Indications for non-transplant surgery in primary sclerosing cholangitis

Transcription

1 HPB, 2005; 7: Indications for non-transplant surgery in primary sclerosing cholangitis BASTIAN DOMAJNKO & STEVEN A. AHRENDT Department of Surgery, University of Rochester Medical School, Rochester, NY 14642, USA Abstract Primary sclerosing cholangitis (PCS) is a progressive disease leading to secondary biliary cirrhosis. Patients are at increased risk of developing cholangiocarcinoma, which is usually diagnosed at an advanced stage. Treatment of PCS includes medical therapy, endoscopic biliary dilation, percutaneous transhepatic stenting, extrahepatic biliary resection and liver transplantation. The most effective management of primary sclerosing cholangitis before the onset of cirrhosis remains unclear. Non-transplant surgical procedures have a limited but defined role in patients with PCS. Resection of the extrahepatic biliary tree in symptomatic non-cirrhotic patients improves hyperbilirubinaemia and prolongs both transplantfree and overall survival when compared with non-operative dilation and/or stenting. Surgical resection may also definitively establish or exclude a diagnosis of cholangiocarcinoma in patients with dominant extrahepatic or perihilar strictures. Extrahepatic bile duct resection may also reduce the risk of cholangiocarcinoma. Extrahepatic biliary resection should be considered in selected non-cirrhotic patients with symptomatic biliary obstruction and dominant extrahepatic and/or perihilar strictures. Those patients in whom cholangiocarcinoma is suspected should also undergo resection. Key Words: Primary sclerosing cholangitis, cholangiocarcinoma, extrahepatic biliary resection, endoscopic dilation Introduction Primary sclerosing cholangitis (PSC) is a progressive chronic inflammatory disease of the intra- and extrahepatic biliary tree resulting in multifocal biliary strictures, chronic cholestasis and eventual cirrhosis. PSC is most commonly associated with inflammatory bowel disease, and it may be diagnosed in up to 8% of patients with ulcerative colitis. Patients are at increased risk for developing cholangiocarcinoma, with a reported lifetime prevalence of 10 30% [1]. These cholangiocarcinomas are usually diagnosed at an advanced stage, and the likelihood that they will be resectable is quite low. The natural history of patients with PSC is variable; many patients remain asymptomatic for years, yet others will rapidly develop advanced disease. Most patients with PSC will develop symptoms of fatigue, itching and jaundice within several years of diagnosis. Progression to portal hypertension and cirrhosis ensues, and once liver failure develops, liver transplantation is the only therapeutic option. PSC is currently the fourth leading indication for liver transplantation in adults in the USA. For patients early in the course of their disease, however, the most effective management remains controversial. Multiple treatment options exist for patients with PSC and symptomatic biliary strictures. Surgical resection has been used in patients with PSC with varying degrees of success [2 8]. Medical therapy has also been utilized but with no proven benefit in outcome [9 15]. In addition, several non-operative modalities have been used to relieve symptoms and improve overall liver function. Endoscopic balloon dilation with or without stenting and percutaneous transhepatic stenting have become commonly used techniques in managing biliary obstruction in the setting of PSC [16 20]. To date there is no clear-cut evidence that any of these treatment modalities can slow the progression of PSC to cirrhosis. This review will discuss the treatment options for PSC, focusing on the role of non-transplant biliary tract surgery in the management of this disease. Non-operative management Although numerous randomized trials examining a variety of medical therapies for PSC have been reported, no drug has demonstrated that it can slow the progression of the disease to cirrhosis or produce clinically meaningful symptomatic improvement. Ursodeoxycholic acid has been the most extensively studied drug and has been shown to improve serum liver function tests and the histological stage of disease on liver biopsy. However, no difference in clinical outcome has been observed [9,10]. Many other agents have also been evaluated including methotrexate, Correspondence: Steven A. Ahrendt, Department of Surgery, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. Tel: Fax: Steven_ahrendt@urmc.rochester.edu Presented at the 6th World Congress of the International Hepato-Pancreato-Biliary Association, 2 6 June 2004, Washington DC, USA. ISSN X print/issn online # 2005 Taylor & Francis DOI: /

2 tacrolimus, cladibrine, budesonide and colchicine. None of these agents has demonstrated any significant improvement in symptoms or outcome [11 15]. Endoscopic balloon dilation or stenting is being increasingly utilized to relieve biliary obstruction in patients with PSC [16 18]. Such therapy seems most beneficial for patients with one or more dominant extrahepatic strictures (defined as a stricture of the common bile duct or common hepatic duct with a diameter of 41.5 mm and/or a stricture of a hepatic duct with a diameter of 41.0 mm within 2 cm of the hepatic duct bifurcation). The incidence of dominant strictures in patients with PSC is approximately 45% [21]. Stiehl et al. prospectively studied 106 patients treated with ursodeoxycholic acid [22]. Over a 5-year period, 52 patients developed dominant stenoses and were managed endoscopically. The actuarial survival free of liver transplantation at 5 years was significantly better than predicted with the Mayo multicentre survival model (94% vs 77%). Baluyut et al. also demonstrated a significantly higher 5-year survival rate than the predicted 5-year survival (83% vs 65%) in 63 patients undergoing endoscopic therapy over a 6-year period [23]. More long-term studies are needed to fully evaluate the benefit of endoscopic biliary dilation. Dilation of biliary strictures can also be performed percutaneously [19,20]. This technique is most advantageous for patients with intrahepatic or perihilar biliary strictures not amenable to endoscopic approaches, as well as for preoperative stent placement and postoperative dilation and stenting of proximal intrahepatic or anastomotic strictures. However, percutaneous biliary drainage is technically more difficult to perform, and is associated with a higher rate of complications including cholangitis, haemobilia and intra-abdominal abscess. Non-transplant surgical management Surgical resection Prior to the widespread use of liver transplantation and endoscopic balloon dilation to manage PSC, surgical resection was used as the predominant method of treatment. Over the past 15 years, several centres have reported good results after extrahepatic biliary resection or bypass, with long-term improvement in jaundice and survival in non-cirrhotic patients [2 4,6]. Operative management of PSC entails resection of the extrahepatic biliary tree including the hepatic duct bifurcation and postoperative transhepatic stenting. The operative approach for patients with PSC is based on the observation that the hepatic duct bifurcation is frequently involved with a dominant stricture [24]. Percutaneous transhepatic biliary stents are placed preoperatively to serve as technical aids at the time of exploration. The extrahepatic biliary tree and the hepatic duct bifurcation are then resected, and bilateral hepaticojejunostomies are constructed over Silastic Indications for non-transplant surgery in primary sclerosing cholangitis 293 A B Figure 1. (A) Preoperative cholangiogram from a 45-year-old female with primary sclerosing cholangitis, who was referred following a cholecystectomy and placement of a t-tube for acute cholecystitis and cholangitis. She remained jaundiced postoperatively. The cholangiogram demonstrates distal common bile duct, perihilar and intrahepatic strictures. She was managed with resection of the extrahepatic bile duct and hepatic duct bifurcation. (B) Postoperative cholangiogram demonstrates patent bilateral hepaticojejunostomies. The stents were removed 1 year postoperatively. stents. The transhepatic stents are removed at 1 year if there is free flow across the biliary enteric anastomosis (Figure 1). Symptomatic biliary obstruction The largest published non-transplant surgical experience in the management of patients with PSC is from the Johns Hopkins Hospital [6]. Between 1980 and 1994, 146 patients with PSC were treated at Johns Hopkins. Fifty patients underwent resection of the extrahepatic biliary tract; 40 of these patients were non-cirrhotic. Mean follow-up was 62 months. All patients had symptomatic biliary obstruction, and the primary indications for treatment were persistent jaundice and cholangitis. Operative mortality in patients with and without cirrhosis was 20% and 2.5%, respectively. Postoperative complications

3 294 B. Domajnko and S. A. Ahrendt Table I. Overall and transplant-free survival by treatment method in non-cirrhotic patients with primary sclerosing cholangitis Patients n Risk score Actuarial survival (%) 1 year 3 year 5 year Overall survival Resection ES/BD * 58* Percutaneous stenting * 63 Combined non-operative # 59# Transplant-free survival Resection ES/BD * 42* Percutaneous stenting # 51# Combined non-operative * 46* ES/BD, endoscopic sphincterotomy/balloon dilation. *p50.01 versus resection; #p50.05 versus resection. Adapted from Ahrendt et al. [6]. developed in 32% of patients, the most common being cholangitis. The overall 1-, 3- and 5-year survival rates after bile duct resection were 86%, 84% and 76%, respectively (Table I). Patients without cirrhosis had 1-, 3- and 5-year survival rates of 95%, 92% and 85%, respectively. Biliary resection also significantly reduced serum bilirubin levels at 1, 2 and 3 years after resection when compared with preoperative levels. None of the resected patients developed cholangiocarcinoma during a mean follow-up of 62 months. This analysis is the only study comparing the long-term results of extrahepatic bile duct resection with endoscopic and other non-operative therapies in the same clinical setting. Endoscopic balloon dilation was performed in 35 patients with PSC and symptomatic biliary obstruction between 1990 and The overall complication rate was 14%, the most common being mild pancreatitis. Overall survival for resected patients was significantly longer than for patients managed with endoscopic dilation or with both endoscopic and percutaneous biliary drainage methods. The overall 5-year survival rate in non-cirrhotic patients managed with endoscopic dilation was 58%, significantly lower than the 5-year survival after resection (85%). Similarly, transplant-free survival was also longer for patients treated operatively when compared with patients treated non-operatively. Three of 35 patients (8%) treated endoscopically developed cholangiocarcinoma. Several other centres have reported excellent results with extrahepatic biliary resection in patients with primary sclerosing cholangitis. Myburgh reported results with the Hepp-Couinaud hepaticojejunostomy in PSC patients [4]. Actuarial survival in the 16 patients without cirrhosis managed with this approach was 100% with a median follow-up of 6.5 years. This approach leaves in situ the extrahepatic biliary tree, with its malignant potential, but clearly improves the natural history of this disease in patients with dominant hilar and extrahepatic strictures. Hutson et al. have recently reviewed their experience with serial dilations of the biliary tree through a subcutaneously placed afferent limb of a choledochojejunostomy in patients with PSC [25]. This prospective 15-year evaluation included 36 patients treated by repeat dilatation. Operative mortality was 3% and only one major complication occurred during dilatation. The 5-year survival of all patients was 74%. If patients with cirrhosis or unsuspected cholangiocarcinoma at the time of operation were not included, the 5-year survival was 86%. The 15-year survival of all patients was 30% and was 64% if those with cirrhosis and unsuspected cholangiocarcinoma at the time of operation were not included. Six patients remained alive with an average survival of 159 months. Repeated dilatation of biliary strictures in patients with sclerosing cholangitis through a subcutaneously placed afferent limb of a choledochojejunostomy is technically feasible and safe. This study suggests that a combination of choledochojejunostomy with repeated dilatations combined with later liver transplantation is the approach of choice in selected patients. Two additional recent case reports have also demonstrated long-term survival with surgical management of PSC [26,27]. Thus, in carefully selected patients without significant hepatic fibrosis and with predominantly extrahepatic biliary strictures, resection of the extrahepatic biliary tree may prolong the interval to liver transplantation and provide relief of jaundice. Cholangiocarcinoma Surgical resection also plays a critical role in the management of patients with a confirmed diagnosis of or suspected cholangiocarcinoma. Cholangiocarcinoma is the most feared complication of PSC and is a major cause of death in patients with PSC. The disease develops in approximately 10 15% of PSC patients followed for 5 years and up to 30% of patients followed for 410 years [28]. Widespread biliary strictures make cholangiographic diagnosis of cholangiocarcinoma difficult. Methods for early detection have been studied, such as the tumour markers CA 19-9 and CEA, as well as cytologic brushings from ERCP. A recent study suggests that CA 19-9, when used in conjunction with available tests, aids in the differential diagnosis of cholangiocarcinoma [29]. Biliary cytology has a high false negative rate for the diagnosis of cholangiocarcinoma in the setting of PSC. Despite the more widespread use of tumour markers in the surveillance of patients with PSC, these screening techniques are inadequate and most patients diagnosed with cholangiocarcinoma in the setting of PSC present with unresectable disease. We previously reviewed the experience with cholangiocarcinoma complicating PSC at Johns Hopkins [30]. Among the 139 patients with PSC treated between 1984 and 1997, 25 patients (18%) were diagnosed with cholangiocarcinoma. Fourteen of these

4 Indications for non-transplant surgery in primary sclerosing cholangitis 295 Primary sclerosing cholangitis Cirrhosis H&P, serum lab tests, CT or MRI, and/or Liver biopsy Portal fibrosis Liver transplantation evaluation Negative Cholangiocarcinoma screening Asymptomatic Biliary obstructive Symptoms-jaundice, pruritus Positive or equivocal Dominant extrahepatic or perihilar stricture? EHBDR No therapy or experimental trial No Yes Consider ES/BD or EHBDR Figure 2. Treatment algorithm for the management of patients with primary sclerosing cholangitis (PSC). At the time of diagnosis patients with PSC should be staged to determine the severity of liver fibrosis. Patients should also be screened for cholangiocarcinoma at the time of diagnosis and annually thereafter. Screening includes an ERCP with brush cytology, MRI, and/or serum CA Extrahepatic bile duct resection (EHBDR) should be considered in patients with dominant strictures and atypical or suspicious biliary cytology. H&P, history and physical; ES/BD, endoscopic sphincterotomy/balloon dilation. 25 patients (56%) were diagnosed within 1 year of the diagnosis of PSC. Serum CA 19-9 was elevated in all six patients with cholangiocarcinoma who were analysed and in none of eight patients without cholangiocarcinoma. Serum CEA was elevated in only half the patients with cholangiocarcinoma and was normal in 8 of 10 patients without cholangiocarcinoma. Of nine patients with cholangiocarcinoma that were deemed resectable, five were managed with either extrahepatic bile duct resection and/or partial hepatic resection and four underwent liver transplantation. The remaining 16 patients were unresectable at presentation. Actuarial 1- and 3-year survival rates in the resected patients were 56% and 28%, respectively, compared with 13% and 0% in the unresected patients. In the Johns Hopkins experience, none of the patients with PSC managed with extrahepatic biliary resection later developed cholangiocarcinoma [6]. Natural history data suggest that seven or eight of these patients should have developed a bile duct malignancy [7]. Resection of the entire extrahepatic biliary tree including the hepatic duct bifurcation in 80% of these patients may have reduced their risk of developing cholangiocarcinoma. In contrast, cholangiocarcinoma has been reported in most series of patients undergoing endoscopic dilation for PSC, underscoring the difficulty of diagnosing the disease in these patients. Of 106 patients in Stiehl s series 3% developed cholangiocarcinoma, while 8% of the 63 patients in Baluyut s study were diagnosed with cholangiocarcinoma [22,23]. Incidental cholangiocarcinomas discovered at the time of liver transplantation are most often located at the hepatic duct bifurcation (72% of the time), and only 11% are intrahepatic [31]. This distribution supports the potential role of bifurcation resection in lowering the risk of cholangiocarcinoma in PSC patients. The lower incidence of cholangiocarcinoma in the surgically resected patients may have been responsible, in part, for the greater overall survival in the non-cirrhotic patients managed with this technique versus endoscopic balloon dilation [6]. Because the early diagnosis of cholangiocarcinoma remains elusive, extrahepatic bile duct resection should be considered in patients with PSC in whom the diagnosis of cholangiocarcinoma is suspected but not proven. In many patients, cholangiocarcinoma is identified soon after the initial diagnosis of PSC, and clinical suspicion must be high at this time. Dominant strictures that recur or persist after endoscopic dilation should be resected to exclude the possibility of cholangiocarcinoma [32]. Patients may also be diagnosed with PSC after the pathological evaluation of a resected isolated biliary stricture is benign and has the

5 296 B. Domajnko and S. A. Ahrendt characteristics of sclerosing cholangitis. A variety of benign conditions including PSC can present with an isolated biliary stricture mimicking cholangiocarcinoma [33,34]. Summary PSC is a progressive disease that eventually leads to cirrhosis, portal hypertension and liver failure. Management of the patient with PSC is based on a careful assessment of the cholangiographic appearance of the biliary tract, histological stage of disease on liver biopsy and the presence of symptoms. Our management approach to the patient with PSC is depicted in Figure 2. Non-operative biliary dilation provides symptomatic and biochemical improvement in patients, although this option results in shorter overall and transplant-free survival than resection and may be associated with a higher incidence of cholangiocarcinoma. Resection of the hepatic duct bifurcation with long-term transhepatic stenting should be considered for selected non-cirrhotic patients who have symptomatic biliary obstruction and dominant extrahepatic strictures particularly in those who fail endoscopic therapy. This approach has provided long-term improvement in serum bilirubin levels and appears to delay the need for liver transplantation in several recent surgical series. Non-transplant biliary surgery has not significantly increased the operative morbidity and mortality of liver transplantation and should be considered as a treatment option in patients with early stage PSC [35]. Cholangiocarcinoma continues to be a leading cause of mortality in patients with PSC. Patients with dominant strictures and equivocal results on cancer screening tests should be managed with resection rather than prolonged efforts at cancer diagnosis. Liver transplantation is clearly the best treatment option once cirrhosis has developed. References [1] Mendes FD, Lindor KD. Primary sclerosing cholangitis. Clin Liver Dis. 2004;8: [2] Cameron JL, Pitt HA, Zinner MJ, Herlong HF, Kaufman SL, Boitnott JK, et al. Resection of hepatic duct bifurcation and transhepatic stenting for sclerosing cholangitis. Ann Surg. 1988;207: [3] Pitt HA, Thompson HH, Tompkins RK, Longmire WP Jr. Primary sclerosing cholangitis: results of an aggressive surgical approach. Ann Surg. 1982;196: [4] Myburgh JA. Surgical biliary drainage in primary sclerosing cholangitis: the role of the Hepp-Couinaud approach. Arch Surg. 1994;129: [5] Martin FM, Rossi RL, Nugent FW, Scholz FJ, Jenkins RL, Lewis WD, et al. Surgical aspects of sclerosing cholangitis. Ann Surg. 1990;212: [6] Ahrendt SA, Pitt HA, Kalloo AN, Venbrux AC, Klein AS, Herlong HF, et al. Primary sclerosing cholangitis: resect, dilate, or transplant? Ann Surg. 1998;227: [7] Farges O, Malassagne B, Sebagh M, Bismuth H. Primary sclerosing cholangitis: liver transplantation or biliary surgery. Surgery 1995;117: [8] Ismail T, Angrisani L, Powell JE, Hubscher S, Buckels J, Neuberger J, et al. Primary sclerosing cholangitis: surgical options, prognostic variables, and outcome. Br J Surg. 1991; 78: [9] Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med. 1997;336: [10] De Maria N, Colantoni A, Rosenbloom E, Van Thiel DH. Ursodeoxycholic acid does not improve the clinical course of primary sclerosing cholangitis over a 2-year period. Hepatogastroenterology 1996;43: [11] Knox TA, Kaplan MM. A double-blind controlled trial of oralpulse methotrexate therapy in the treatment of primary sclerosing cholangitis. Gastroenterology 1994;106: [12] Van Thiel DH, Carroll P, Abu-Elmagd K, Rodriguez-Rilo H, Irish W, McMichael J, et al. Tacrolimus (FK 506), a treatment for primary sclerosing cholangitis: results of an open-label preliminary trial. Am J Gastroenterol. 1995;90: [13] Duchini A, Younossi ZM, Saven A, Bordin GH, Knowles HJ, Pockros PJ. An open-label pilot trial of cladibrine (2-cholorodeoxyadenosine) in patients with primary sclerosing cholangitis. J Clin Gastroenterol. 2000;31: [14] Angulo P, Batts KP, Jorgensen RA, LaRusso NA, Lindor KD. Oral budesonide in the treatment of primary sclerosing cholangitis. Am J Gastroenterol. 2000;95: [15] Olsson R, Broome U, Danielsson A, Hagerstrand I, Jarnerot G, Loof L, et al. Colchicine treatment of primary sclerosing cholangitis. Gastroenterology 1995;108: [16] Gaing AA, Geders JM, Cohen SA, Siegel JH. Endoscopic management of primary sclerosing cholangitis: review, and report of an open series. Am J Gastroenterol. 1993;88: [17] Lee JG, Schutz SM, England RE, Leung JW, Cotton PB. Endoscopic therapy of sclerosing cholangitis. Hepatology 1995;21: [18] Ponsioen CY, Lam K, van Milligen de Wit AW, Huibregtse K, Tytgat GN. Four years experience with short term stenting in primary sclerosing cholangitis. Am J Gastroenterol. 1999;94: [19] May GR, Bender CE, LaRusso NF, Wiesner RH. Nonoperative dilation of dominant strictures in primary sclerosing cholangitis. Am J Roentgenol. 1985;145: [20] Kaya M, Petersen MT, Angulo P, Baron TH, Andrews JC, Gostout CJ, et al. Balloon dilation compared to stenting of dominant strictures in primary sclerosing cholangitis. Am J Gastroenterol. 2001;96: [21] Bjornsson E, Lindqvist-Ottosson J, Asztely M, Olsson R. Dominant stricture in patients with primary sclerosing cholangitis. Am J Gastroenterol. 2004;99: [22] Stiehl A, Rudolph G, Kloters-Plachky P, Sauer P, Walker S. Development of dominant bile duct stenosis in patients with primary sclerosing cholangitis treated with ursodeoxycholic acid: outcome after endoscopic treatment. J Hepatol. 2002; 36: [23] Baluyut AR, Sherman S, Lehman GA, Hoen H, Chalasoni N. Impact of endoscopic therapy on the survival of patients with primary sclerosing cholangitis. Gastrointest Endosc. 2001; 53: [24] Cameron JL, Gayler BW. Sclerosing cholangitis: anatomical distribution of obstructive lesions. Ann Surg. 1984;200: [25] Hutson DG, Russell E, Levi JU, Jeffers LJ, Reddy KR, Yrizarry JM, et al. Dilatation of biliary strictures through the afferent limb of a Roux-en-Y choledochojejunostomy in patients with sclerosing cholangitis. World J Surg. 2001;25: [26] Yamamoto T, Hirohashi K, Kubo S, Tsukamoto T, Uenishi T, Shuto T, et al. Surgery for segmental primary sclerosing cholangitis. Hepatogastroenterology 2004;51: [27] Hirai I, Ishiyama S, Fuse A, Kuzu H, Sakurai F, Kimura S, et al. Primary sclerosing cholangitis successfully treated by resection of the confluence of the hepatic duct. J Hepatobiliary Pancreat Surg. 2001;8:

6 Indications for non-transplant surgery in primary sclerosing cholangitis 297 [28] Rosen CB, Nagorney DM, Wiesner RH, Coffey RJ Jr, LaRusso NF. Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg. 1991;213:21 5. [29] Qin XL, Wang ZR, Shi JS, Lu M, Wang L, He QR. Utility of serum CA 19 9 in diagnosis of cholangiocarcinoma: in comparison with CEA. World J Gastroenterol. 2004;10: [30] Ahrendt SA, Pitt HA, Nakeeb A, Klein AS, Lillemoe KD, Kalloo AN, et al. Diagnosis and management of cholangiocarcinoma in primary sclerosing cholangitis. J Gastrointest Surg. 1999;3: [31] Abu-Elmagd KM, Selby R, Iwatsuki S, Fung J, Tzakis A, Todo S, et al. Cholangiocarcinoma and sclerosing cholangitis: clinical characteristics and effect on survival after liver transplantation. Transplant Proc. 1993; 25: [32] Ahrendt SA, Pitt HA. Surgical treatment for primary sclerosing cholangitis. J Hepatobiliary Pancreat Surg. 1999;6: [33] Binkley CE, Eckhauser FE, Colletti LM. Unusual causes of benign biliary strictures with cholangiographic features of cholangiocarcinoma. J Gastrointest Surg. 2002;6: [34] Koea J, Holden A, Chau K, McCall J. Differential diagnosis of stenosing lesions at the hepatic hilus. World J Surg. 2004; 28: [35] Abu-Elmagd KM, Malinchoc M, Dickson ER, Fung JJ, Murtaugh PA, Langworthy AL, et al. Efficacy of hepatic transplantation in patients with primary sclerosing cholangitis. Surg Gynecol Obstet. 1993;177: