA release by rBPI21 may have important clinical implications. Decreased availability of alpha2-M may be a factor in post-operative DIC.

High plasma levels of arginine and liver arginase in Kupffer-cell-depleted rats after partial hepatectomy.

Abstract Background/Aims: The remnant liver after partial hepatectomy releases arginase into the plasma, which is a reliable indicator of hepatocellular damage. Little information is available on how this release affects arginine plasma levels. We hypothesized that Kupffer cells after partial hepatectomy may prevent further hepatocellular damage, contributing to lower arginase release. The aim of the study was to evaluate the role of Kupffer cells in plasma arginase activity and arginine plasma levels after partial hepatectomy. Methods: Wag/Rij rats ( n =72, 250–275 g) were randomly assigned to receive 1 ml liposome-encapsulated dichloromethylene-diphosphonate in order to eliminate Kupffer cells (DMDP, n =24), 1 ml liposome encapsulated-phosphate buffered saline (PBS, n =24) or 1 ml NaCl 0.9% (NaCl, n =24) intravenously. Forty-eight hours later, all rats had a two-third liver resection. Rats were killed at 0, 24, 48 and 96 h after partial hepatectomy. Results: Arginase plasma activity was higher in the DMDP-treated group compared to NaCl and PBS (both p p p p p Conclusion: The study showed that Kupffer cell depletion results in a higher arginase release from the remnant liver after partial hepatectomy, indicating a hepatocellular protective function of Kupffer cells. Despite this arginase release, arginine plasma levels were increased after partial hepatectomy.

Perioperative Anti-endotoxin Strategies

Lipopolysaccharides from the outer membrane of Gram-negative bacteria are potent stimuli for the production of numerous cytokines by the immune cells. The systemic inflammatory response to these gut-derived endotoxins is therefore dependent on the responsiveness of the immune system. This paper presents results on anti-endotoxin strategies and the responsiveness to endotoxin in animal models of liver failure. Following partial hepatectomy in the normal rat, anti-endotoxin treatment using the enteral endotoxin binder cholestyramine and the bactericidal permeability-increasing protein showed beneficial effects in terms of reducing the exaggerated metabolic and inflammatory responses. Similar beneficial effects of gut endotoxin restriction were found in bile duct ligated rats subjected to a laparotomy. The beneficial effects of anti-endotoxin strategies in these models were explained by completely different mechanisms. In partial hepatectomized rats the effects were explained by the direct inhibition of the stimulatory action of endotoxin on immune cells preventing an exaggerated inflammatory response. In contrast, in postoperative BDL rats the effects of anti-endotoxin therapy were explained by the restoration of endotoxin sensitivity of the immune cells resulting in an inflammatory response necessary for an adequate reaction to surgery. These different mechanism will be discussed in the light of the phenomenon of endotoxin tolerance.Lipopolysaccharides from the outer membrane of Gram-negative bacteria are potent stimuli for the production of numerous cytokines by the immune cells. The systemic inflammatory response to these gut-derived endotoxins is therefore dependent on the responsiveness of the immune system. This paper presents results on anti-endotoxin strategies and the responsiveness to endotoxin in animal models of liver failure. Following partial hepatectomy in the normal rat, anti-endotoxin treatment using the enteral endotoxin binder cholestyramine and the bactericidal permeability-increasing protein showed beneficial effects in terms of reducing the exaggerated metabolic and inflammatory responses. Similar beneficial effects of gut endotoxin restriction were found in bile duct ligated rats subjected to a laparotomy. The beneficial effects of anti-endotoxin strategies in these models were explained by completely different mechanisms. In partial hepatectomized rats the effects were explained by the direct inhibition of the stimulatory action of endotoxin on immune cells preventing an exaggerated inflammatory response. In contrast, in postoperative BDL rats the effects of anti-endotoxin therapy were explained by the restoration of endotoxin sensitivity of the immune cells resulting in an inflammatory response necessary for an adequate reaction to surgery. These different mechanism will be discussed in the light of the phenomenon of endotoxin tolerance.

The role of Kupffer cells after major liver surgery.

BACKGROUND Kupffer cells (KCs) are the resident macrophages of the liver. KCs have an enormous endotoxin eliminating capacity. Endotoxins play an important role in the development of systemic complications after partial hepatectomy by activating KCs. The role of KCs and endotoxins after partial hepatectomy is investigated. METHODS Wistar rats (n = 16, 250-275 g) were randomly assigned to have 1 mL dichloromethylene-diphosphonate (CL2MDP) or 1 mL NaCl 0.9% i.v. Forty-eight hours later, all rats received a two-thirds liver resection. Twenty-four hours later, rats received at random 50 microg/kg endotoxin (LPS) in 1 mL or 1 mL of NaCl 0.9% IV. The rats were killed 4 hours after LPS or SAL infusion. RESULTS CL2MDP infusion resulted in a complete KC elimination. KC-depleted rats had the lowest mean arterial pressure, the highest heart and ventilatory rate after endotoxemia. All rats were able to maintain pH in normal ranges. The KC-depleted rats after partial hepatectomy had the lowest CO2 levels and the highest levels of lactate during endotoxemia. Oxygen levels were similar in all groups. Hepatic, pulmonary, and renal mRNA expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta were decreased in KC-depleted rats. Plasma levels of TNF-alpha were significantly decreased in KC-depleted rats. Furthermore, the highest influx of macrophages and polymorphonuclear cells in the lung and kidney were measured in KC-depleted rats during endotoxemia. CONCLUSIONS Partial hepatectomy in KC-depleted rats result in a more pronounced endotoxin-mediated systemic inflammation and decreased synthesis of cytokines.

High plasma levels of arginine and liver arginase in Kupffer-cell-depleted rats after partial hepatectomy

BACKGROUND/AIMS The remnant liver after partial hepatectomy releases arginase into the plasma, which is a reliable indicator of hepatocellular damage. Little information is available on how this release affects arginine plasma levels. We hypothesized that Kupffer cells after partial hepatectomy may prevent further hepatocellular damage, contributing to lower arginase release. The aim of the study was to evaluate the role of Kupffer cells in plasma arginase activity and arginine plasma levels after partial hepatectomy. METHODS Wag/Rij rats (n=72, 250-275 g) were randomly assigned to receive 1 ml liposome-encapsulated dichloromethylene-diphosphonate in order to eliminate Kupffer cells (DMDP, n=24), 1 ml liposome encapsulated-phosphate buffered saline (PBS, n=24) or 1 ml NaCl 0.9% (NaCl, n=24) intravenously. Forty-eight hours later, all rats had a two-third liver resection. Rats were killed at 0, 24, 48 and 96 h after partial hepatectomy. RESULTS Arginase plasma activity was higher in the DMDP-treated group compared to NaCl and PBS (both p<0.01, p<0.05, p<0.01 and p<0.05 for 0, 24, 48 and 96 h after partial hepatectomy respectively). Arginine plasma levels increased, but were lower in the DMDP group compared to NaCl and PBS (both p<0.05, 24 h after hepatectomy). CONCLUSION The study showed that Kupffer cell depletion results in a higher arginase release from the remnant liver after partial hepatectomy, indicating a hepatocellular protective function of Kupffer cells. Despite this arginase release, arginine plasma levels were increased after partial hepatectomy.

Gut Injury after Major Abdominal Surgery: The Role of Neutrophil Activation and Enteral Nutrition

© 1998 S. Karger GmbH, Freiburg Fax (07 61) 4 52 07 14 www.karger.com Received: July 24, 1997 Accepted: November 6, 1997 P.A.M. van Leeuwen, PhD Department of Surgery, Free University Hospital De Boelelaan 1117 NL-1081 HV Amsterdam (The Netherlands) Tel. +31 20 44436-01, Fax -20 E-mail mj-wiezer@azvu.nl This article is also accessible online at: http://BioMedNet.com/karger Originalarbeit · Original Article