SEMINARS IN LIVER DISEASE-VOL.
I I , NO. 1, 1991
Surgical Approaches to Primary Sclerosing Cholangitis
The surgical management of primary sclerosing cholangitis (PSC) has evolved significantly in the last decade. Historically, surgical treatment of this disease was limited and results poor. Operative dilation of the sclerotic bile ducts and prolonged T-tube drainage in the past was the treatment of choice. Proctocolectomy in patients with ulcerative colitis and PSC was also advocated by many. Neither procedure is performed any longer because of ineffective results. Currently, surgical management can be divided into two categories: Procedures to relieve mechanical biliary obstruction by biliary-enteric bypass with or without long-term bile duct stenting, and replacement of the diseased liver by orthotopic hepatic transplantation. In this article we will review the past and present surgical management of PSC and provide our current recommendations for the treatment of this disorder.
CHOLECYSTECTOMY AND COMMON BILE DUCT DRAINAGE Much of the early experience with the surgical management of PSC preceded current techniques for imaging the biliary tree. Thus, historically, surgical exploration and operative cholangiography often led to the initial diagnosis of PSC. Patients were explored for obstructive jaundice of unknown etiology. The findings of an obliterated common bile duct often was the first suggestion of the diagnosis of PSC, with operative cholangiography providing the first delineation of ductal anatomy (Fig. I ) . Operative biopsy of the ductal wall was performed to exclude carcinoma. Once the diagnosis of PSC was entertained, gentle dilation of the major bile ducts was performed with a Bake's dilator. The biliary tree was irrigated free of stones, sludge, and debris. Cholecystectomy was performed, since the gallbladder is of little use as a conduit for biliary bypass in this disease. A T tube would be placed via the choledochotomy and external drainage provided. In many series external T-tube drainage was maintained for months or even years in hopes to stent the biliary tree and to provide access for cholangi-
From The Depurtmeni oJ'Surger1, The Johns Hopkins Medicul Instiiutions, Bulrimore, Murvland Reprint requests: Dr. Lillemoe, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, M D 2120.5
FIG. 1. T-tube cholangiogram of a patient with PSC. (From Thompson et a1.22Reprinted with permission.)
ography. Attempts at medical management, often with corticosteroids, were instituted, with little clinical or radiographic improvement. The small numbers of patients with PSC in most early surgical series, as well as the variable course with remissions and exacertations, make the results of operative dilation and T-tube drainage difficult to interpret. Long-term follow-up, however, in most cases showed progression of disease with the development of liver failure similar to patients not undergoing surgery. Often, operative manipulation and external drainage added the element of biliary infection to the previously sterile biliary system with subsequent bacterial cholangitis or liver abscesses (Fig. 2). The results of Pitt and colleagues5 were typical of the early surgical experience. These authors reported on five patients treated with choledochotomy, dilation, and T-tube drainage, with success obtained in only two patients. Two patients died following surgery of progressive disease and one other surviving patient had a poor functional result with persistent jaundice and episodes of sepsis. Similarly, Thompson and coworkers' reported
Copyright O 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
49
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KEITH D. LILLEMOE, M.D., and JOHN L. CAMERON, M.D.
FIG. 2. T-tube cholangiogra"' fro"' a patient with PSC who had been taking steroids. Note the multiple hepatic abscesses, (From Thompson et a1,22Reprinted with permission,)
that six of nine patients treated with T-tube drainage and steroids died of progressive disease, resulting in secondary biliary cirrhosis and liver failure. Finally, in the largest early series Warren and colleagues' in 1966 reported the surgical management of 42 patients with PSC. Common duct exploration with T-tube drainage was the most commonly performed procedure in this series. There were four operative deaths. Poor results, often despite multiple surgical procedures, were reported in 25 of the patients with mean follow-up of less than 5 years. Frequent late complications included biliary cirrhosis and portal hypertension, with 12 deaths noted in this short period of follow-up. These overall poor results led many authors in the 1970s and early 1980s to conclude that there was little role for surgery in the management of PSC.
PROCTOCOLECTOMY FOR CHRONIC ULCERATIVE COLITIS AND PSC The overall poor results with surgical procedures directed at the biliary tree led clinicians to look elsewhere in hopes of providing a surgical cure for PSC. The frequent association of ulcerative colitis and PSC suggested an etiologic role and thus a potential role for surgery directed at the colonic disease. Theories suggested that ulcerative colitis resulted in low-grade chronic portal bacteremia or portal transport of toxic bile acids absorbed from the colon, resulting in portal triaditis. Theoretically, colectomy would interrupt this process and there-
1 I , NUMBER 1 , 1991
fore improve or stabilize the liver and biliary disease. Although, a number of small series have suggested a potential favorable effect of proctocolectomy for chronic ulcerative colitis in ~ a t i e n t swith PSC or other chronic liver diseases, many of these studies were limited by inadequate documentation of the extent of PSC as well as small numbers of patients.'-' The question of the role of proctocolectomy has probably bken laid to rest by a recent report by Cangemi and colleagues9 from the Mayo Clinic. In this report, 45 patients with both PSC and chronic ulcerative colitis were reviewed. Twenty patients had undergone proctocolectomy, whereas 25 had not. The two groups were similar with regard to clinical, biochemical, cholangiographic, and hepatic histologic findings. All of the patients were followed for a minimum of 1 year and the overall duration of follow-up was similar in both groups. Clinically, new onset of hepatomegaly, splenomegaly, esophageal varices, and ascites did not differ in patients with or without proctocolectomy. Biochemically, the serial changes in bilirubin, alkaline phosphatase, liver transaminases, prothrombin time, and albumin were also similar. Histologic progression on liver biopsy also did not differ between the two groups, nor did changes in serial cholangiograms. Finally, proctocolectomy had no effect on overall survival. The authors concluded from this retrospective, nonrandomized study that proctocolectomy for chronic ulcerative colitis has no beneficial effect on the subsequent course of PSC. It is the recommendations of theseauthors that proctocolectomy be performed only in patients with conventional indications such as medical intractability or severe bleeding. Moreover, the need for colectomy should not be influenced by the presence of PSC, prior biliary surgery, or even hepatic transplantation.
BlLlARY ENTERIC DRAINAGE The poor results observed in the early surgical management of PSC led some surgeons to institute a more aggressive approach at biliary decompression. In the late 1960s and early 1970s, reports of biliary-enteric bypass in the management of PSC appeared. IN 1966, Warren and colleagues2 at the Lahey Clinic reported managing 7 of 42 patients (17%) with a choledochoenteric anastomosis. In 1982, Pitt and colleagues5 at the UCLA Medical Center reported that 17 of 22 patients (77%) managed surgically from 1974 to 1980 had undergone a choledochoenteric anastomosis. Transhepatic stents were employed for prolonged periods (6 to 18 months) in six of the patients. Of the 17 patients undergoing choledochoenteric bypass, 13 (77%) had an excellent or good result following surgery. In addition, 18 of the entire group of 22 patients (82%) were still alive, a mean of 52.2 months after operation, and 64.7 months following establishment of the diagnosis. These results were thought to represent a significant improvement in the traditional surgical management and, although uncontrolled, suggested an improvement in long-term survival. This aggressive approach has been further extended at the Johns Hopkins Hospital. At this institution, an an-
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TABLE 1. Cholangiographic Findings in 36 Patients with Primary Sclerosing Cholangitis* Nurnher o f ' P ~ r i r r ~ t s Involved areas Extrahepatic ducts Hepatic duct bifurcation lntrahepatic ducts Areas of most severe involvement Extrahepatic ducts Hepatic duct bifurcation lntrahepatic ducts Bifurcation and extrahepatic ducts Bifurcation and intrahepatic ducts Bifurcation and extra- and intrahepatic ducts Extrahepatic ducts and intrahepatic ducts *From Cameron JL et al."' Reprinted with permission.
atomic study of the distribution of the bile duct strictures suggested a directed surgical approach at the hepatic duct bifurcation might be warranted (Table I)."' Despite the finding of diffuse disease throughout the biliary tree, the hepatic duct bifurcation was involved in 33 of 36 patients studied and represented the area of most severe involvement in 24 of these patients (Fig. 3). The finding of hepatic duct bifurcation involvement with PSC occurred regardless of whether or not ulcerative colitis was present. Currently therefore we advocate a direct surgical approach with resection of the hepatic duct bifurcation and dilation of the right and left intrahepatic ducts with prolonged transhepatic stenting for patients with this characteristic cholangiographic pattern. An additional advantage of this technique is the resection of the hepatic duct bifurcation that addresses the possibility of cholangiocarcinoma. Cholangiocarcinoma can occur as an isolated
FIG. 3. Percutaneous transhepatic cholangiogram of a patient with sclerosing cholangitis and with persistent jaundice, with the most severe disease being at the hepatic duct bifurcation. Note that the T tube, inserted at another institution, has been displaced. (From Cameron et aI.l3 Reprinted with permission.)
hepatic duct stricture, most commonly at the bifurcation, or be seen in association with PSC. Aggressive resection of such tumors with the addition of postoperative radiation therapy can result in significant long-term survival. I ' An extensive review of the management of such "Klatskin" tumors may be found in the May 1990 issue of Seminars in Liver Diseuses.
Current Operative Approach Our operative technique has been modified in recent years. In the initial report, the right and left hepatic ducts were carefully and tediously dilated with the use of Bake's dilators (Fig. 4)." After dilation, a Bake's dilator is gently passed through the liver capsule and a transhepatic stent is sutured to the dilator and the stent pulled into position. In recent years, we have taken advantage of the skill and expertise of our biliary radiographers in the preoperative placement of percutaneous biliary stents in both the right and left hepatic ductal systems. Despite the technical difficulty in nondilated systems in PSC, stents were successfully placed preoperatively in 14 of our last 16 patients, with bilateral catheters in 9 of the 14 (Fig. 5).13These stents are then used intraoperatively to guide the placement of larger permanent stents. The operative technique first involves dissection of the common bile duct. The preoperatively placed stents are often very useful for identification and mobilization of the obliterated common bile duct. After mobilization, the common bile duct is divided and the distal end is oversewn. The transected bile duct is then mobilized to a point just above the hepatic bifurcation in both the right and left systems. The bile duct, including the bifurcation, is resected at this point and submitted for pathologic examination (Fig. 6A). A radiologic guidewire is then placed through the preoperatively placed transhepatic catheters. A 12 F Coude catheter, with its smallest diameter pointed toward the hepatic hilum, is then
FIG. 4. Hepatic ducts are carefully dilated with Bake's dilators prior to insertion of Silastic transhepatic stents. (From Cameron et a1.12 Reprinted with permission.)
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1 I , NUMBER 1, 1991
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SEMINARS IN LIVER DISEASE-VOLUME
FIG. 5. A patient with sclerosing cholangitis, persistent jaundice, and severe bifurcation involvement. Ring catheters have been inserted percutaneously before operation, to serve as technical aids at the time of surgery. (From Cameron JL, et aI.l3 Reprinted with permission.)
passed over the guidewire and sutured to the transhepatic catheter (Fig. 6B). The CoudC catheter is then pulled upward through the preexisting catheter tract into the hepatic parenchyma by withdrawing the preoperatively placed biliary catheter upward through the liver. A 14 F Coude catheter is then sutured to the 12 F catheter and used to further dilate the biliary tree. This is followed by pulling up a 16 F CoudC catheter, and then finally a 18 F Silastic transhepatic biliary stent. These maneuvers are performed over a guidewire, so that if a catheter breaks or becomes unsutured, the tract is not lost. The progressive catheter dilation has made what in the past has been a relatively unsafe and uncertain dilation into a safe and certain way to ensure dilation of the intrahepatic ducts. After stent placement, a Roux-en-Y jejunal loop is prepared for biliary-enteric anastomosis. The use of the defunctionalized Roux-en-Y limb minimizes the risk of anastomotic leak and prevents reflux of intestinal contents into the biliary tree. The Roux-en-Y limb should be at least 60 cm in length with its closed end brought up to the hepatic hilum in a tension-free retrocolic position. Anastomosis is then performed as an end-to-side bilateral hepaticojejunostomy (Fig. 6C). The anastomoses should be performed as individual right and left hepaticojejunostomies. The Silastic stents are 70 cm in length and come in 12 to 22 F sizes. The small sizes are often needed in cases of PSC because of the small fibrotic intrahepatic biliary radicals. Multiple side holes are present along 40% of the length of the stent. These side holes are left inside the intrahepatic biliary tree and a portion of the Roux-en-Y jejunal loop used for the biliary anastomosis. The end of the stent without the side holes exits through the top of the liver and is brought out directly through a stab wound in the upper abdomen. The stent is fixed to
FIG. 6. A: Illustration of resection of hepatic duct bifurcation. The gallbladder has been removed and the common duct has been divided distally and oversewn. The right hepatic duct has been divided after the extrahepatic ducts were dissected from the portal vein. Note the bilateral percutaneous transhepatic stents. B: Preoperatively placed transhepatic catheters are used to facilitate passage of Silastic transhepatic stents into left and right hepatic ducts. C: Individual right and left hepaticojejunostomies are performed around the Silastic transhepatic tubes. (From Cameron et al.I3 Reprinted with permission.)
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CAMERON
FIG. 7. Postoperative cholangiogram after bifurcation reconstruction demonstrating the biliary drainage achievable with this procedure. (From Cameron et aI.l3 Reprinted with permission.)
the skin with wire sutures and is attached initially to a bile bag for dependent drainage. Postoperatively, the stents are left to external drainage for 5 to 7 days, at which time postoperative cholangiography is performed. If no evidence of a leak is apparent on the postoperative cholangiogram, external drainage can be discontinued and operatively placed drains can be removed. We have left these stents in permanently to prevent restricturing of the major intrahepatic ducts (Fig. 7). The stents are changed over guidewires on an outpatient basis every 3 months.
Recent Surgical Results in PSC In the most recent report from Johns Hopkins 31 patients with PSC were managed surgically from 1980 to 1986." The majority of these patients had undergone
prior biliary tract surgery at another institution. In this series, the indications for surgery were persistent jaundice in 29 patients, jaundice plus cholangitis in 11, and recurrent cholangitis in 2. Five of the 31 patients had cirrhosis at the time of surgery, and 26 patients had variable degrees of fibrosis. The presence of cirrhosis influenced both short- and long-term outcome. Two of the five cirrhotic patients died following surgery. Only one survived for 5 years. In comparison, 25 of the 26 noncirrhotic patients survived surgery, (operative mortality, 3.9%) and actuarial 5-year survival of this group was 77%. Long-term follow-up of these 26 patients, plus an additional five noncirrhotic patients operated on more recently, indicates excellent long-term survival (Fig. 8). If the prognostic factors of Wiesner et all4 are applied to these patients, the predicted 5-year survival would be approximately 20% (compared with the observed survival in these patients of 77% at 5 years). Four of the surviving patients have, however, undergone successful liver transplantation. Another surgical approach to patients with PSC has been introduced by Hutson and colleagues'"'lh at the University of Miami. This technique creates a choledochojejunostomy or hepaticojejunostomy as well as a choledochojejunocutaneous fistula through which repeated balloon dilations may be carried out. This approach avoids the necessity of long-term transhepatic stents. In the most recent report of this group, a total of 65 dilations have been performed in 16 patients." However, a mean duration of follow-up was only 17 months (1 to 3 l), and four patients with advanced cirrhosis have died, two postoperatively and two late deaths. These authors have concluded that patients with advanced cirrhosis are not candidates for this procedure and should be considered for hepatic transplantation. A variant of this technique, which may also serve as a useful adjunct to surgical management, has recently been reported by Maroney and Ring." In this report, seven patients with PSC have undergone percutaneous jejunal catheterization and successful dilation of surgically constructed Roux-en-Y biliary-jejunal anastomosis. In this report, the patients have not undergone the creation of a choledochojejunocutaneous fistula. Thus, it appears that strictures developing in patients having undergone a previous biliary enteric anastomosis may be amenable to direct percutaneous dilation via the Rouxen-Y loop in hopes of improving long-term results.
HEPATIC TRANSPLANTATION Survival 4 0
i
01 0
I
I
1
2
I
I
I
3 4 5 Years of Survival
I
I
I
6
7
6
FIG. 8. Actuarial survival among 31 noncirrhotic patients with PSC undergoing bypass surgery with long-term transhepatic stenting at Johns Hopkins. (From Cameron et aI.l3 Reprinted with permission.)
As experience and availability of liver transplantation have increased during the last decade, many patients with PSC have become candidates. In general, most transplant centers consider transplantation for advanced cases of PSC in which any number of the following indications exist: (1) significant esophageal varices with hypersplenism; (2) persistent bilirubin more than 10 mg/ dl; (3) history of variceal bleeding even with normal liver synthetic function; (4) history of spontaneous bacterial peritonitis; (5) history of repeated bouts of cholangitis;
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SURGICAL APPROACHES TO PSC-LILLEMOE.
SEMINARS IN LIVER DISEASE-VOLUME
and ( 6 ) loss of synthetic liver function. In many cases PSC spares synthetic function in the liver until late in the course of the disease. Thus, some patients may present with severe portal hypertension and reasonable liver function. These patients may be candidates for elective portal decompression, thus delaying the need for liver transplantation. Portal-systemic shunting, of course, has no effect on the disease process and may perhaps increase the risk of subsequent liver transplantation by increasing the risk of portal vein thrombosis. The initial results of hepatic transplantation for PSC were not encouraging. In a 1984 review by Scharschmidt,I8 the 2-year survival among 19 patients was 20%. In this analysis the 3-year survival was only 14% in seven patients undergoing transplantation before 1980 and increased to 25% in 12 patients transplanted in the cyclosporinelsteroid immunosuppressive era. These poor results may be explained, in part, because many of these patients had been subjected to multiple previous operations to treat biliary obstruction and because referral for transplantation was often delayed until patients were moribund from hepatic failure. More recently, however, reports of hepatic transplantation for PSC have been more encouraging. '"-?' In the largest series, which comes from the University of Pittsburgh, PSC was the third most common indication for liver transplantation among adults, following posthepatic cirrhosis and primary biliary cirrhosis." Fifty-five of 604 orthotopic liver transplants (9.1%) were performed for end-stage PSC. Seventeen of these 55 patients had undergone previous unsuccessful internal biliary drainage operations, and eight others had T-tube or percutaneous transhepatic catheter drainage before transplantation. Actuarial 1- and 3-year survival rates were 71 and 57%, respectively. Eleven patients (20%) died within 3 months of transplantation, all of direct complications of transplantation or the associated immunosuppression. Previously unrecognized cholangiocarcinoma was found in the surgical specimen of 5 of 55 patients. Two of these patients died as a result of recurrent cholangiocarcinoma 4 and 12 months after transplantation. The three patients who are alive were all within 1 year of transplantation at the time of the report. All had received adjuvant chemotherapy and radiotherapy, with one patient already having recurrent disease. Two important questions in those patients with PSC undergoing liver transplantation are: (1) whether those with ulcerative colitis are at increased risk for developing colonic malignancy after immunosuppression, and (2) whether sclerosing cholangitis will develop in the transplanted livers. In an analysis from Pittsburgh, only 9 of 26 patients with inflammatory bowel disease developed reactivation or exacerbation of bowel disease after transp l a n t a t i ~ n . ~In ' addition, no colorectal malignancies have been discovered after the observation period of 3 months to 4 years. The answer is less clear concerning the recurrence of PSC after liver transplantation. In the Pittsburgh experience, only one patient developed radiologic abnormalities consistent with PSC 1 year after transplantat i ~ n . Three ~' other patients, however, whose primary disease was not PSC, have also developed the same ab-
11, NUMBER 1 , 1991
normalities after histologically proven graft rejection. These authors thus concluded that rejection may be the cause of biliary sclerosis after transplantation. In contrast, in a recent report from the Mayo Clinic, intrahepatic bile duct strictures and beading compatible with PSC were seen in 5 of 39 patients undergoing liver transplantation for end-stage PSC.20 No cholangiographic changes suggestive of PSC were noted in 36 liver transplants performed for primary biliary cirrhosis.
PREFERRED SURGICAL APPROACH The approach to the management of individual patients with PSC is based on their symptoms, cholangiographic pattern, and the degree of hepatic fibrosis or cirrhosis. In the absence of prospective controlled trials supporting specific drug therapy, we recommend only surveillance of asymptomatic, nonjaundiced patients regardless of their cholangiographic pattern. Patients presenting with symptoms or jaundice need more aggressive therapy. In general, we have considered that a persistent elevation of bilirubin greater than 5 mgldl for more than 3 months is an indication for surgery. In those patients under consideration for surgery, two important pieces of information must be obtained to determine appropriate management. First, liver biopsy should be obtained to determine the degree of fibrosis or cirrhosis on liver histologic findings. It is our recommendation that the patients with established cirrhosis should be considered for liver transplantation regardless of their cholangiographic pattern. If the liver biopsy does not show cirrhosis, the cholangiographic pattern should be carefully interpreted. If a dominant stricture exists at the hepatic bifurcation, we would advocate resection of the hepatic duct bifurcation, dilation of the intrahepatic biliary tree, and the placement of transhepatic biliary stents. It is our belief that this policy does not preclude, but may very well postpone or avoid, the need for liver transplantation.
REFERENCES Glenn F, Whitsell JC: Primary sclerosing cholangitis. Surg Gynecol Obstet 123: 1037-1046, 1966. 2. Warren KW, Athanassiades S, Monge JI: Primary sclerosing cholangitis. A study of forty-two cases. Am J Surg 1 1 1:2338, 1966. 3. Thompson BW, Read RC, White HJ: Sclerosing cholangitis. Arch Surg 104:460464, 1972. 4. Chapman RWG, Marborgh BA, Rhodes JM, et al: Primary sclerosing cholangitis. A review of its clinical features, cholangiography and hepatic histology. Gut 21:870-877, 1980. 5 . Pitt HA, Thompson HH, Tomkins RK, et al: Primary sclerosing cholangitis: Results of an aggressive surgical approach. Ann Surg 196:259-268, 1982. 6. Eade MN, Cooke WT, Brooke BN. Liver disease in ulcerative colitis. 11. The long-term effect of colectomy. Ann Intern Med 72:489-497, 1970. 7. Cooperman AM, Judd ES: The role of colectomy in hepatic disease accompanying ulcerative and granulomatous colitis: Current status of a continuing problem. Mayo Clin Proc 47:36-38, 1972. I.
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Olsson R, Hulten L: Concurrence of ulcerative colitis and chronic active hepatitis: Clinical courses and results of colectomy. Scand J Gastroenterol 10:331-335, 1975. Cangemi RJ, Wiesner RH, Beaver SJ, et al: Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis. Gastroenterology 966:790794, 1989. Cameron JL, Gayler BW, Sanfey H, et al: Sclerosing cholangitis. Anatomical distribution of obstructive lesions. Ann Surg 20054-60, 1984. Cameron JL, Pitt HA, Zinner MJ, et al: Management of proximal cholangiocarcinomas by surgical resection and radiotherapy. Am J Surg 159:91-98, 1990. Cameron JL, Gayler BW, Herlong HF, et al: Sclerosing cholangitis: Biliary reconstruction with Silastic transhepatic stents. Surgery 94:324-330, 1983. Cameron JL, Pitt HA, Zinner MJ, et al: Resection of hepatic duct bifurcation and transhepatic stenting for sclerosing cholangitis. Ann Surg 207:614-622, 1988. Wiesner RH, Grambsch PM, Dickson ER, et al: Primary sclerosing cholangitis: Natural history, prognostic factors and survival analysis. Hepatology 10:430-436, 1989. Hutson DG, Russell E, Schiff E, et al: Balloon dilatation of
16.
17.
18.
19.
20. 21.
22.
biliary strictures through a choledochojejuno-cutaneous fistula. Ann Surg 199-637-647, 1984. Hutson D, Russell E, Jeffers L, et al: Balloon dilatation of biliary strictures in primary sclerosing cholangitis through a choledochojejuno-cutaneous fistula: A new therapeutic approach. (Abstr.) Gastroenterology 90: 1470, 1986. Maroney TP, Ring EJ: Percutaneous transjejunal catheterization of Roux-en-Y biliary jejunal anastomoses. Radiology 164:151-153, 1987. Scharschmidt BF: Human liver transplantation: Analysis of data on 540 patients from four centers. Hepatology 4:95S101s. 1984. Busuttil RW, Memsic LD, Quinones-Baldrich W, et al: Liver transplantation at UCLA: Program development, organization, initiation, and early results. Am J Surg 152:75-80, 1986. Krom RAF: Liver transplantation at the Mayo Clinic. Mayo Clin Proc 61:278-282, 1986. Marsh JW, lwatsuki S, Makoka L, et al: Orthotopic liver transplantation for primary sclerosing cholangitis. Ann Surg 207:21-25, 1988. Pitt HA, Thompson HH, Longmire WP Jr: Primary sclerosing cholangitis: A heterogeneous disease. Ann Surg 196:127-136, 1982.
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SURGICAL APPROACHES TO PSC-LILLEMOE.
I I , NO. 1, 1991
Surgical Approaches to Primary Sclerosing Cholangitis
The surgical management of primary sclerosing cholangitis (PSC) has evolved significantly in the last decade. Historically, surgical treatment of this disease was limited and results poor. Operative dilation of the sclerotic bile ducts and prolonged T-tube drainage in the past was the treatment of choice. Proctocolectomy in patients with ulcerative colitis and PSC was also advocated by many. Neither procedure is performed any longer because of ineffective results. Currently, surgical management can be divided into two categories: Procedures to relieve mechanical biliary obstruction by biliary-enteric bypass with or without long-term bile duct stenting, and replacement of the diseased liver by orthotopic hepatic transplantation. In this article we will review the past and present surgical management of PSC and provide our current recommendations for the treatment of this disorder.
CHOLECYSTECTOMY AND COMMON BILE DUCT DRAINAGE Much of the early experience with the surgical management of PSC preceded current techniques for imaging the biliary tree. Thus, historically, surgical exploration and operative cholangiography often led to the initial diagnosis of PSC. Patients were explored for obstructive jaundice of unknown etiology. The findings of an obliterated common bile duct often was the first suggestion of the diagnosis of PSC, with operative cholangiography providing the first delineation of ductal anatomy (Fig. I ) . Operative biopsy of the ductal wall was performed to exclude carcinoma. Once the diagnosis of PSC was entertained, gentle dilation of the major bile ducts was performed with a Bake's dilator. The biliary tree was irrigated free of stones, sludge, and debris. Cholecystectomy was performed, since the gallbladder is of little use as a conduit for biliary bypass in this disease. A T tube would be placed via the choledochotomy and external drainage provided. In many series external T-tube drainage was maintained for months or even years in hopes to stent the biliary tree and to provide access for cholangi-
From The Depurtmeni oJ'Surger1, The Johns Hopkins Medicul Instiiutions, Bulrimore, Murvland Reprint requests: Dr. Lillemoe, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, M D 2120.5
FIG. 1. T-tube cholangiogram of a patient with PSC. (From Thompson et a1.22Reprinted with permission.)
ography. Attempts at medical management, often with corticosteroids, were instituted, with little clinical or radiographic improvement. The small numbers of patients with PSC in most early surgical series, as well as the variable course with remissions and exacertations, make the results of operative dilation and T-tube drainage difficult to interpret. Long-term follow-up, however, in most cases showed progression of disease with the development of liver failure similar to patients not undergoing surgery. Often, operative manipulation and external drainage added the element of biliary infection to the previously sterile biliary system with subsequent bacterial cholangitis or liver abscesses (Fig. 2). The results of Pitt and colleagues5 were typical of the early surgical experience. These authors reported on five patients treated with choledochotomy, dilation, and T-tube drainage, with success obtained in only two patients. Two patients died following surgery of progressive disease and one other surviving patient had a poor functional result with persistent jaundice and episodes of sepsis. Similarly, Thompson and coworkers' reported
Copyright O 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.
49
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KEITH D. LILLEMOE, M.D., and JOHN L. CAMERON, M.D.
FIG. 2. T-tube cholangiogra"' fro"' a patient with PSC who had been taking steroids. Note the multiple hepatic abscesses, (From Thompson et a1,22Reprinted with permission,)
that six of nine patients treated with T-tube drainage and steroids died of progressive disease, resulting in secondary biliary cirrhosis and liver failure. Finally, in the largest early series Warren and colleagues' in 1966 reported the surgical management of 42 patients with PSC. Common duct exploration with T-tube drainage was the most commonly performed procedure in this series. There were four operative deaths. Poor results, often despite multiple surgical procedures, were reported in 25 of the patients with mean follow-up of less than 5 years. Frequent late complications included biliary cirrhosis and portal hypertension, with 12 deaths noted in this short period of follow-up. These overall poor results led many authors in the 1970s and early 1980s to conclude that there was little role for surgery in the management of PSC.
PROCTOCOLECTOMY FOR CHRONIC ULCERATIVE COLITIS AND PSC The overall poor results with surgical procedures directed at the biliary tree led clinicians to look elsewhere in hopes of providing a surgical cure for PSC. The frequent association of ulcerative colitis and PSC suggested an etiologic role and thus a potential role for surgery directed at the colonic disease. Theories suggested that ulcerative colitis resulted in low-grade chronic portal bacteremia or portal transport of toxic bile acids absorbed from the colon, resulting in portal triaditis. Theoretically, colectomy would interrupt this process and there-
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fore improve or stabilize the liver and biliary disease. Although, a number of small series have suggested a potential favorable effect of proctocolectomy for chronic ulcerative colitis in ~ a t i e n t swith PSC or other chronic liver diseases, many of these studies were limited by inadequate documentation of the extent of PSC as well as small numbers of patients.'-' The question of the role of proctocolectomy has probably bken laid to rest by a recent report by Cangemi and colleagues9 from the Mayo Clinic. In this report, 45 patients with both PSC and chronic ulcerative colitis were reviewed. Twenty patients had undergone proctocolectomy, whereas 25 had not. The two groups were similar with regard to clinical, biochemical, cholangiographic, and hepatic histologic findings. All of the patients were followed for a minimum of 1 year and the overall duration of follow-up was similar in both groups. Clinically, new onset of hepatomegaly, splenomegaly, esophageal varices, and ascites did not differ in patients with or without proctocolectomy. Biochemically, the serial changes in bilirubin, alkaline phosphatase, liver transaminases, prothrombin time, and albumin were also similar. Histologic progression on liver biopsy also did not differ between the two groups, nor did changes in serial cholangiograms. Finally, proctocolectomy had no effect on overall survival. The authors concluded from this retrospective, nonrandomized study that proctocolectomy for chronic ulcerative colitis has no beneficial effect on the subsequent course of PSC. It is the recommendations of theseauthors that proctocolectomy be performed only in patients with conventional indications such as medical intractability or severe bleeding. Moreover, the need for colectomy should not be influenced by the presence of PSC, prior biliary surgery, or even hepatic transplantation.
BlLlARY ENTERIC DRAINAGE The poor results observed in the early surgical management of PSC led some surgeons to institute a more aggressive approach at biliary decompression. In the late 1960s and early 1970s, reports of biliary-enteric bypass in the management of PSC appeared. IN 1966, Warren and colleagues2 at the Lahey Clinic reported managing 7 of 42 patients (17%) with a choledochoenteric anastomosis. In 1982, Pitt and colleagues5 at the UCLA Medical Center reported that 17 of 22 patients (77%) managed surgically from 1974 to 1980 had undergone a choledochoenteric anastomosis. Transhepatic stents were employed for prolonged periods (6 to 18 months) in six of the patients. Of the 17 patients undergoing choledochoenteric bypass, 13 (77%) had an excellent or good result following surgery. In addition, 18 of the entire group of 22 patients (82%) were still alive, a mean of 52.2 months after operation, and 64.7 months following establishment of the diagnosis. These results were thought to represent a significant improvement in the traditional surgical management and, although uncontrolled, suggested an improvement in long-term survival. This aggressive approach has been further extended at the Johns Hopkins Hospital. At this institution, an an-
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TABLE 1. Cholangiographic Findings in 36 Patients with Primary Sclerosing Cholangitis* Nurnher o f ' P ~ r i r r ~ t s Involved areas Extrahepatic ducts Hepatic duct bifurcation lntrahepatic ducts Areas of most severe involvement Extrahepatic ducts Hepatic duct bifurcation lntrahepatic ducts Bifurcation and extrahepatic ducts Bifurcation and intrahepatic ducts Bifurcation and extra- and intrahepatic ducts Extrahepatic ducts and intrahepatic ducts *From Cameron JL et al."' Reprinted with permission.
atomic study of the distribution of the bile duct strictures suggested a directed surgical approach at the hepatic duct bifurcation might be warranted (Table I)."' Despite the finding of diffuse disease throughout the biliary tree, the hepatic duct bifurcation was involved in 33 of 36 patients studied and represented the area of most severe involvement in 24 of these patients (Fig. 3). The finding of hepatic duct bifurcation involvement with PSC occurred regardless of whether or not ulcerative colitis was present. Currently therefore we advocate a direct surgical approach with resection of the hepatic duct bifurcation and dilation of the right and left intrahepatic ducts with prolonged transhepatic stenting for patients with this characteristic cholangiographic pattern. An additional advantage of this technique is the resection of the hepatic duct bifurcation that addresses the possibility of cholangiocarcinoma. Cholangiocarcinoma can occur as an isolated
FIG. 3. Percutaneous transhepatic cholangiogram of a patient with sclerosing cholangitis and with persistent jaundice, with the most severe disease being at the hepatic duct bifurcation. Note that the T tube, inserted at another institution, has been displaced. (From Cameron et aI.l3 Reprinted with permission.)
hepatic duct stricture, most commonly at the bifurcation, or be seen in association with PSC. Aggressive resection of such tumors with the addition of postoperative radiation therapy can result in significant long-term survival. I ' An extensive review of the management of such "Klatskin" tumors may be found in the May 1990 issue of Seminars in Liver Diseuses.
Current Operative Approach Our operative technique has been modified in recent years. In the initial report, the right and left hepatic ducts were carefully and tediously dilated with the use of Bake's dilators (Fig. 4)." After dilation, a Bake's dilator is gently passed through the liver capsule and a transhepatic stent is sutured to the dilator and the stent pulled into position. In recent years, we have taken advantage of the skill and expertise of our biliary radiographers in the preoperative placement of percutaneous biliary stents in both the right and left hepatic ductal systems. Despite the technical difficulty in nondilated systems in PSC, stents were successfully placed preoperatively in 14 of our last 16 patients, with bilateral catheters in 9 of the 14 (Fig. 5).13These stents are then used intraoperatively to guide the placement of larger permanent stents. The operative technique first involves dissection of the common bile duct. The preoperatively placed stents are often very useful for identification and mobilization of the obliterated common bile duct. After mobilization, the common bile duct is divided and the distal end is oversewn. The transected bile duct is then mobilized to a point just above the hepatic bifurcation in both the right and left systems. The bile duct, including the bifurcation, is resected at this point and submitted for pathologic examination (Fig. 6A). A radiologic guidewire is then placed through the preoperatively placed transhepatic catheters. A 12 F Coude catheter, with its smallest diameter pointed toward the hepatic hilum, is then
FIG. 4. Hepatic ducts are carefully dilated with Bake's dilators prior to insertion of Silastic transhepatic stents. (From Cameron et a1.12 Reprinted with permission.)
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FIG. 5. A patient with sclerosing cholangitis, persistent jaundice, and severe bifurcation involvement. Ring catheters have been inserted percutaneously before operation, to serve as technical aids at the time of surgery. (From Cameron JL, et aI.l3 Reprinted with permission.)
passed over the guidewire and sutured to the transhepatic catheter (Fig. 6B). The CoudC catheter is then pulled upward through the preexisting catheter tract into the hepatic parenchyma by withdrawing the preoperatively placed biliary catheter upward through the liver. A 14 F Coude catheter is then sutured to the 12 F catheter and used to further dilate the biliary tree. This is followed by pulling up a 16 F CoudC catheter, and then finally a 18 F Silastic transhepatic biliary stent. These maneuvers are performed over a guidewire, so that if a catheter breaks or becomes unsutured, the tract is not lost. The progressive catheter dilation has made what in the past has been a relatively unsafe and uncertain dilation into a safe and certain way to ensure dilation of the intrahepatic ducts. After stent placement, a Roux-en-Y jejunal loop is prepared for biliary-enteric anastomosis. The use of the defunctionalized Roux-en-Y limb minimizes the risk of anastomotic leak and prevents reflux of intestinal contents into the biliary tree. The Roux-en-Y limb should be at least 60 cm in length with its closed end brought up to the hepatic hilum in a tension-free retrocolic position. Anastomosis is then performed as an end-to-side bilateral hepaticojejunostomy (Fig. 6C). The anastomoses should be performed as individual right and left hepaticojejunostomies. The Silastic stents are 70 cm in length and come in 12 to 22 F sizes. The small sizes are often needed in cases of PSC because of the small fibrotic intrahepatic biliary radicals. Multiple side holes are present along 40% of the length of the stent. These side holes are left inside the intrahepatic biliary tree and a portion of the Roux-en-Y jejunal loop used for the biliary anastomosis. The end of the stent without the side holes exits through the top of the liver and is brought out directly through a stab wound in the upper abdomen. The stent is fixed to
FIG. 6. A: Illustration of resection of hepatic duct bifurcation. The gallbladder has been removed and the common duct has been divided distally and oversewn. The right hepatic duct has been divided after the extrahepatic ducts were dissected from the portal vein. Note the bilateral percutaneous transhepatic stents. B: Preoperatively placed transhepatic catheters are used to facilitate passage of Silastic transhepatic stents into left and right hepatic ducts. C: Individual right and left hepaticojejunostomies are performed around the Silastic transhepatic tubes. (From Cameron et al.I3 Reprinted with permission.)
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FIG. 7. Postoperative cholangiogram after bifurcation reconstruction demonstrating the biliary drainage achievable with this procedure. (From Cameron et aI.l3 Reprinted with permission.)
the skin with wire sutures and is attached initially to a bile bag for dependent drainage. Postoperatively, the stents are left to external drainage for 5 to 7 days, at which time postoperative cholangiography is performed. If no evidence of a leak is apparent on the postoperative cholangiogram, external drainage can be discontinued and operatively placed drains can be removed. We have left these stents in permanently to prevent restricturing of the major intrahepatic ducts (Fig. 7). The stents are changed over guidewires on an outpatient basis every 3 months.
Recent Surgical Results in PSC In the most recent report from Johns Hopkins 31 patients with PSC were managed surgically from 1980 to 1986." The majority of these patients had undergone
prior biliary tract surgery at another institution. In this series, the indications for surgery were persistent jaundice in 29 patients, jaundice plus cholangitis in 11, and recurrent cholangitis in 2. Five of the 31 patients had cirrhosis at the time of surgery, and 26 patients had variable degrees of fibrosis. The presence of cirrhosis influenced both short- and long-term outcome. Two of the five cirrhotic patients died following surgery. Only one survived for 5 years. In comparison, 25 of the 26 noncirrhotic patients survived surgery, (operative mortality, 3.9%) and actuarial 5-year survival of this group was 77%. Long-term follow-up of these 26 patients, plus an additional five noncirrhotic patients operated on more recently, indicates excellent long-term survival (Fig. 8). If the prognostic factors of Wiesner et all4 are applied to these patients, the predicted 5-year survival would be approximately 20% (compared with the observed survival in these patients of 77% at 5 years). Four of the surviving patients have, however, undergone successful liver transplantation. Another surgical approach to patients with PSC has been introduced by Hutson and colleagues'"'lh at the University of Miami. This technique creates a choledochojejunostomy or hepaticojejunostomy as well as a choledochojejunocutaneous fistula through which repeated balloon dilations may be carried out. This approach avoids the necessity of long-term transhepatic stents. In the most recent report of this group, a total of 65 dilations have been performed in 16 patients." However, a mean duration of follow-up was only 17 months (1 to 3 l), and four patients with advanced cirrhosis have died, two postoperatively and two late deaths. These authors have concluded that patients with advanced cirrhosis are not candidates for this procedure and should be considered for hepatic transplantation. A variant of this technique, which may also serve as a useful adjunct to surgical management, has recently been reported by Maroney and Ring." In this report, seven patients with PSC have undergone percutaneous jejunal catheterization and successful dilation of surgically constructed Roux-en-Y biliary-jejunal anastomosis. In this report, the patients have not undergone the creation of a choledochojejunocutaneous fistula. Thus, it appears that strictures developing in patients having undergone a previous biliary enteric anastomosis may be amenable to direct percutaneous dilation via the Rouxen-Y loop in hopes of improving long-term results.
HEPATIC TRANSPLANTATION Survival 4 0
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FIG. 8. Actuarial survival among 31 noncirrhotic patients with PSC undergoing bypass surgery with long-term transhepatic stenting at Johns Hopkins. (From Cameron et aI.l3 Reprinted with permission.)
As experience and availability of liver transplantation have increased during the last decade, many patients with PSC have become candidates. In general, most transplant centers consider transplantation for advanced cases of PSC in which any number of the following indications exist: (1) significant esophageal varices with hypersplenism; (2) persistent bilirubin more than 10 mg/ dl; (3) history of variceal bleeding even with normal liver synthetic function; (4) history of spontaneous bacterial peritonitis; (5) history of repeated bouts of cholangitis;
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and ( 6 ) loss of synthetic liver function. In many cases PSC spares synthetic function in the liver until late in the course of the disease. Thus, some patients may present with severe portal hypertension and reasonable liver function. These patients may be candidates for elective portal decompression, thus delaying the need for liver transplantation. Portal-systemic shunting, of course, has no effect on the disease process and may perhaps increase the risk of subsequent liver transplantation by increasing the risk of portal vein thrombosis. The initial results of hepatic transplantation for PSC were not encouraging. In a 1984 review by Scharschmidt,I8 the 2-year survival among 19 patients was 20%. In this analysis the 3-year survival was only 14% in seven patients undergoing transplantation before 1980 and increased to 25% in 12 patients transplanted in the cyclosporinelsteroid immunosuppressive era. These poor results may be explained, in part, because many of these patients had been subjected to multiple previous operations to treat biliary obstruction and because referral for transplantation was often delayed until patients were moribund from hepatic failure. More recently, however, reports of hepatic transplantation for PSC have been more encouraging. '"-?' In the largest series, which comes from the University of Pittsburgh, PSC was the third most common indication for liver transplantation among adults, following posthepatic cirrhosis and primary biliary cirrhosis." Fifty-five of 604 orthotopic liver transplants (9.1%) were performed for end-stage PSC. Seventeen of these 55 patients had undergone previous unsuccessful internal biliary drainage operations, and eight others had T-tube or percutaneous transhepatic catheter drainage before transplantation. Actuarial 1- and 3-year survival rates were 71 and 57%, respectively. Eleven patients (20%) died within 3 months of transplantation, all of direct complications of transplantation or the associated immunosuppression. Previously unrecognized cholangiocarcinoma was found in the surgical specimen of 5 of 55 patients. Two of these patients died as a result of recurrent cholangiocarcinoma 4 and 12 months after transplantation. The three patients who are alive were all within 1 year of transplantation at the time of the report. All had received adjuvant chemotherapy and radiotherapy, with one patient already having recurrent disease. Two important questions in those patients with PSC undergoing liver transplantation are: (1) whether those with ulcerative colitis are at increased risk for developing colonic malignancy after immunosuppression, and (2) whether sclerosing cholangitis will develop in the transplanted livers. In an analysis from Pittsburgh, only 9 of 26 patients with inflammatory bowel disease developed reactivation or exacerbation of bowel disease after transp l a n t a t i ~ n . ~In ' addition, no colorectal malignancies have been discovered after the observation period of 3 months to 4 years. The answer is less clear concerning the recurrence of PSC after liver transplantation. In the Pittsburgh experience, only one patient developed radiologic abnormalities consistent with PSC 1 year after transplantat i ~ n . Three ~' other patients, however, whose primary disease was not PSC, have also developed the same ab-
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normalities after histologically proven graft rejection. These authors thus concluded that rejection may be the cause of biliary sclerosis after transplantation. In contrast, in a recent report from the Mayo Clinic, intrahepatic bile duct strictures and beading compatible with PSC were seen in 5 of 39 patients undergoing liver transplantation for end-stage PSC.20 No cholangiographic changes suggestive of PSC were noted in 36 liver transplants performed for primary biliary cirrhosis.
PREFERRED SURGICAL APPROACH The approach to the management of individual patients with PSC is based on their symptoms, cholangiographic pattern, and the degree of hepatic fibrosis or cirrhosis. In the absence of prospective controlled trials supporting specific drug therapy, we recommend only surveillance of asymptomatic, nonjaundiced patients regardless of their cholangiographic pattern. Patients presenting with symptoms or jaundice need more aggressive therapy. In general, we have considered that a persistent elevation of bilirubin greater than 5 mgldl for more than 3 months is an indication for surgery. In those patients under consideration for surgery, two important pieces of information must be obtained to determine appropriate management. First, liver biopsy should be obtained to determine the degree of fibrosis or cirrhosis on liver histologic findings. It is our recommendation that the patients with established cirrhosis should be considered for liver transplantation regardless of their cholangiographic pattern. If the liver biopsy does not show cirrhosis, the cholangiographic pattern should be carefully interpreted. If a dominant stricture exists at the hepatic bifurcation, we would advocate resection of the hepatic duct bifurcation, dilation of the intrahepatic biliary tree, and the placement of transhepatic biliary stents. It is our belief that this policy does not preclude, but may very well postpone or avoid, the need for liver transplantation.
REFERENCES Glenn F, Whitsell JC: Primary sclerosing cholangitis. Surg Gynecol Obstet 123: 1037-1046, 1966. 2. Warren KW, Athanassiades S, Monge JI: Primary sclerosing cholangitis. A study of forty-two cases. Am J Surg 1 1 1:2338, 1966. 3. Thompson BW, Read RC, White HJ: Sclerosing cholangitis. Arch Surg 104:460464, 1972. 4. Chapman RWG, Marborgh BA, Rhodes JM, et al: Primary sclerosing cholangitis. A review of its clinical features, cholangiography and hepatic histology. Gut 21:870-877, 1980. 5 . Pitt HA, Thompson HH, Tomkins RK, et al: Primary sclerosing cholangitis: Results of an aggressive surgical approach. Ann Surg 196:259-268, 1982. 6. Eade MN, Cooke WT, Brooke BN. Liver disease in ulcerative colitis. 11. The long-term effect of colectomy. Ann Intern Med 72:489-497, 1970. 7. Cooperman AM, Judd ES: The role of colectomy in hepatic disease accompanying ulcerative and granulomatous colitis: Current status of a continuing problem. Mayo Clin Proc 47:36-38, 1972. I.
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Olsson R, Hulten L: Concurrence of ulcerative colitis and chronic active hepatitis: Clinical courses and results of colectomy. Scand J Gastroenterol 10:331-335, 1975. Cangemi RJ, Wiesner RH, Beaver SJ, et al: Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis. Gastroenterology 966:790794, 1989. Cameron JL, Gayler BW, Sanfey H, et al: Sclerosing cholangitis. Anatomical distribution of obstructive lesions. Ann Surg 20054-60, 1984. Cameron JL, Pitt HA, Zinner MJ, et al: Management of proximal cholangiocarcinomas by surgical resection and radiotherapy. Am J Surg 159:91-98, 1990. Cameron JL, Gayler BW, Herlong HF, et al: Sclerosing cholangitis: Biliary reconstruction with Silastic transhepatic stents. Surgery 94:324-330, 1983. Cameron JL, Pitt HA, Zinner MJ, et al: Resection of hepatic duct bifurcation and transhepatic stenting for sclerosing cholangitis. Ann Surg 207:614-622, 1988. Wiesner RH, Grambsch PM, Dickson ER, et al: Primary sclerosing cholangitis: Natural history, prognostic factors and survival analysis. Hepatology 10:430-436, 1989. Hutson DG, Russell E, Schiff E, et al: Balloon dilatation of
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biliary strictures through a choledochojejuno-cutaneous fistula. Ann Surg 199-637-647, 1984. Hutson D, Russell E, Jeffers L, et al: Balloon dilatation of biliary strictures in primary sclerosing cholangitis through a choledochojejuno-cutaneous fistula: A new therapeutic approach. (Abstr.) Gastroenterology 90: 1470, 1986. Maroney TP, Ring EJ: Percutaneous transjejunal catheterization of Roux-en-Y biliary jejunal anastomoses. Radiology 164:151-153, 1987. Scharschmidt BF: Human liver transplantation: Analysis of data on 540 patients from four centers. Hepatology 4:95S101s. 1984. Busuttil RW, Memsic LD, Quinones-Baldrich W, et al: Liver transplantation at UCLA: Program development, organization, initiation, and early results. Am J Surg 152:75-80, 1986. Krom RAF: Liver transplantation at the Mayo Clinic. Mayo Clin Proc 61:278-282, 1986. Marsh JW, lwatsuki S, Makoka L, et al: Orthotopic liver transplantation for primary sclerosing cholangitis. Ann Surg 207:21-25, 1988. Pitt HA, Thompson HH, Longmire WP Jr: Primary sclerosing cholangitis: A heterogeneous disease. Ann Surg 196:127-136, 1982.
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