Yang-Il Kim

Hepatocyte protection by a protease inhibitor against ischemia/reperfusion injury of human liver.

BACKGROUND Total clamping of the hepatic pedicle can induce profound hepatic ischemia/reperfusion (I/R) injury, which remains a potentially lethal problem after hepatectomy. STUDY DESIGN The purpose of this study was to evaluate the efficacy of a protease inhibitor in ameliorating I/R injury of the human liver. In a prospective, randomized, clinical study, 66 patients who underwent liver resection under conditions of continuous inflow occlusion were randomly assigned to three groups: 25 patients were given a synthetic protease inhibitor (gabexate mesilate [GM], 2.0 mg/kg/hr) intravenously starting 24 hours before surgery until postoperative day 3 (preop GM group); 16 were similarly given GM at the beginning of surgery (intraop GM group); and 25 served as controls (without GM group). Laboratory data and intraoperative and postoperative variables were analyzed and plasma levels of cytokines--tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6)--were measured to determine the relationship between surgical stress and hepatic I/R injury. RESULTS The three groups of patients were similar in terms of age, gender, preoperative assessments, hepatic inflow occlusion time (approximately 50 minutes), extent of resection (proportion of major and minor hepatectomy), and background liver conditions. Preoperative administration of gabexate mesilate (preop GM group) substantially ameliorated hepatic I/R injury as compared with the other patients (intraop and without GM groups); postoperative serum transaminase levels were notably decreased in association with marked suppression of IL-6 levels in blood circulation during liver surgery. This was accompanied by a lower rate of postoperative complications and no mortality. Gabexate mesilate pretreatment abrogated the positive correlation between postreperfusion hepatocyte injury and hepatic ischemia time. CONCLUSIONS Preoperative administration of GM is useful for preventing I/R injury of the human liver, accompanied by suppression of the plasma proinflammatory cytokine IL-6.

Hepatoprotection by a PGI2 analogue in complete warm ischemia of the pig liver. Prostanoid release from the reperfused liver.

We examined the hepatoprotective effect of a prostaglandin (PG)I2 analogue by analyzing the endogenous release of prostanoid from the pig liver. Fourteen female pigs underwent 1 hr complete hepatic vascular exclusion (HVE); the portal and vena caval circulation was actively decompressed. The animals were divided into one of two groups (n = 7, each) according to pretreatment with the prostacyclin analogue (OP 2507, OP) administered via a mesenteric vein branch for 30 min at a rate of 2 micrograms/kg/min immediately prior to HVE. The plasma levels of prostaglandin E2 (PGE2), 6-keto-prostaglandin F1-alpha (6-keto-PGF1 alpha), and thromboxane B2 (TXB2), from the blood samples from the aorta, the hepatic vein, and the portal vein were serially compared for 60 min after the restoration of blood flow. Other parameters included 7-day survival rate, serum biochemistry, and endotoxin assay. A significant improvement in 7-day survival rate (6/7 vs. 1/7 for the control, P < 0.02) was observed in the OP-treated animals, associated with amelioration of serum transaminase activities but with no differences in plasma endotoxin levels. The reperfused liver progressively and substantially released PGE2 but did not generate other prostanoids (TXB2 and 6-keto-PGF1 alpha). OP pretherapy substantially suppressed hepatic generation of the PGE2 postreflow, correlating with serum transaminase levels (rs = 0.80; P < 0.01, at 60 min). We conclude that the PGI2 analogue ameliorates hepatic ischemia/reperfusion injury by down-regulating PGE2 production from the reperfused liver.

Liver Resections Performed Under Prolonged Portal Triad Occlusion in Patients with Active Chronic Liver Diseases

We analyzed the results of hepatic resections performed during the past 5 years on 27 patients with active chronic liver diseases. The patients included 5 with chronic active hepatitis and 22 with active liver cirrhosis, all of whom had a serum alaninine aminotransferase (ALT) level of more than 100 U/I on admission. Fourteen patients underwent hepatectomy by the conventional method (group 1), and 13 were treated by liver resection with portal triad occlusion (PTO) ranging from 32 to 75 min (group 2). The mean blood loss was significantly lower in group 2 than in group 1, being 630 versus 1,491 ml (P<0.05). No serious complications developed in any of the group 2 patients, whereas liver failure occurred in three of the group 1 patients, two of whom died. The serum bilirubin levels were stabilized in group 2 from 14 days after surgery, whereas the values in group 1 remained elevated. These results indicate that prolonged hepatic inflow occlusion can be used during surgery in selected patients with active chronic liver diseases.