Layton F. Rikkers

Hilar Cholangiocarcinoma: Current Management

Objective:To review the literature with regard to outcome of surgical management for hilar cholangiocarcinoma (Klatskin tumor). Background:Hilar cholangiocarcinoma is a rare tumor with a poor prognosis. Surgical resection provides the only possibility for cure. Advances in hepatobiliary imaging and surgical strategies to treat this disease have resulted in improved postoperative outcomes. Methods:We performed a review of the English literature on hilar cholangiocarcinoma from 1990 to 2007. This review included preoperative evaluation, surgical techniques, issues and controversies in management, prognostic variables, and considerations for future directions. Results:Complete resection remains the most effective and only potentially curative therapy for hilar cholangiocarcinoma. Negative resection margins are associated with improved outcomes, and major hepatic resections have enhanced the likelihood of R0 resection. Portal vein embolization may be indicated in selected patients before extensive hepatic resection. Staging laparoscopy should be considered to detect occult metastatic disease. Orthotopic liver transplantation might be applicable for a highly selected subgroup. Conclusions:Surgical resection including major hepatic resection remains the mainstay of treatment of hilar cholangiocarcinoma. Additional evidence is needed to fully define the role of orthotopic liver transplantation. Improvements in adjuvant therapy are essential for improving long-term outcome.

A randomized, controlled trial of the distal splenorenal shunt.

In 1971 a prospective, randomized trial was initiated to determine efficacy of the distal splenorenal shunt in the management of cirrhotic patients who had previously bled from esophageal varices. When entry into the trial was terminated in 1976, 26 patients had received the distal splenorenal shunt (selective) and 29 had undergone a nonselective shunting procedure (18 interposition mesorenal, six interposition mesocaval, and five other nonselective shunts). Three operative deaths occurred in each group. Early postoperative angiography revealed preservation of hepatic portal perfusion in 14 of 16 selective patients (88%), but in only one of 20 non-selective patients (5%; p <.001). Quantitative measures of hepatic function (maximal rate of urea synthesis or MRUS and Childs score) were similar to preoperative values in the selective group but were significantly decreased in nonselective patients on the first postoperative evaluation (p <.001 for MRUS; p <.05 for Childs score). Eighty-seven per cent of selective and 81% of nonselective patients have now been followed for three to six years since surgery. Late postoperative evaluation of 29 survivors (12 selective, 17 non-selective) still shows an advantage to the selective group with respect to MRUS, Childs score, and incidence of hepatopetal portal blood flow, but differences are no longer statistically significant. However, if the seven patients with portal flow (five selective; two nonselective) are compared to the 20 with absent portal flow (seven selective; 13 nonselective), the former group has significantly higher values for MRUS (p <.05) and Childs score (p <.025). No patient with continuing portal perfusion has developed encephalopathy as compared to a 45% incidence of this complication in individuals without portal flow (p <.05). No significant differences between selective and nonselective groups have appeared with respect to total cumulative mortality (ten selective; 38%; eight nonselective, 28%), shunt occlusion (two selective, 10%; five nonselective, 18%), or recurrent variceal hemorrhage (one selective, 4%; two nonselective, 8%). Overall, significantly fewer selective patients have developed postoperative encephalopathy (three selective, 12%; 15 non-selective, 52%; p <001). Therefore, we conclude that the distal splenorenal shunt, especially when its objective of maintaining hepatic portal perfusion is achieved, results in significantly less morbidity than nonselective shunting procedures.

Shunt surgery versus endoscopic sclerotherapy for long-term treatment of variceal bleeding. Early results of a randomized trial

In September 1982, a prospective randomized trial comparing shunt surgery and endoscopic sclerotherapy for the elective management of variceal hemorrhage in patients with cirrhosis was initiated. Twenty-seven patients have received shunts (distal splenorenal = 23, nonselective = 4) and 30 patients have had chronic sclerotherapy. Eighty-six per cent of patients had alcoholic cirrhosis and 33% were Childs class C. After a mean follow-up of 25 months, 19% of shunt and 57% of sclerotherapy patients have had rebleeding (p = 0.003). Kaplan-Meier survival analysis reveals similar 2-year survival rates for shunt (65%) and sclerotherapy (61%) groups. Only two of 10 sclerotherapy failures have been salvaged by surgery. Posttherapy quantitative hepatic function, frequency of encephalopathy, and cumulative medical costs were similar for both groups. Hepatic portal perfusion and portal pressure at 1 year were better maintained by sclerotherapy than by distal splenorenal shunt. In conclusion, endoscopic sclerotherapy and shunt surgery provide similar results with respect to survival, hepatic function, frequency of encephalopathy, and costs. Sclerotherapy is an acceptable, but not superior, alternative to shunt surgery for treatment of variceal hemorrhage.

Estimation of the Functional Reserve of Human Liver

Functional hepatic reserve was determined in 32 patients with known liver or biliary tract disease employing kinetic analysis of hepatic removal of indocyanine green (ICG). The initial removal rates of incremental doses of ICG (0.5, 1.0 and 5.0 mg/kg body weight) were plotted as a reciprocal against the inverse of dose (Lineweaver-Burk plot) to provide a means of determining maximal removal rate from submaximal doses (Rmax). This function equalled 3.40 mg/kg/min in ten patients with normal livers, but was only .24 mg/kg/min in eight patients with alcoholic cirrhosis. Portasystemic shunting did not further influence Rmax. Infiltrative liver disease had only a mild depressive effect on this function. The results show that hepatic function can be precisely quantitated by classical enzyme kinetics (Michaelis-Menten). If Rmax is an estimate of protein receptor mass for organic anions, then the technique may allow an indirect means for quantitating hepatocytes even in the presence of changes in blood flow or hepatic function. The profound depression in R(max) observed in patients with alcoholic cirrhosis is consistent with the progressive loss in hepatic mass associated with this disease.

Resection of hilar cholangiocarcinoma: concomitant liver resection decreases hepatic recurrence.

Background:Hilar cholangiocarcinoma is an uncommon tumor with a poor prognosis. We sought to evaluate recurrence patterns and prognostic factors for disease-specific and disease-free survival in patients with surgically resected hilar cholangiocarcinoma in a single institution over the last 21 years. Methods:From 1985 to 2006, all patients with hilar cholangiocarcinoma referred to a tertiary surgical clinic were evaluated. Demographic data, tumor characteristics, and outcome were analyzed retrospectively. Outcome was compared in patients treated in a recent era (1995–2006) compared with an earlier era (1985–1994). Results:Of 91 patients evaluated, 22 patients (24%) had unresectable disease at presentation. Of the 69 patients submitted to laparotomy, resection was possible in 55% and the curative (R0) resection rate was 63%. In patients submitted to exploration, the operative (60 day) morbidity and mortality rates were 26% and 3%. Median disease-specific (DSS) and disease-free survival (DFS) were 29 and 20 months, respectively (median FU, 29 months.). In patients undergoing R0 resection, the median survival was prolonged (65 months). In the more recent era, resectability rates improved (69% vs. 17%; P = 0.0002), and this was associated with an improvement in median survival (30 vs. 4 months; P < 0.001). Factors predictive of improved disease-specific and disease-free survival included negative histologic margins, concomitant hepatic lobectomy, lack of nodal disease, well-differentiated histology, and an earlier tumor stage (P < 0.05). Concomitant liver resection was associated with a higher R0 resection rate (P = 0.006) and improved DSS and DFS (P = 0.005). In addition, concomitant liver resection was associated with a decreased incidence of initial recurrence in liver (P = 0.031). Conclusions:In patients with hilar cholangiocarcinoma, concomitant hepatic resection is associated with improved DFS, DSS, and decreased hepatic recurrence. Therefore, hepatectomy combined with bile duct resection should be considered standard treatment.

Bacterial translocation in the portal-hypertensive rat: Studies in basal conditions and on exposure to hemorrhagic shock

BACKGROUND Portal hypertension is associated with altered intestinal motor and mucosal function. The aim of this study was to determine whether portal hypertension, per se, or in association with acute hemorrhagic shock, predisposes to the translocation of bacteria across the intestine. METHODS Translocation to both mesenteric lymph nodes and blood was compared in three groups of rats: portal-hypertensive (single-stage calibrated stenosis of portal vein), sham-operated, and unoperated controls. Half of the animals in each group were exposed to hemorrhagic shock. RESULTS In the basal state, translocation to both mesenteric lymph nodes (portal hypertension vs. sham vs. controls, 411.5 +/- 119 vs. 151.1 +/- 42.6 vs. 18.1 +/- 12.6 colony-forming units [CFU]/g; P < 0.05) and blood (portal hypertension vs. sham vs. controls, 100% vs. 30% vs. 0% positive blood cultures; P < 0.05) was significantly increased in the portal-hypertensive animals. Furthermore, translocation was strikingly increased in these animals after hemorrhagic shock (mesenteric lymph node cultures, portal hypertension vs. portal hypertension with shock, 411 +/- 119 vs. 1018.2 +/- 372.2 CFU/g; P < 0.05). CONCLUSIONS Portal hypertension promotes bacterial translocation, especially in relationship to acute hemorrhage. These findings may, in part, explain the susceptibility of patients with liver disease to sepsis of enteric origin.

Biliary obstruction and host defense failure

Abstract To determine whether biliary obstruction impairs reticuloendothelial system (RES) phagocytic function, the corrected plasma disappearance rate (α) of a blood flow-independent dose (16 mg/100 g body wt) of colloidal carbon was determined 3, 7, 14, and 21 days after ligation and division of the common hepatic duct in male Sprague-Dawley rats. Although α was not significantly different between control and obstructed animals at 3, 7, or 14 days, at 21 days α was significantly depressed in obstructed rats. Animals with biliary obstruction had a greater weight loss than controls between 14 and 21 days. Therefore, to eliminate malnutrition as a possible influence on RES phagocytosis, RES function studies were performed in animals with biliary obstruction and pair-fed, sham-operated controls. RES function was significantly depressed in obstructed animals (21 days) when compared to pair-fed, control animals. Splenectomy had a variable influence on RES activity. Although carbon clearance was not decreased in asplenic animals acutely (3 days), α of asplenic rats with biliary obstruction for 21 days was significantly depressed relative to asplenic, unobstructed controls. In addition, α in asplenic obstructed rats was significantly greater than in obstructed animals with intact spleens. Finally, mortality rate following intravenous administration of Escherichia coli endotoxin was increased in 21-day obstructed rats when compared to controls. We conclude that biliary obstruction of 21 days in the rat results in a significant depression of RES phagocytic function. RES dysfunction may result in impaired systemic bacterial clearance and is associated with decreased survival following E. coli endotoxemia.

Distal spleno-renal shunt versus endoscopic sclerotherapy in the prevention of variceal rebleeding A meta-analysis of 4 randomized clinical trials

Meta-analysis was used to evaluate 4 clinical trials comparing distal spleno-renal shunt (DSRS) with endoscopic sclerotherapy (EVS) in the prevention of variceal rebleeding: the interval between bleeding and therapy ranges from < 14 days to > 100 days. A questionnaire was sent to each author of the published trials concerning methods, definitions and results of the trials in order to obtain more detailed and up-to-date information. The selected end-points for the meta-analysis were: rebleeding, mortality and chronic encephalopathy. Analysis of the results in the questionnaires was made using the method proposed by Collins. The pooled relative risk (i.e. the combined Odds ratio of each trial as an estimate of overall efficacy) of rebleeding was statistically reduced by DSRS (0.16; 95% confidence interval 0.10-0.27). Despite this, the overall risk of death following DSRS was only marginally decreased (0.78; 95% confidence interval 0.47-1.29); the lack of homogeneity in the results does not permit any significant conclusions on this end-point. However, in non-alcoholic patients, the decrease in risk of death was greater, and this without heterogeneity, following DSRS than EVS (0.59; 95% confidence interval 0.23-1.50). The overall risk of chronic encephalopathy was slightly increased after DSRS (1.86; 95% confidence interval 0.90-3.86). In conclusion, DSRS significantly reduced the risk of rebleeding compared to EVS without increasing the risk of chronic hepatic encephalopathy. However, DSRS did not significantly affect the overall death risk. Only in non-alcoholic disease did it seem to show an advantage over EVS.

Splenic Vein Thrombosis and Gastrointestinal Bleeding in Chronic Pancreatitis

The most common cause of isolated thrombosis of the splenic vein is chronic pancreatitis caused by perivenous inflammation. Although splenic vein thrombosis (SVT) has been reported in up to 45% of patients with chronic pancreatitis, most patients with SVT remain asymptomatic. In those patients with gastrointestinal bleeding secondary to esophageal or gastric varices, the diagnostic test of choice to assess for the presence of SVT is late-phase celiac angiography. Splenectomy effectively eliminates the collateral outflow and is the treatment of choice. Other underlying pathology, such as pseudocysts, can be treated at the same time.

Shunt surgery versus endoscopic sclerotherapy for variceal hemorrhage: Late results of a randomized trial

Between September 1982 and April 1988, 60 cirrhotic patients with prior variceal hemorrhage were randomized to undergo the placement of an elective shunt (distal splenorenal: 26; nonselective: 4) or long-term endoscopic sclerotherapy (n = 30). Eighty-six percent of patients had alcoholic cirrhosis, and 33% were classified as Childs class C. After a mean follow-up of 87 months, 60% of patients undergoing sclerotherapy and 17% of shunt patients experienced rebleeding (p < 0.001). Shunt patients have survived longer than those who had sclerotherapy (6-year survival rates of 53% and 26%, respectively; p < 0.05). In part because of the wide geographic distribution of patients, only 4 of 13 patients in whom sclerotherapy failed (31%) could undergo salvage by shunt surgery. Although hepatic portal perfusion was better maintained after sclerotherapy, there were no major differences between the groups in terms of post-therapy hepatic or psychoneurologic function. In a predominantly alcoholic cirrhotic patient population (half non-urban), the results of elective shunt surgery were superior to those of chronic endoscopic sclerotherapy with respect to the prevention of recurrent variceal hemorrhage and survival.