Obstructive jaundice caused by lymphatic remetastasis from the hepatic metastasis of rectosigmoid cancer.

The significant benefit of performing hepatic resection for hepatic metastases from colorectal primary cancers is well established; however, the effectiveness of dissection of the lymph nodes draining the liver remains uncertain. Herein, we report the case of a 52-year-old man who was found to have obstructive jaundice caused by lymphatic remetastasis from the hepatic metastasis of primary rectosigmoid cancer. He had previously undergone a high anterior resection for the rectosigmoid cancer, in April 1990, and a hepatic resection for metastasis was done in March 1994. When the hepatic resection was carried out, dissection of the regional lymph nodes of the liver (i.e., the nodes in the hepatoduodenal ligament) was not performed because no obvious metastatic nodes were identified. Three years after the hepatic resection, enlarged lymph nodes compressing the extrahepatic bile duct from outside were identified by cholangiography and computed tomography (CT). Because radiological studies were unable to determine the lesion capable of metastasizing to these nodes, they were diagnosed as remetastasized lymph nodes from the hepatic metastasis that had been resected 3 years earlier. The lymphatic remetastases were intractable to treatment, and the patient finally died of hepatic failure and malignant cachexia. This case serves to demonstrate that lymphatic dissection of the regional lymph nodes may need to be taken into consideration when resection of hepatic metastases from colorectal cancers is performed.

Contribution of serotonin to liver injury following canine small-intestinal ischemia and reperfusion.

Intestinal ischemia and reperfusion (I/R) has been shown to be associated with multiple organ damages. Serotonin (5-hydroxytriptamine; 5-HT), which is synthesized in the enterochromaffin cells in the intestine and stored in platelets, is known to play an important role in platelet aggregation and vasoconstriction and may ultimately enhance such organ injuries. The purpose of this study was to investigate the association between liver damage and 5-HT levels in the liver after intestinal I/R. The entire canine small intestine, isolated on a vascular pedicle that consisted of the proximal superior mesenteric artery and superior mesenteric vein, was subjected to 4-h ischemia by clamping these vessels and the marginal arteries supplying the proximal and distal ends of the small intestine. Hepatic blood flow, liver tissue blood flow, bile flow rate, and hepatic venous ketone body ratio (HVKBR) were measured before and at the end of intestinal ischemia and at 5, 15, and 30 min, and 1 and 2 h after reperfusion. 5-HT levels in plasma of the portal vein and hepatic vein were assayed at the same intervals. Time-matched, sham-operated animals served as controls. Intestinal I/R significantly decreased the liver tissue flow, bile flow rate, and HVKBR. Compared to those in controls, 5-HT levels in the portal vein and hepatic vein were markedly increased after reperfusion. Furthermore, intravenous administration of 5-HT receptor antagonists attenuated the liver dysfunction after intestinal reperfusion. These results suggest that intestinal I/R induces continuous disturbance of hepatic microcirculation, leading to liver dysfunction, and that 5-HT may be implicated as one of the mediators of liver dysfunction after intestinal I/R.

Multiple duodeno-jejunal diverticula causing massive intestinal bleeding.

A case of massive intestinal blood loss from multiple duodeno-jejunal diverticula is described. A 39-year-old man was referred to our hospital because of recurrent bloody stool and worsening anemia. Upper and lower endoscopy, selective abdominal angiography, and radionuclide scanning were performed to seek the cause of the intestinal bleeding, but none of these studies revealed the source of bleeding. Small-bowel barium follow-through examination showed numerous diverticula in the distal duodenum and proximal jejunum. Excision of the duodenal diverticulum and resection of the involved portion of the jejunum cured the patient. On histopathological examination, an ulcerative lesion with an exposed vessel suggestive of the source of bleeding was seen in the resected duodenal diverticulum. Although duodeno-jejunal diverticula are rare, the importance of a careful search for this malformation in a patient with intestinal blood loss is stressed.

Protective role of nitric oxide in ischemia and reperfusion injury of the liver.

BACKGROUND: The suppressed production of nitric oxide (NO), associated with endothelial dysfunction, is thought to be a cause of ischemia and reperfusion injury of the liver. But findings of the salutary effects of NO enhancement on such injury have been conflicting. In this study, we tested our hypothesis that NO enhancement would attenuate ischemic liver injury. For this purpose, an NO precursor, L-arginine, and a novel NO donor, FK409, were applied to a 2-hour total hepatic vascular exclusion model in dogs. STUDY DESIGN: L-arginine was administered IV at a dose of 100 mg/kg twice (n = 5), while 300 mg/kg twice of FK409 was infused continuously into the portal vein (n = 5). The drugs were given to the animals for 30 and 60 minutes before and after ischemia, respectively. Non-treated animals were used as the control (n = 10). Two-week survival, systemic and hepatic hemodynamics indices, liver function tests, energy metabolism, and histopathology were analyzed. RESULTS: Both treatments comparably augmented hepatic tissue blood flow, decreased liver enzyme release, and increased high-energy phosphate restoration during the reperfusion period, all of which contributed to rescuing all of the treated animals from the 2-hour total hepatic ischemia. In contrast, ischemia caused 70% mortality in the control group. Histologically, structural abnormality and neutrophil infiltration were markedly attenuated by the treatments. Systemic hypotension was observed in the animals treated with FK409, however. CONCLUSIONS: Our data demonstrate that NO enhancement alleviates the liver injury caused by ischemia and reperfusion. The supplementation of L-arginine, rather than FK409, is considered more applicable to clinical use because of the absence of systemic adverse effects.

Attenuation of ischemic liver injury by prostaglandin E1 analogue, misoprostol, and prostaglandin I2 analogue, OP-41483.

BACKGROUND: Prostaglandin has been reported to have protective effects against liver injury. Use of this agent in clinical settings, however, is limited because of drug-related side effects. This study investigated whether misoprostol, prostaglandin E1 analogue, and OP-41483, prostaglandin I2 analogue, which have fewer adverse effects with a longer half-life, attenuate ischemic liver damage. STUDY DESIGN: Thirty beagle dogs underwent 2 hours of hepatic vascular exclusion using venovenous bypass. Misoprostol was administered intravenously for 30 minutes before ischemia and for 3 hours after reperfusion. OP-41483 was administered intraportally for 30 minutes before ischemia (2 microg/kg/min) and for 3 hours after reperfusion (0.5 microg/kg/min). Animals were divided into five groups: untreated control group (n=10); high-dose misoprostol (total 100 microg/kg) group (MP-H, n=5); middle-dose misoprostol (50 microg/kg) group (MP-M, n=5); low-dose misoprostol (25 microg/kg) group (MP-L, n=5); and OP-41483 group (OP, n=5). Animal survival, hepatic tissue blood flow (HTBF), liver function, and histology were analyzed. RESULTS: Two-week animal survival rates were 30% in control, 60% in MP-H, 100% in MP-M, 80% in MP-L, and 100% in OP. The treatments with prostaglandin analogues improved HTBF, and attenuated liver enzyme release, adenine nucleotrides degradation, and histologic abnormalities. In contrast to the MP-H animals that exhibited unstable cardiovascular systems, the MP-M, MP-L, and OP animals experienced only transient hypotension. CONCLUSIONS: These results indicate that misoprostol and OP-41483 prevent ischemic liver damage, although careful dose adjustment of misoprostol is required to obtain the best protection with minimal side effects.

A long-term surviving patient with cancer of papilla of Vater after local resection.

We report successful local resection for cancer of papilla of Vater in an 86-year-old woman. She was referred to our hospital because of right hypochondralgia. Abdominal ultrasonography and computed tomography showed marked dilatation of the common bile duct (CBD). Endoscopic retrograde cholangiography disclosed a small shadow defect in the terminal of the dilated CBD. Biopsy of the papilla revealed well-to-moderately differentiated adenocarcinoma. Considering her extreme old age and keeping in mind her quality of life after the operation, and the finding that the tumor was localized within the papilla and highly differentiated, we performed local resection. In addition, the intrapancreatic portion of the CBD and part of the main pancreatic duct (MPD) were further resected to secure a negative margin, confirmed by frozen section. The MPD was reapproximated to the duodenal mucosa and a choledocho-duodenostomy was performed for CBD reconstruction. Histopathological examination showed the tumor was papillary adenocarcinoma, 10 x 15 mm in size; there was no invasion beyond the sphincter of Oddi, it had partly infiltrated the CBD, but had not invaded to the pancreas or duodenum. The patient's postoperative course was not eventful and she has had good quality of life for the past 6 years since the operation, without any evidence of recurrence. Although radical pancreaticoduodenectomy is now the standard procedure in patients with malignant tumor of the papilla of Vater, local resection is a reasonable alternative for high-risk patients with highly differentiated, apparently localized carcinomas.

Division of donor liver for successful split-liver transplantation in pigs.

Split Liver Transplantation (SLT) is an attractive method to solve the problem of a shortage of liver grafts. A through knowledge of the anatomy of the porcine liver vessels and bile duct is essential in performing the experimental SLT. This study was undertaken to decide the split line for successful SLT in pigs by examining the main branching patterns both vessels and bile duct in 30 porcine livers macroscopically and angiographically. The hepatic arterial branching patterns were divided into three types and bile duct patterns into two types. There was no exception in branching patterns of the portal vein and the hepatic vein. We conclude it is desirable that the donor liver should be divided into two grafts between the left medial lobe and quadrate lobe.

Attenuation of ischemic liver injury by monoclonal anti-endothelin antibody, AwETN40.

BACKGROUND: Enhanced production of endothelin-1 (ET-1), vasoconstrictive 21 amino acids produced by endothelial cells during ischemia and after reperfusion of the liver, is known to cause sinusoidal constriction and microcirculatory disturbances, which lead to severe tissue damage. Using a 2-hour hepatic vascular exclusion model in dogs, we tested our hypothesis that neutralization of ET-1 by monoclonal anti-ET-1 and anti-ET-2 antibody (AwETN40) abates vascular dysfunction and ameliorates ischemia/reperfusion injury of the liver. STUDY DESIGN: After skeletonization, the liver was made totally ischemic by cross-clamping the portal vein, the hepatic artery, and the vena cava (above and below the liver). Veno-venous bypass was used to decompress splanchnic and inferior systemic congestion. AwETN40, 5 mg/kg, was administered intravenously 10 minutes before ischemia (treatment group, n = 5). Nontreated animals were used as controls (control group, n = 10). Animal survival, hepatic tissue blood flow, liver function tests, total bile acid, high-energy phosphate, ET-1 levels, and liver histopathology were studied. RESULTS: Treatment with AwETN40 improved 2-week animal survival from 30% to 100%. Hepatic tissue blood flow after reperfusion was significantly higher in the treatment group. The treatment significantly attenuated liver enzyme release, total bile acid, and changes in adenine nucleotides. Immunoreactive ET-1 levels in the hepatic venous blood of the control group showed a significant increase and remained high for up to 24 hours after reperfusion. Histopathologic alterations were significantly lessened in the treatment group. CONCLUSIONS: These results indicate that ET-1 is involved in ischemia/reperfusion injury of the liver, which can be ameliorated by the monoclonal anti-ET-1 and anti-ET-2 antibody AwETN40.

Lazaroid U-74500A for warm ischemia and reperfusion injury of the canine small intestine.

BACKGROUND: Although lazaroids have been shown to protect various organs from ischemia/reperfusion injury, results obtained in the small intestine have been conflicting. STUDY DESIGN: The canine small intestine was made totally ischemic for 2 hours by occluding the superior mesenteric artery and the superior mesenteric vein with interruption of the mesenteric collateral vessels. A lazaroid compound, U74500A, or a citrate vehicle was given intravenously to each of the six animals for 30 minutes before intestinal ischemia. Intestinal tissue blood flow, lipid peroxidation, neutrophil infiltration, adenine nucleotides and their catabolites, and histologic changes after reperfusion were determined. RESULTS: Lazaroid treatment attenuated decline of the mucosal and serosal blood flow after reperfusion. Accumulation of lipid peroxidation products and neutrophils in mucosal tissues was markedly inhibited by the treatment. Postischemic energy resynthesis was also augmented by lazaroid. Morphologically, mucosal architectures were better preserved with lazaroid treatment after reperfusion, and recovered to normal by postoperative day 3 in the treated group and by postoperative day 7 in control animals. CONCLUSIONS: Lazaroids protect the canine small intestine from ischemia/reperfusion injury by inhibiting lipid peroxidation and neutrophil infiltration. Dogs are tolerant of 2-hour normothermic complete intestinal ischemia.

Comparison of various lazaroid compounds for protection against ischemic liver injury.

Lazaroids are a group of 21-aminosteroids that lack steroid action but have a potent cytoprotective effect by inhibiting iron-dependent lipid peroxidation. However, there have been conflicting reports on the effectiveness and potency of the various lazaroid compounds. In this study, we compared the effectiveness of three major lazaroids on warm liver ischemia in dogs using a 2-hr hepatic vascular exclusion model. The agents were given to the animals intravenously for 30 min before ischemia. The animals were divided into 5 groups: Control (n=10), no treatment; Group F (n=6), U-74006F (10 mg/kg); Group G (n=6), U-74389G (10 mg/kg); Group A1 (n=6), U-74500A (10 mg/kg); Group A2 (n=6), U-74500A (5 mg/kg). The effect of treatment was evaluated by two-week animal survival, hepatic tissue blood flow, liver function tests, blood and tissue biochemistry, and histological analyses. Animal survival in all treated groups was significantly improved compared with the control (83-100% versus 30%). Elevation of liver enzymes after reperfusion was markedly attenuated in treated groups, except for an early significant increase in Group G. Postreperfusion hepatic tissue blood flow was much higher in all treated animals (50% of the preischemic level vs. 25% in the control). Lazaroids, particularly U-74500A at 5 mg/kg (Group A2), suppressed adenine nucleotide degradation during ischemia and enhanced the resynthesis of high-energy phosphates after reperfusion. Although structural abnormalities in postreperfusion liver tissues were markedly ameliorated in all treated groups, Group A2 showed significantly less neutrophil infiltration. Liver injury from warm ischemia and reperfusion was attenuated with all lazaroid compounds, of which U-74500A at 5 mg/kg exhibited the most significant protective activity.

Attenuation of ischemic liver injury by augmentation of endogenous adenosine.

Hepatic grafts from non-heartbeating donors may alleviate the organ shortage, but they inherently suffer from warm ischemia. In the present study, we tested our hypothesis that augmentation of endogenous adenosine by inhibition of nucleoside transport with R75231 attenuates ischemic liver injury. Adult female beagle dogs underwent 2-hr hepatic vascular exclusion with venovenous bypass. R75231 was given to the animals by continuous intravenous infusion for 30 min before ischemia at a dose of 0.1 mg/kg (Group 2, n=6), 0.05 mg/kg (Group 3, n=6), or 0.025 mg/kg (Group 4, n=6). Nontreated animals were used as the control (Group 1, n= 10). Animal survival, hepatic tissue blood flow, liver function, and histopathology were analyzed. Two-week animal survival was 30% in Group 1, 83% in Group 2, 100% in Group 3, and 100% in Group 4. Postreperfusion hepatic tissue blood flow was markedly improved by the treatment. Treatment significantly attenuated liver enzyme release, lipid peroxidation, and changes in adenine nucleotides and purine catabolites. Structural abnormality of the liver after reperfusion was markedly improved by R75231 treatment, showing better architecture and less neutrophil infiltration. Preischemic administration of a nucleoside transport inhibitor ameliorated ischemic liver injury due to the positive effects of augmented endogenous adenosine, and is applicable clinically when the liver is procured from a controlled non-heartbeating donor.