Inhibitory effects of safe and novel SOD derivatives, galactosylated-SOD, on hepatic warm ischemia/reperfusion injury in pigs.

BACKGROUND/AIMS: Oxygen-derived free radicals such as superoxide play an important role in ischemia/reperfusion (IR) injury during and after extensive liver surgery or liver transplantation. Superoxide dismutase (SOD) has protective effects against hepatic IR injury. The effect of native SOD is, however, limited because of rapid elimination from the blood circulation and poor affinity for liver cells. It was reported by our collaborators that a SOD derivative modified with galactose (Gal-SOD) was selectively delivered well to hepatocytes by direct attachment to galactose receptors. In the present study, the efficacy of this agent for attenuating hepatic warm IR injury was investigated using the pig model. METHODOLOGY: After 45-min clamping of the hepatic artery and portal vein, pigs were divided into 3 groups according to the following treatments. Ten milliliters of normal saline in Group 1 (n=5), 10,000 units/kg of native SOD in Group 2 (n=5) and 10,000 units/kg of Gal-SOD in Group 3 (n=5) were given just prior to hepatic reperfusion. Liver function including clearance of total bile acid (TBA) and hyaluronic acid (HA) was investigated. Lipid peroxidase of the liver tissue (LPO) and histological findings were examined. In addition, survival rates of the pigs in each group were evaluated. RESULTS: The survival rates at the 7th day after the operation were 60%, 80%, 100% in Groups 1, 2 and 3, respectively. Liver function tests, clearance of TBA and HA, and LPO levels were significantly improved in Groups 3 over findings in Groups 1 and 2. Congestion of hepatic tissues and vacuolization of hepatocytes in Group 3 were less than those in Groups 1 and 2. These results suggested that oxygen-derived free radicals were scavenged by Gal-SOD and IR injury was attenuated. CONCLUSIONS: A safe and novel agent, Gal-SOD has a protective effect against hepatic warm IR injury.

Successful treatment of bleeding due to ileal varices in a patient with hepatocellular carcinoma.

This case report concerns a 62-year-old female who was known to have cirrhosis. An endoscopic examination showed no evidence of haemorrhaging due to either oesophageal or gastric varices. Angiographic studies demonstrated extravasation from the ileal varices. There was a prominent arterio-portal shunt in the liver, and the shunt was considered to be a contributing factor to induce portal hypertension and variceal bleeding in the ileum. Therefore, transcatheter arterial embolization was performed, but was unsuccessful. As a result, the patient underwent a laparotomy, and a dilatating ileocaecal vein and a communicating ovarian vein were selectively ligated. Following the procedure, the haemorrhaging stopped and she then recovered. The patient is doing well 21 months after surgery at the time of writing.

Antibody studies of factor VIII inhibitor in a case with Waldenström's macroglobulinemia.

We report a case of Waldenström's macroglobulinemia with prominent bleeding tendency; laboratory investigation revealed an elevated activated partial thromboplastin time. Further laboratory evaluation showed circulating factor VIII anticoagulant, deemed polyclonal IgG, with a titer of 700 Bethesda Units/ml. The factor VIII inactivation kinetics of the patient plasma were identical to those of a type II inhibitor, and the inhibitor was found to recognize the A2 domain of the factor VIII heavy chain. Apparently, paraprotein is not always the cause of reduced activity of coagulation factors in neoplastic dysproteinemias.

Transcatheter arterial embolization for advanced hepatocellular carcinoma resulting in a curative resection: report of two cases.

Transcatheter hepatic arterial embolization and lipiodolization have been reported to be effective palliative treatments for patients with unresectable hepatocellular carcinoma. We experienced 2 patients with advanced hepatocellular carcinoma which were initially considered to be unresectable due to the extreme extension of the primary lesions. Therefore, transcatheter hepatic arterial embolization with lipiodolization were selected as the treatments of choice. Thereafter, these tumors markedly decreased in size and, as a result, curative resections could subsequently be performed. The pathological examination of the resected specimens revealed necrosis and hyaline degeneration in the main tumors. Viable tumor cells, however, still remained adjacent to the main tumors. Such evidence indicated the limited efficacy of transcatheter hepatic arterial embolization with lipiodolization and the necessity of performing surgical treatment in combination with transcatheter hepatic arterial embolization with lipiodolization. Based on these findings, transcatheter hepatic arterial embolization with lipiodolization both appear to be a good mode of therapy for advanced hepatocellular carcinoma, and in selected patients, subsequent surgery can also be considered.

The significance of measuring the serum total bile acids levels during orthotopic liver transplantation.

BACKGROUND/AIMS: Bile acid is confined to the enterohepatic circulation and consists of intestinal absorption and hepatic elimination. We investigated whether measuring the serum total bile acids (TBA) levels was useful for both evaluating the function of the grafted liver and predicting the outcome in porcine orthotopic liver transplantation (OLT). METHODOLOGY: Twenty-two female Yorkshire pigs undergoing OLT were divided into 2 groups as follows: Group A consisted of 11 pigs which survived over 7 days with an uneventful early post-operative course, while Group B consisted of 11 pigs which died within 5 days due to hepatic failure. The serum TBA levels were measured before and after reperfusion in the recipients. RESULTS: Between Groups A and B, no significant difference was observed in the operative backgrounds including the operation time as well as the cold and warm ischemic time. In Group A, the levels of serum TBA rapidly increased during the anhepatic phase, and thereafter promptly decreased after the reperfusion of the grafted liver. A significant difference was observed in the levels of serum TBA before and after reperfusion (p < 0.01), whereas no significant difference was seen in Group B. The delta TBA, which represents the difference in the levels of serum TBA between just prior to reperfusion and 10 min after reperfusion, was 71.8 +/- 43.5 mumol/L in Group A and 20.1 +/- 34.5 mumol/L in Group B, and demonstrated a significant difference between these 2 groups (p < 0.01). On the other hand, no significant differences were seen in the levels of serum AST, ALT, ALP and TB at each time point between Groups A and B. CONCLUSIONS: The level of serum TBA was found to be a more sensitive parameter and also reflected the developing grafted liver function earlier than the conventional parameters for liver function. Moreover, delta TBA thus appeared to be a valuable predictor for the post-operative outcome.

Utility of technetium-99m-labeled-galactosyl human serum albumin scintigraphy for estimating the hepatic functional reserve.

Technetium-99m-diethylenetriaminepentaacetic acid-galactosyl-human serum albumin (Tc-GSA) is a receptor binding agent, specific for asialoglycoprotein receptor, that resides exclusively on the plasma membrane of mammalian hepatocytes. The usefulness of Tc-GSA for estimating the hepatic functional reserve was retrospectively evaluated in patients undergoing a hepatic resection. Tc-GSA scintigraphy was performed in 35 patients before hepatectomy, and the hepatic uptake ratio (LHL15) was calculated. The LHL15 was then compared with the findings of conventional liver function tests, the indocyanine green retention rate in 15 minutes (ICG R15), and histologic activity index (HAI) score. Significant correlations were observed between the LHL15 and values of ICG R15, prothrombin time activity, serum levels of total bilirubin, hyaluronic acid, and values of HAI score. Ratios of LHL15 to preoperative liver volume (LHL-V) correlated well with the regenerative rates of the residual liver after major hepatectomy. In addition, patients with more than 0.76 of LHL-V value had no complications in postoperative course, whereas those with less than 0.73 had several complications due to hepatic dysfunction. Tc-GSA scintigraphy thus appears to be a useful diagnostic tool for evaluating functioning mass of the liver and the values of LHL-V seems to be able to demonstrate regenerative activity in the residual liver after hepatectomy.

Systematic laparoscopic left lateral segmentectomy of the liver for hepatocellular carcinoma.

A systematic technique for the resection of hepatocellular carcinoma (HCC) prevents the dissemination of cancer cells through the portal vein of the remnant liver. We successfully performed a systematic laparoscopic left lateral segmentectomy in a 62-year-old man with HCC. The tumor was located in the left lateral segment of the liver, and measured approximately 4 cm in diameter. Since no other tumors were detected in the liver or in any distant organs, the patient was considered to be a candidate for surgery. A laparoscopic hepatic resection was selected as the procedure of choice. Prior to dissection of the liver parenchyma, the arteries and branches of the portal vein feeding the left lateral segment were divided and dissected, together with the branches of the biliary tree in the umbilical portion of the left pedicle of Glisson's capsule. The liver parenchyma was then dissected and the left hepatic vein divided and dissected, and transection of the left lateral segment was completed. The patient's postoperative course was uneventful and he was discharged on postoperative days 14. No evidence of recurrence has been noted in the 22 months after surgery (the time of this report). This less invasive surgery, taking into consideration the pathogenesis of HCC, may be a useful new approach in selected patients with this tumor.

Primary leiomyosarcoma of the jejunal mesentery: report of a case.

The occurrence of a primary leiomyosarcoma of the mesentery is rare. A 61-year-old man was admitted to the hospital complaining of an abdominal mass. The findings of both abdominal ultrasonography and a computed tomography (CT) scan revealed an irregular and heterogeneous mass located in the mesentery. A laparotomy was performed and a 7.0 x 6.5 cm tumor was thus found within the jejunal mesentery. The tumor was successfully resected by a combined resection of 40 cm of the jejunum and end-to-end anastomosis of the jejunum. Pathological examination of the resected specimen revealed leiomyosarcoma. The patient had an uneventful postoperative course, but multiple liver metastases were discovered 1 year and 5 months after the initial operation. A second operation was performed, but the patient died due to hepatic failure and unexpected bleeding from the cut surface of the remnant liver. Preoperative imaging examinations, including abdominal ultrasonography and CT scan, were thus found to be useful tools for both identifying and diagnosing the origin and extension of a mesenteric mass. However, even using such diagnostic techniques an accurate diagnosis of intraabdominal leiomyosarcoma remains difficult.

A case of hepatocellular carcinoma with marked hyperfibrinogenemia.

The present report concerns a case of hepatocellular carcinoma (HCC) with marked hyperfibrinogenemia. The plasma fibrinogen level reached as high as 1,704 mg/dl. Since treatment against HCC resulted in reduction of plasma fibrinogen and PIVKA-II, an HCC marker, the hyperfibrinogenemia appears to be related to HCC. Immunohistochemically, the HCC specimen from this patient reacted strongly with antiserum to human fibrinogen, suggesting that the elevated fibrinogen was due to synthesis of this protein by the carcinoma cells, not to decreased fibrinolytic activity.

Preventive effects of superoxide dismutase derivatives modified with monosaccharides on reperfusion injury in rat liver transplantation.

BACKGROUND: Superoxide dismutase (SOD) derivatives modified with monosaccharides such as mannosylated SOD (Man-SOD) and galactosylated SOD (Gal-SOD) are taken up by parenchymal and nonparenchymal cells of the liver, respectively, via receptor-mediated endocytosis. We examined the preventive effects of Man- or Gal-SOD on cold ischemia-reperfusion injury in orthotopic liver transplantation (OLT) in rats. METHODS: Male Lewis rats underwent OLT. Native SOD and modified SOD with mannose (Man-SOD) or galactose (Gal-SOD) were intravenously given just prior to reperfusion of the grafted liver. RESULTS: After OLT, no significant changes in serum levels of aspartate aminotransferase or lactate dehydrogenase were evident among rats, with or without various types of SOD. However, tissue levels of Na+,K+-ATPase, an indicator of tissue viability, were significantly higher in rats treated with Man- and Gal-SODs compared with that in untreated OLT rats. When comparisons were made between Gal-SOD and Man-SOD, higher levels of Na+,K+-ATPase were evident in rats treated with Gal-SOD. Elevations of tissue levels of lipid peroxides were significantly inhibited by modified SODs. The survival rates of rats following OLT after prolonged cold preservation correlated with results of graft viability. CONCLUSIONS: SOD derivatives, particularly Gal-SOD, have protective effects on cold ischemia-reperfusion injury during OLT in rats.

Indocyanine green elimination test in orthotopic liver recipients.

OBJECTIVE: To determine its predictive capability on graft quality and resultant clinical outcome, the indocyanine green (ICG) elimination test was performed by a spectrophotometric method and a noninvasive finger-piece method with 50 orthotopic liver transplantations. BACKGROUND: Early detection of poor-functioning hepatic grafts is one of the most important issues in liver transplantation, but no reliable methods exist. METHODS: The ICG test was performed after 50 orthotopic liver transplantations on postoperative days 1, 3, and 7. Indocyanine green elimination constants (K(ICG)) were measured by both a standard spectrophotometric analysis (K(ICG)-B) and by a finger-piece method (K(ICG)-F). The patients were followed for a minimum of 3 months after transplantation. Results of ICG tests were correlated with various clinical determinations. RESULTS: Twelve of the 50 grafts were lost within three months, of which 7 were related to graft failure. Multivariate analysis using the Cox proportional hazard model revealed that K(ICG) on postoperative day 1 was a better predictor of liver-related graft outcome than any of the conventional liver function tests. Furthermore, K(ICG) values showed significant correlation with the severity of preservation injury, longer intensive care unit (ICU) and hospital stay, prolonged liver dysfunction, and septic complications. Correlation of K(ICG) values by the spectrophotometric method with those by the finger-piece method was highly satisfactory in the grafts that had K(ICG)-B <0.15 min-1 (y = 0.868x -0.011, r = .955). CONCLUSION: The ICG elimination test, conducted spectrophotometrically or optically on the day after liver transplantation, is a reliable indicator of graft quality and subsequent graft outcome early after liver transplantation.