Liver Transplantation for Primary Sclerosing Cholangitis and Inflammatory Bowel Disease

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Introduction

Primary sclerosing cholangitis (PSC) is a chronic cholestatic syndrome characterised by diffuse inflammation and fibrosis of both intra- and extrahepatic bile ducts [1]. Although PSC is most likely a multifactorial disease with genetic predisposition, its exact aetiology remains unknown. In 75% of cases, there is comorbidity with inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn’s disease. This underscores the role of immunological alterations in the pathophysiology of the disease. Mean age at diagnosis is 40 years, and men are affected about twice as often as women [2].

PSC lacks a definitive medical therapy. Promising regimens are high doses of ursodeoxycholic acid alone or in combination with immunosuppression.

Endoscopic treatment of biliary strictures is frequently needed in the late course of PSC disease.

Repeated stenting may be an option in treating dominant strictures [3]. Occasionally, surgical treatment of severe extrahepatic strictures is necessary. In general, however, most hepatobiliary surgeons are reluc- tant to perform such procedures, as they may com- plicate a future liver transplantation (Ltx) and reduce the chance of long-term survival following Ltx [4].

PSC runs an unpredictable clinical course leading to liver cirrhosis and terminal liver disease in the majority of affected individuals.

Primary Sclerosing Cholangitis and Liver Transplantation

At present, PSC is the fifth most important indication for liver transplantation in the United States [5].

There are two major difficulties associated with predicting the course of the disease in each individual case as well as the increased risk for hepatobiliary malignancies, primarily cholangiocellular carcinoma (CCC). The risk for CCC is highest during the first year of diagnosis and is not linked to the stage of disease [6, 7]. A PSC patient with cirrhosis and a liver

tumour should also be evaluated for possible hepatocellular carcinoma (HCC) and in this case considered for Ltx if no extrahepatic metastases are detected and the tumour is within accepted criteria. Liver resection for HCC is rarely indicated in a PSC patient with advanced liver disease, as previous hepatobiliary surgery is a negative prognostic factor for transplant candidates [4].

The problem of identifying PSC patients with a high risk for developing CCC has not been resolved so far. No specific tumour markers exist. This has a great impact because CCC has traditionally been considered a contraindication to Ltx. Experience with CCC in patients undergoing Ltx is limited, and treatment guidelines are still lacking. The value of routine brush cytology obtained during endoscopic retrograde cholangiography remains unclear. Patients with severe dysplasia in cytologic smears should be considered as running a very high risk for CCC development and therefore evaluated to exclude possible systemic malignant disease. No consensus exists as to what imaging modality should be preferred in the management of these patients. Positron emission tomography (PET) is promising but its exact role remains unclear [8].

Studies indicate that Ltx results in highly selected patients with CCC are satisfactory if the patients undergo multidisciplinary treatment including chemotherapy and local radiation therapy prior to Ltx [9, 10]. Due to the fact that the diagnosis of CCC can be extremely difficult to establish, PSC patients are usually evaluated for Ltx even when CCC is sus- pected and the final decision to perform transplantation is taken during laparotomy. If a limited tumour without extrahepatic tumour growth is found, the procedure should be continued and transplantation performed. Positive lymph nodes contraindicate transplantation, and the patient is given palliative therapy. Brandsaeter et al. reported that clinical sus- picion of cancer, recent diagnosis of PSC and previous colon cancer are predictors of malignancy, which was found in 20% of more than 500 patients [11]. Ide- ally, a PSC patient should be listed for Ltx at the time

Liver Transplantation for Primary Sclerosing Cholangitis and Inflammatory Bowel Disease

Ingmar Königsrainer, Ruth Ladurner, Claudia Schulz, Wolfgang Steurer, Alfred Königsrainer

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318 I. Königsrainer, R. Ladurner, C. Schulz, W. Steurer, A. Königsrainer

when survival with Ltx supersedes survival without Ltx. Prognostic models such as the Child-Pugh score or the model for end-stage liver disease (MELD) score have been demonstrated to be superior to PSC- specific prognostic models in predicting posttransplantation survival in PSC patients [12]. Short dura- tion of PSC, a high bilirubin and an elevated MELD score are associated with poor outcome [13]. When assessing a PSC patient for Ltx a colonoscopy is mandatory. Patients with severe ulcerative colitis or mucosal dysplasia are candidates for colectomy before listing them for transplantation. Particular care is necessary to avoid life-threatening liver decompensation [14].

When reconstructing the biliary tract during transplantation two options are available. As experience with end-to-end biliary anastomosis is limited, most surgeons prefer a hepaticoenterostomy with a Roux-en-Y-loop in patients undergoing Ltx for PSC.

There are a few reports that a duct-to-duct anastomosis is associated with a higher recurrence rate.

From the pathophysiological point of view, neither alternative is logical since a possible source for malignancy remains untouched in situ. Whether an obligatory resection of the whole bile duct, meaning a pancreas head resection, is justified, has not yet been determined. Heightened attention is needed for the possibility of growth of malignant tissue infiltrat- ing the choledochus duct. In this case, a simultaneous pancreatic head resection is generally accepted [15].

From the recipient’s point of view and considering the development in waiting time in recent years, living related liver transplantation is the best option for PSC, not only in order to reduce waiting time but also to prevent patients from dropping off the list due to tumour formation [16]. Patients with PSC in general have good physical status with low Child-Pugh score and therefore face a long waiting time. The risk of developing CCC correlates directly with the length of time the disease remains untreated.

Outcome after Liver Grafting

Survival rates are comparable with those achieved in patients with other autoimmune liver diseases, such as primary biliary cirrhosis and autoimmune hepatitis, with 1-year patient survival exceeding 90 % in recently published series [14]. PSC patients are reported to have a slightly higher retransplantation rate without impact on long-term patient survival [4]. Again, this increased retransplantation rate has been ascribed to PSC-specific long-term complications, in particular, biliary strictures [17]. However, patient survival following Ltx has been shown to be

clearly improved compared with the natural course of the disease predicted by prognostic models [18].

A number of pretransplantation factors have been shown to predict poorer posttransplantation survival, such previous hepatobiliary surgery, elevated creatinine levels, reduced nutritional status and the occurrence of hepatobiliary malignancy [4, 18]. Pres- ence of IBD has also been claimed to affect survival following Ltx [18]. Other studies failed to identify IBD as a risk factor [4]. The greatest impact on long- term outcome is from CCC, which has been considered poor even in patients with occult tumours [19, 20].

Considering the lack of alternatives and the significant benefit in patients with small tumours, strict exclusion from transplantation is not justified. More- over, improved patient survival has been reported in smaller series with strictly selected patients [21].

HCC is not observed frequently and has less impact on patient survival following Ltx in PSC patients [22].

Postoperative Complications

Hepatic artery thrombosis (HAT) with an incidence of 1–5% following adult Ltx is a feared complication frequently leading to graft loss and retransplantation. The reason for the increased incidence of hepatic artery thrombosis in PSC patients is unclear [17].

New immunosuppressive regimens have significant- ly reduced rejection episodes in liver allograft recipients. Patients with PSC, PBC or autoimmune hepatitis seem to experience more acute rejections compared with patients with alcoholic cirrhosis or chronic viral hepatitis who are thus on a higher level of immunosuppression [23]. On the other hand, some centres have also reported fully satisfactory results after early steroid withdrawal in patients with PSC [24]. With regard to postoperative infection episodes, positive bacterial cultures are found in bile samples from a large portion of PSC patients at the time of Ltx [25].

Another major concern is recurrent disease. Stric- tures can be single or multiple, anastomotic or nonanastomotic, and they can develop early within the first 3 months or later [26]. Differentiation of PSC-associated or nonrelated complications can be a challenge in follow-up. An increased rate of biliary problems in PSC liver allograft recipients, especially after duct-to-duct reconstruction of the biliary system, was identified by Sheng et al. more than 10 years ago [27].

Diagnostic criteria, prevalence and prognosis of PSC recurrence are not established. Cholangiography has been complicated because it is usually impossible to perform an endoscopic retrograde cholangiogra-

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Liver Transplantation for Primary Sclerosing Cholangitis and Inflammatory Bowel Disease 319

phy in patients in whom a hepaticoenterostomy has been constructed. However, magnetic resonance cholangiography (MRC) now permits noninvasive cholangiography to be performed in these patients.

Even in a graft biopsy, PSC recurrence can be difficult to identify. In some cases, typical fibrous cholangitis and/or fibro-obliterative lesions are seen, supporting the diagnosis of recurrent PSC. About 20–40% of PSC patients will experience recurrent disease. The Mayo Clinic has defined PSC recurrence as either cholangiographic changes occurring more than 90 days after Ltx or characteristic liver biopsy findings, such as fibrous cholangitis and/or fibro- obliterative lesions with or without ductopenic biliary fibrosis or cirrhosis, namely in a PSC patient without HAT or stenosis, ABO incompatibility, chronic ductopenic rejection, early biliary complications or biliary strictures [28]. Therefore, the diagnosis of recurrent PSC should be made only in patients with typical cholangiographic findings and/or positive histology as well as patent arterial circulation.

The improving quality of MRC will probably enable us to diagnose and characterise PSC recurrence more precisely in the near future. Pretransplantation colectomy has been claimed to be associated with a lower rate of recurrence [29]. The impact of different immunosuppression regimens has not yet been resolved. Cytomegalovirus (CMV) and donor–recipient gender mismatch have also been proposed as risk factors for recurrence [30].

The prognosis of PSC recurrence was originally thought to be favourable, with no cases progressing to graft failure [20], but more recent reports question this [28]. To date, no one can propose strategies for retransplantation.

Management of Inflammatory Bowel Disease

In spite of immunosuppressive medication, a significant number of patients undergoing Ltx due to PSC will experience an exacerbation of IBD following transplantation, in some cases necessitating colectomy. Patients without IBD prior to Ltx have also been diagnosed with de novo IBD in the posttransplantation period [31]. Dvorchik et al. described a high incidence of progression of IBD following Ltx [31].

Haagsma et al. found that tacrolimus is more frequently associated with posttransplantation exacerbation of IBD and that patients on triple immunosuppression (cyclosporine, azathioprine, prednisolone) have less active bowel disease in follow-up [32]. Dis- continuation of steroids has also been reported to increase the risk of IBD exacerbation [33]. Colorectal cancer in patients with IBD and PSC undergoing Ltx has been reported in several series [28].

Conclusive evidence that immunosuppression administered following Ltx may further increase the risk of colorectal cancer compared with the risk in the nontransplanted PSC patient with IBD is still lacking [34, 35]. PSC patients with a diagnosis of IBD and in whom a colectomy has not been performed should undergo colonoscopy on a yearly basis. If dysplasia is detected, colectomy should be considered.

If severe colitis or dysplasia is found during the waiting period, colectomy can also be performed during laparotomy for the transplantation provided the patient’s general condition permits. Indeed, the ideal time to perform colectomy is not yet known. So far, it is a matter of local preference and the condition of the individual patient.

Follow-Up

Due to the risk of PSC-specific complications, it is advisable that these patients be subjected to further detailed follow-up controls routinely, including a cholangiogram. The risk of developing de novo hepatobiliary malignancy is especially given in those patients with severe pretransplantation dysplasia. Surveillance of the remnant biliary duct should not be forgotten, and endoscopic ultrasound examination, including brush cytology, might be advisable.

Summary

PSC runs an unpredictable clinical course leading to liver cirrhosis and terminal liver disease in the majority of affected individuals. The ideal time to perform colectomy in colitis ulcerosa patients is still unclear; so far, it is a matter of local preference and patient condition. The problem of identifying PSC patients with a particular risk for developing CCC is multifactorial. Diagnostic features are still lacking.

Living related donor liver transplantation for PSC could reduce waiting time and thus secondary complications as well as drop-out probability due to malignancy [16]. Major surgery with simultaneous pancreatic head resection may be necessary in cases with extrahepatic duct infiltration in order to achieve no residual tumour (R0) status [15].

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