IL-6, a key cytokine in liver regeneration.
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Animals↗
Biomedical subjects
P A Clavien
Publications and source records attributed to P A Clavien.
Acute reactant cytokines and neutrophil adhesion after warm ischemia in cirrhotic and noncirrhotic human livers.
Animal studies suggest that acute phase reactant cytokines and polymorphonuclear leukocytes (PMN) may play a critical role in ischemia-reperfusion injury. To evaluate whether similar mechanisms are operative in human liver, six cirrhotic and nine noncirrhotic patients undergoing right hepatectomy were randomized for utilization of hepatic vascular exclusion (HVE) as a model of ischemia-reperfusion injury. Portal and systemic levels of acute reactant cytokines (interleukin 6 [IL-6], interleukin 1 [IL-1], tumor necrosis factor alpha [TNF-alpha]) and neutrophil adhesion in serial liver biopsy specimens were studied. Correlations among mediators, leukocyte adhesion, and markers of liver injury were also evaluated. Hepatic vascular exclusion resulted in substantial and reproducible changes in portal and arterial IL-6 levels in both cirrhotic and noncirrhotic patients. Portal and systemic cytokine levels were comparable in most instances, whereas levels were usually higher in cirrhotic patients than in noncirrhotic patients. Negative correlations were found between IL-6 levels at the time of reperfusion and later TNF-alpha levels. IL-6 levels correlated negatively with numerous markers of hepatocellular injury and the number of postoperative complications. Hepatic vascular exclusion increased neutrophils adhesion after reperfusion in cirrhotic patients but not in noncirrhotic patients. In cirrhotic patients, the degree of leukocyte adhesion after reperfusion correlated with several postoperative markers of liver injury. This study in humans shows that acute reactant cytokines are released during liver ischemia and, interestingly, that IL-6 levels strongly correlate with clinical and laboratory measures of injury. Further studies to evaluate possible causal relationship with hepatic injury are warranted, with emphasis on the role of IL-6 and PMN adhesion.
Adult↗
Kupffer cell erythrophagocytosis and graft-versus-host hemolysis in liver transplantation.
BACKGROUND & AIMS: Graft-versus-host hemolysis (GVHH) syndrome develops in approximately half of patients undergoing ABO-unmatched liver transplantation. The clinical and laboratory presentations of GVHH syndrome often mimic acute rejection, leading to liver biopsy for definitive diagnosis. The purpose of this study was to investigate if there are specific histological findings that permit diagnosis of GVHH syndrome and to assess the relationship between GVHH syndrome and rejection. METHODS: Clinical and laboratory evidence of GVHH syndrome, results of liver biopsy, and clinical outcome were assessed in 30 ABO-unmatched liver transplant recipients. Biopsy results were compared with those of two control groups consisting of patients who had normal liver test findings (protocol biopsy) and rejection. RESULTS: Sixteen of the 30 patients (53%) had evidence of GVHH syndrome. Erythrophagocytosis was noted in each biopsy specimen, and the degree of phagocytosis correlated significantly with the amount of blood given after postoperative day 5 (r = 0.9; P < 0.02). Electron-microscopic studies performed randomly in 5 patients showed that the red cells were located in Kupffer cells. In contrast, erythrophagocytosis was minimal in the two control groups. Despite an incidence and severity of rejection similar to those in other liver transplant patients, serum transaminase levels were significantly higher in patients with GVHH syndrome. CONCLUSIONS: Erythrophagocytosis is a sensitive histological marker of GVHH syndrome. The severity of rejection and response to antirejection therapy should be monitored by markers other than transaminases in patients with GVHH syndrome.
Adult↗
Cytomegalovirus infection following liver transplantation: review of the literature.
Cytomegalovirus (CMV) remains a major cause of problems following solid organ transplantation, accounting for a significant increase in morbidity and affiliated costs. Infection with CMV following orthotopic liver transplantation (OLT) is commonly seen as a result of marked cell-mediated immunosuppression and is an independent risk factor for opportunistic and fungal infections. The role of CMV infection in acute cellular or chronic rejection remains unclear. Recent advances in diagnostic modalities, particularly the use of the antigenemia assay and the polymerase chain reaction, have provided ways to quantitate viral load during infection or disease, as well as providing a useful marker of response to therapy. Ganciclovir remains the best antiviral agent for the treatment of CMV disease, but the use of combination therapy with other antivirals or CMV immunoglobulin may improve outcome for patients with severe disease. The ideal prophylactic therapy for patients undergoing OLT remains to be identified, as tested regimens have shown variable efficacy when analyzed with regard to defined risk groups. The use of risk group-specific prophylaxis may prove to be most successful, however, in terms of efficacy and cost savings. Future advances in basic CMV virology and transplant immunology will be essential in defining rational approaches to control and prevention of CMV infection and disease following liver transplantation.
Animals↗
Evidence that ursodeoxycholic acid prevents steroid-resistant rejection in adult liver transplantation.
Steroid-resistant rejection continues to be a serious problem in liver transplantation. Since ursodeoxycholic acid (UDCA) is beneficial in several cholestatic disorders and possesses in vitro immunomodulatory and immunosuppressive effects, we have tested in a pilot study the effects of adjuvant UDCA in the prevention of steroid-resistant rejection. Fifty consecutive liver transplant patients were treated with a standard cyclosporine immunosuppressive regimen. Treatment with UDCA (10 mg/kg/d) was initiated in each patient who developed biopsy-proven rejection or biochemical evidence of cholestasis. Clinical and laboratory features were monitored for evidence of rejection. Data were analyzed after at least a 10-month follow-up period was available in each patient. Seven patients died during the study period, all within 4 wk of surgery. No evidence of rejection was documented in these patients. Twenty three of the 43 survivors 53% (23/43) developed an episode of rejection, and UDCA was initiated in each of them. Only one patient had a second episode of rejection, which responded to intravenous methylprednisolone therapy; no patient required antilymphocyte therapy. There was no evidence of toxicity for UDCA. These data suggest that UDCA can be given safely following OLT and may contribute to prevention of steroid-resistant rejection in liver transplant recipients.
Adolescent↗
Sphincter of Oddi dysfunction after liver transplantation.
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Common Bile Duct Diseases↗
Acute pancreatitis following liver transplantation.
BACKGROUND: Acute pancreatitis (AP) has not been recognized as a frequent complication following orthotopic liver transplantation (OLT). Reports have suggested that this condition is associated with high morbidity and mortality rates. STUDY DESIGN: A retrospective review of 354 patients who underwent OLT at the University of Toronto, with at least one-year follow-up, was done to identify the incidence, etiology, risk factors, and severity of pancreatitis following OLT, as well as to discuss its management. A possible correlation between AP and hepatitis B was also investigated. Prognostic score systems, including Ranson, Imrie, and APACHE II, were also evaluated. RESULTS: Acute pancreatitis occurred in 5.9 percent of the OLT recipients. Based on clinical presentation and diagnostic tests, AP could be subdivided into three distinct categories: biochemical AP, significant increase of serum amylase or lipase levels in absence of objective radiologic or surgical evidence of the disease; clinical AP, pancreatitis with radiologic or surgical evidence of the disease; and AP in the critically ill patient. Biochemical AP occurred in the early postoperative period and was consistently a benign condition. Clinical AP occurred after a delay and was associated with a 40 percent mortality rate. Acute pancreatitis in the critically ill patient was only one component of multiorgan failure, which was lethal in each case. About one-half of the patients with biochemical and clinical AP were hepatitis surface antigen positive prior to OLT. The incidence of AP was significantly higher in patients with hepatitis B (17 percent) than in patients without hepatitis B (3 percent) (p < 0.01). APACHE II was the best prognostic score system in the clinical group with a positive and negative predictive value for a score equal to or greater than 10 points of 67 and 100 percent, respectively. CONCLUSIONS: Acute pancreatitis is not an uncommon complication of OLT. Clinical presentation and diagnostic tests have important prognostic values. In some patients, hepatitis B virus may play an important role. APACHE II scores appear to be useful in the evaluation of clinical AP following OLT. Treatment of AP should be similar in both the transplant and nontransplant setting.
APACHE↗
Definition and classification of negative outcomes in solid organ transplantation. Application in liver transplantation.
OBJECTIVE: This study defined negative outcomes of solid organ transplantation, proposed a new classification of complications by severity, and applied the classification to evaluate the results of orthotopic liver transplantation (OLT). SUMMARY AND BACKGROUND DATA: The lack of uniform reporting of negative outcomes has made reports of transplantation procedures difficult to interpret and compare. In fact, only mortality is well reported; morbidity rates and severity of complications have been poorly described. METHODS: Based on previous definition and classification of complications for general surgery, a new classification for transplantation in four grades is proposed. Results including risk factors of the first 215 OLTs performed at the University of Toronto have been evaluated using the classification. RESULTS: All but two patients (99%) had at least one complication of any kind, 92% of patients surviving more than 3 months had grade 1 (minor) complications, 74% had grade 2 (life-threatening) complications, and 30% had grade 3 (residual disability or cancer) complications. Twenty-nine per cent of patients had grade 4 complications (retransplantation or death). The most common grade 1 complications were steroid responsive rejection (69% of patients) and infection that did not require antibiotics or invasive procedures (23%). Grade 2 complications primarily were infection requiring antibiotics or invasive procedures (64%), postoperative bleeding requiring > 3 units of packed red cells (35%), primary dysfunction (26%), and biliary disease treated with antibiotics or requiring invasive procedures (18%). The most frequent grade 3 complication was renal failure, which is defined as a permanent rise in serum creatinine levels > or = twice the pretransplantation values (11%). Grade 4 complications (retransplantation or death) mainly were infection (14%) and primary dysfunction (11%). Comparison between the first and last 50 OLTs of the series indicates a significant decrease in the mean number of grade 1 and 2 complications. This was partially a result of better medical status of patients at the time of transplantation. Using univariate and multivariate analyses of risk factors, the best predictor of grade 1 complications was donor obesity; for grade 2 complications, the best predictor was a donor liver rewarming time of > 90 minutes, and for grade 3 and 4 complications, the best predictor was the APACHE II scoring system and donor cardiac arrest. CONCLUSIONS: Standardized definitions and classifications of complications of transplantation will allow us to better evaluate and compare results of transplantation among centers and over time, and better compare effectiveness of new therapies. Orthotopic liver transplantation still is a procedure with high morbidity that requires careful analysis of risk factors to optimize selection of patients and organ sharing.
Adolescent↗
[Endocrine tumors of the pancreas. Status of the question].
Progress in radioimmunology and immunohistochemistry and the use of intraoperative ultrasonography has considerably improved the diagnosis of endocrine tumors. These advances have changed the prognosis of these tumors since the outcome directly depends on early diagnosis. Surgery is the treatment of choice, in many cases even in the presence of hepatic metastasis. Medical treatment should be used when surgery is contraindicated and includes cytostatic agents (e.g. streptozotocin, 5-FU) or interferons and drugs preventing hormone release such as long-acting somatostatin analogs (SMS 201-995). Finally, symptomatic treatment alone should be confined to cases of unresectable tumors with diffuse metastasis.
Antineoplastic Combined Chemotherapy Protocols↗
The early treatment of acute biliary pancreatitis.
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Acute Disease↗
Overview of therapeutic modalities for the treatment of gallstone diseases.
The management of gallstone diseases has been revolutionized in less than 2 years by the advent of laparoscopic cholecystectomy (LC). However, the rapid adoption of LC has occurred without comparative randomized trials with other available therapies. Thus, the evaluation of LC versus other therapies can only be based on case series. The criteria used for this evaluation are clinical effectiveness, cost-effectiveness, and the patient's level of acceptance and satisfaction with the procedure. The techniques of both LC and open cholecystectomy (OC) have the advantage over other approaches, such as extracorporeal shock-wave lithotripsy or bile acid therapy, of eliminating not only the gallstones but also the gallbladder, thereby preventing recurrence of the disease. Additionally, medical therapies are effective in only a subgroup of patients. Since the complications of surgery are more frequent and more severe in older patients and, due to life expectancy, the risk of recurrence is lower in this population, cost-effectiveness analyses have shown that medical therapies may be preferable in older patients in the subgroup eligible for the respective medical therapies. Compared with OC, LC results in a reduction in hospital stay and time to return to work, in lower cost, and in higher patient satisfaction with the procedure. However, a major concern with the laparoscopic approach has been an increase in the incidence of bile duct injury, particularly during the learning phase of the procedure. Clearly, this problem must be solved. The development of training courses in laparoscopy and the adoption of rigorous criteria for ductal identification are critical in preventing such injuries. Bile duct injury can probably be reduced at least to the level of OC (about 1 in 1,000). Acute cholecystitis may also be treated by LC, but the safety and timing of surgery should be conclusively evaluated. Patients with gallbladder stones and choledocholithiasis are usually treated by endoscopic sphincterotomy either before or soon after laparoscopic surgery. Laparoscopic techniques of common bile duct exploration that will obviate the need for endoscopic sphincterotomy are in the developmental stages. When such a technique is available, comparative trials with endoscopic sphincterotomy will be necessary to assess the best approach.
Acute Disease↗
Evidence of the existence of a soluble mediator of cold preservation injury.
A study was designed to determine whether soluble mediators of injury are released during cold preservation. A first set of livers consisting of three groups was stored in cold Euro-Collins solution. These were a control group stored for 10 min (group 1), an experimental group stored for 16 hr (group 2), and an "antiprotease" group to which a cocktail of antiproteases had been added, which was also stored for 16 hr (group 3). The preservation solution in these livers was washed out at the end of preservation, and this effluent was concentrated and infused into a second set of livers that were all cold-stored for 4 hr. Then, the second-set livers were either perfused-fixed at 4 degrees C with universal fixative or reperfused at 37 degrees C for 180 min in the isolated perfused rat liver (IPRL). Morphometric assessment of sinusoidal lining cells (SLC) on light and electron microscopy showed an increased degree of microcirculatory injury in livers preserved with concentrates from livers of the experimental group. On light microscopy, only 2.2 +/- 0.4% (mean +/- SD) of the SLC had a normal flattened morphology compared with 11.9 +/- 2.0% in the control group, and 10.7 +/- 2.3% of the SLC appeared completely detached from the underlying hepatocytes compared with 2.6 +/- 0.8% in the control group, the differences being statistically significant (P < 0.05). This injury was prevented by the addition of antiproteases to EC solution. Similar results were obtained in the IPRL model, in which a number of typical changes related to cold preservation injury were noted in livers preserved with concentrates from the experimental group. Compared with controls, livers preserved with concentrates from the experimental group had early and significant alterations in markers of microcirculatory injury, including a reduction in portal flow and an increase in creatinine kinase-BB isoenzyme release, followed by an increase in perfusate transaminases, LDH, and a decrease in bile production. Again the injuries were largely prevented by the addition of antiproteases. There were no differences among groups in the degree of white cell and platelet adherence during reperfusion. Experiments using UW solution showed similar results, indicating that the soluble mediator(s) is not specific for a particular preservation solution. These observations are consistent with the hypothesis that soluble mediators are produced during the hypothermic period, and are responsible for a significant part of cold preservation injury, and that proteolytic reactions are involved in this type of injury.
Alanine Transaminase↗
Laparoscopic versus open cholecystectomy: a matched study.
To determine the efficacy of laparoscopic cholecystectomy (LC) in the treatment of gallstone disease, all patients who underwent elective surgery for cholelithiasis during three consecutive periods (1989, 1990 and 1991) were studied. There were 121 patients in each period. All patients in the first period underwent open cholecystectomy (OC), whereas 70 (58%) patients underwent laparoscopic procedures in the second period (OC-LC). LC was the treatment of choice in the third period. Multiple factors, including sex, age, clinical and biochemical presentation of the disease and modified Apache II score were comparable among the three groups. The authors found significant differences in length of hospitalization (6.4 +/- 4.2 days in the OC group, 3.6 +/- 2.4 days in the OC-LC group and 2.4 +/- 1.7 days in the LC group, p < 0.01 when compared with the OC group) and return to work after surgery (5.8 +/- 2.8 weeks, 2.8 +/- 1.2 weeks and 1.3 +/- 1.8 weeks respectively, p < 0.01 when compared with the OC group). There was no significant difference in postoperative complications among the groups, but complications in the OC patients were more severe. Although operative time increased significantly after the introduction of LC, it returned to the range of OC after 36 procedures. Nine patients (5%) with LC required conversion to OC. Benefits of LC include a shorter hospital stay and a shorter recovery period. There were no deaths, very low morbidity, a substantial decrease in overall cost and a high degree of patient satisfaction with LC.
Adult↗
Multiple intrahepatic cholesterol stones.
The authors report a case of multiple intrahepatic cholesterol stones found in an asymptomatic patient who had undergone cholecystectomy 12 years before. Biochemical abnormalities and radiologic and pathologic findings are noted. The patient underwent liver resection with Roux-en-Y choledochojejunostomy and received ursodeoxycholic acid postoperatively. Recovery was uncomplicated, and the patient was well at 1-year follow-up. Intrahepatic cholesterol lithiasis is rare but can be diagnosed preoperatively. Treatment depends on the presence of complications and the distribution of the stones.
Adult↗
Lymphocyte adherence in the reperfused rat liver: mechanisms and effects.
Leukocyte adhesion may play a central role in the pathogenesis of preservation-reperfusion injury to liver grafts. We previously showed that lymphocyte adhesion to sinusoids is dependent on the length of cold ischemia. In the present study we examined the mechanisms of lymphocyte adherence after harvesting combined with a short and a long preservation time. The effects of lymphocyte adherence on liver function were also examined. Rat livers were stored at 1 degrees C in University of Wisconsin solution for 45 min or 30 hr and then reperfused at 37 degrees C in the isolated perfused rat liver with isogeneic lymphocytes in an asanguineous perfusate. The role of reactive oxygen intermediates was investigated with allopurinol, a vitamin E analog and ascorbate or superoxide dismutase and catalase. For us to determine the role of Kupffer cells, Kupffer cell blockade was produced by gadolinium chloride. Leukotriene B4 effects were examined with the lipooxygenase inhibitor, nordihydroguaiaretic acid. We evaluated the possible presence of mechanical obstruction by studying flow rates and the circulation of red blood cells. We examined the role of adhesion molecules by pretreating lymphocytes with trypsin or neuraminidase and by exposing livers to arabinogalactan. We investigated the effects of lymphocyte adhesion on liver function by comparing perfusate liver enzymes in livers reperfused with and without lymphocytes, with trypsinized lymphocytes and with an increased number of lymphocytes. Allopurinol significantly reduced hypoxanthine degradation, and nordihydroguaiaretic acid inhibited leukotriene B4 release into the perfusate. The ability of gadolinium chloride to inhibit Kupffer cells was shown by colloid carbon uptake. In livers harvested and preserved for 45 min, lymphocytes decreased about 40% during reperfusion. In livers preserved for 30 hr, the reduction was significantly greater (about 80%). Lymphocyte adherence was lessened in livers preserved for 45 min by all three of the reactive oxygen intermediate protectants and by gadolinium chloride. In contrast, neither reactive oxygen intermediate protectants nor gadolinium chloride reduced adherence in livers preserved for 30 hr. Nordihydroguaiaretic acid had no effect in livers preserved for either 45 min or 30 hr. Portal flow in livers preserved for 45 min and 30 hr was similar, suggesting an absence of mechanical obstruction, and this finding was supported by a complete absence of red cell trapping. Trypsinization of lymphocytes and exposure of livers to arabinogalactan significantly lessened lymphocyte adherence in livers preserved for 30 hr but not in those preserved for 45 min.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Cholecystolithiasis: lithotherapy for the 1990s.
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Algorithms↗
Effect of intraportal glucose infusion on hepatic glycogen content and degradation, and outcome of liver transplantation.
Recent animal studies suggest that nutritional repletion may improve function of liver allografts, and the authors have found that intraportal glucose infusion in pigs produces rapid and substantial hepatic glycogenation. A controlled prospective randomized study in 32 patients was done to determine glycogen content and degradation in human livers during transplantation, and the effect of intraportal glucose-insulin infusions during the donor operation on these variables and on outcome of transplantation. Peripheral blood glucose concentrations were "clamped" at 14 mmol/L during the glucose-insulin infusion. Liver biopsies were taken at various stages of the procedure. Liver glycogen decreased 2.0 +/- 1.2 g/100 g dry weight liver (mean +/- standard error of the mean) in controls, but increased 6.8 +/- 1.8 g/100 g dry weight in glucose-infused donors. In both groups there was glycogen degradation during periods of cold preservation, anoxic rewarming, and after reperfusion with portal blood. Degradation rates were greater in the glucose-infused group than in controls in all three periods (p less than 0.05). Despite wide variation in postoperative aspartate aminotransferase (AST) levels among recipients in both groups, the difference in peak postoperative AST levels approached significance (p = 0.06). In addition, peak AST levels were closely correlated to anoxic rewarming time in both groups, but the slope of the relationship was much lower (3834 versus 734, p less than 0.01) in the glucose-infused group. Thus at anoxic rewarming times over 90 minutes, glycogenation was protective of liver function. Peak postoperative AST was significantly correlated to glycogen degradation in the cold preservation and rewarming periods in the glucose-infused group only. Intraoperative glucose infusions in humans can reglycogenate the liver, increase glycogen degradation, and improve certain outcome measures in liver transplantation.
Adult↗
Recent results of elective open cholecystectomy in a North American and a European center. Comparison of complications and risk factors.
Results of elective open cholecystectomy in 1252 patients treated in a North American and a European center were examined using a recent standardized classification of complications. Although there were significant differences between centers in population age, rate of concomitant disorders, and numbers of operators, the frequency and severity of complications were comparable. There were no deaths, but 12% and 14% of the patients developed complications in the two centers. About 6% of the patients developed grade I complications. Grade II complications were noted in 6% and 8%, and grade III in 0% and 0.3%. Using univariate and multivariate analysis, individual risk factors for developing complications were found to be different in the two centers. Two preoperative scoring systems, ASA and a simplified APACHE II, were predictive for complications in both centers, but did not account for all risk in these patients. Data from the two centers could not be combined because of significant interaction between risk factors and center. Elective open cholecystectomy is a safe procedure, particularly in terms of highly morbid complications and death. Generalization of risk factors identified in a particular center may be misleading because local conditions may significantly affect risk factors for complications. The data also demonstrate the advantages of a uniform way of reporting surgical complications, which may permit meaningful comparisons among centers.
Adolescent↗