Primary Sclerosing Cholangitis-Associated Inflammatory Bowel Disease

Fig. 3.1

Absolute cumulative risk for colorectal dysplasia or cancer over time among patients with UC and those with PSC-UC [1]

Given the apparent increased incidence of colorectal neoplasia in PSC-IBD patients, a variety of medications have been evaluated as chemoprevention agents. Two recent meta-analyses with similar study inclusions have suggested a possible decrease in CRC risk associated with low- to medium-dose ursodeoxycholic acid (UDCA) [59, 60]. Hansen et al. reported a nonsignificant trend toward benefit with an RR of 0.64 (95 % CI 0.38–1.07, p = 0.09) for CRC with UDCA dosed less than 25 mg/kg/day [59]. Conversely, Singh et al. found a statistically significant benefit with an OR of 0.18 (95 % CI 0.06–0.52) for CRC with UDCA dosed between 8 and 15 mg/kg/day [60]. Neither analysis demonstrated any benefit with higher-dose UDCA; however, definitions of high-dose UDCA differed. While low-dose UDCA may be associated with reduced CRC risk among PSC-IBD patients, there remains a lack of certainty that is reflected in the discordant recommendations from the American Gastroenterology Association (AGA) and American Association for the Study of Liver Diseases (AASLD) for and against the use of UDCA as CRC chemoprevention, respectively [2, 61].

Despite discrepant results among available observational studies, a 2010 AGA technical review favored the use of aminosalicylates (5-ASA) for chemoprevention in colitis-associated CRC [62]. Thiopurines have been variably associated with a protective effect in reducing colitis-associated CRC; however, their risk profile limits their appeal as chemoprevention agents when not necessary for the treatment of colitis [63–67]. Results to date regarding the chemopreventative benefit of anti-TNF agents are limited and conflicting [68, 69]. Folate supplementation does not appear to protect against CRC in patients with IBD.

Patients with PSC-IBD are recommended to undergo rigorous surveillance colonoscopy to identify and manage colonic neoplasia as early as possible. Given the higher incidence of subclinical or mildly symptomatic colitis among PSC patients, current guidelines recommend a full colonoscopy with random segmental biopsies at the time of PSC diagnosis to assess for coexistent IBD. Patients with PSC-IBD should undergo serial colonoscopy for dysplasia surveillance every 1–2 years starting at the time of IBD diagnosis according to the AASLD; several other society guidelines recommend annual colonoscopic surveillance [2, 61, 70, 71]. There are no current guidelines regarding additional colonoscopic surveillance in PSC patients without concomitant IBD at initial colonoscopy.

Current surveillance colonoscopy guidelines for IBD patients recommend both targeted biopsies of visible lesions and extensive segmental biopsies with four-quadrant biopsies every 10 cm [70, 72, 73]. It should be noted, however, that guidelines for dysplasia surveillance and management differ among societies and are evolving as endoscopic imaging techniques improve the detection of dysplasia [70, 74]. Although the merits of continued surveillance versus colectomy for low-grade dysplasia (LGD) remain debatable, the substantial risk of progression of LGD to CRC in PSC-IBD should prompt a discussion with patients regarding more intensive surveillance or colectomy [75]. A variety of techniques have been evaluated to improve dysplasia detection given the low yield of random biopsies for the detection of dysplasia [76]. There is consensus that high-definition colonoscopy significantly improves dysplasia detection over standard white-light colonoscopy and should be utilized if available [74]. Additionally, chromoendoscopy using intracolonic application of indigo carmine or methylene blue significantly improves dysplasia detection over standard white-light colonoscopy and, to a lesser degree, over high-definition colonoscopy [74] (Fig. 3.2). Because of improved dysplasia detection, chromoendoscopy is frequently utilized for surveillance of high-risk populations, including patients with PSC-IBD, and has been recommended in some society guidelines [71]. Additional image enhancement modalities such as narrow band imaging (NBI) and autofluorescence technology are yet to show significant benefit in dysplasia detection in IBD [74].

Fig. 3.2

Dysplastic colonic tissue identified with the aid of chromoendoscopy with methylene blue

Colectomy and Pouch Function in PSC-IBD Patients

Up to one-third of PSC-IBD patients will ultimately undergo colectomy [77–79]; however, colectomy rates may be decreasing [80]. Although it has not been studied directly, comparison of colectomy rates among study cohorts from similar time periods suggests that PSC-IBD patients may have a two- to threefold increase in colectomy rates over patients with isolated UC [81–84]. While extensive colitis and associated refractory disease is the most significant risk factor for colectomy among non-PSC-UC patients [85], PSC-IBD patients are much more likely to undergo colectomy for colorectal dysplasia/neoplasia [42, 82, 83]. Hepatic dysfunction is an important risk factor for adverse outcomes from colectomy [84]. In patients with portal hypertension who undergo ileostomies, peristomal varices can occur, and variceal bleeding may be very difficult to control, sometimes necessitating TIPS or liver transplantation (Fig. 3.3) [86–88]. As a consequence, proctocolectomy with formation of an ileal pouch anal anastomosis (IPAA), often called a “J pouch,” is the favored procedure for patients requiring colectomy (Fig. 3.4). For patients with poor hepatic reserve, however, concomitant liver transplantation with total colectomy followed subsequently by IPAA may be a preferable approach [89].

Fig. 3.3

Peristomal varices in a patient with PSC-IBD who underwent colectomy with end ileostomy and subsequently developed cirrhosis (Image courtesy of Hugo R. Rosen, MD)

Fig. 3.4

(a) Normal pouch with healthy-appearing mucosa and an owl’s eye configuration demonstrating a patent pouch inlet leading to the pre-pouch ileum; (b) diffuse pouchitis in a patient with PSC-IBD

Patients undergoing proctocolectomy with IPAA can experience a variety of pouch complications. The most common complication is pouchitis, which occurs in approximately 20–45 % of patients, and presents as increased stool frequency and urgency [90]. Pouchitis is thought to be a consequence of microbial dysbiosis and typically responds to a short course of antibiotic therapy, most often with ciprofloxacin and/or metronidazole [91]. A subset of patients will develop chronic antibiotic-refractory pouchitis (CARP) that requires more aggressive immunosuppressive therapy. PSC-IBD patients who undergo IPAA are more likely to develop pouchitis and have higher rates of CARP [92, 93]. This risk does not appear to be affected by liver disease severity [92] or worsen after liver transplantation [94]. De novo CARP appears to occur less frequently if IPAA is performed after liver transplantation (58.3 %) than if IPAA precedes transplantation (100 %; p = 0.047) [95].

Neoplasia of the pouch or anal transition zone (ATZ) following IPAA has been described [96, 97] and occurs more often in patients undergoing colectomy for dysplasia/CRC [96]. Some studies suggest that PSC-IBD patients are at increased risk for pouch or ATZ neoplasia [98, 99]. The overall rate of pouch/ATZ neoplasia remains low, however, and there is no consensus on the need, or optimal protocol, for surveillance for pouch/ATZ neoplasia following IPAA [98, 100]. PSC and/or liver transplant does not appear to be a significant risk factor for other pouch-related complications including infections (Clostridium difficile and CMV) [101, 102], irritable pouch syndrome [103], or pouch failure [104].

Effect of IBD on Transplant Outcomes Among PSC-IBD Patients

Concomitant IBD does not appear to significantly affect overall patient survival following liver transplant for PSC; however, it may adversely impact graft function [105, 106]. The presence of IBD and an intact colon appears to be a significant risk factor for recurrence of PSC posttransplant. Pre- or peri-transplant colectomy is associated with much lower rates of recurrent PSC (2–3 %) than those seen among transplanted PSC patients who retain their colon or undergo colectomy following transplant (40–44 %) [107, 108]. PSC-IBD has also been associated with increased rates of acute cellular rejection [109] and chronic ductopenic rejection [106], while active IBD at the time of transplant has been associated with decreased graft survival and hepatic artery thrombosis [110].

Effect of Liver Transplantation on IBD Activity Among PSC-IBD Patients

PSC-IBD activity in patients requiring liver transplantation tends to be mild [83]. IBD activity following transplant follows a more variable course [111]. Some studies describe generally quiescent disease posttransplant [112, 113], while others document predominantly poor disease control and even the development of de novo IBD in approximately one-fifth of PSC patients despite transplant immunosuppression [13, 105, 114–116]. Although it is a well-described clinical phenomenon, the pathogenesis of de novo IBD posttransplant remains unclear. Theories include the unmasking of autoimmunity through suppression of regulatory T cells by transplant immunosuppressive agents, the loss of tolerance to microbial antigens, and the initiation of a chronic inflammatory response by damage-associated molecular pattern molecules and pathogen-associated molecular pattern molecules [117, 118]. Risk factors for poor IBD outcomes posttransplant also remain unclear. Clinically active IBD at the time of transplant may be a risk factor for worse disease after transplant [13], and inactive IBD at transplant has been associated with good disease control afterward [112]; however, as with many other reported predictors of posttransplant disease course, these associations have not been found in all studies. Another relatively common, but not universal, finding is that tacrolimus-based transplant immunosuppressive regimens are associated with higher rates of IBD flares [13, 119, 120] than regimens using azathioprine and cyclosporine [13, 116, 120, 121].

Management of PSC-IBD Following Liver Transplantation

The management of active IBD in the posttransplant setting is complicated by the competing need for antirejection immunosuppressive agents that are not always effective as IBD treatments and may actually promote disease activity. The successive use of calcineurin inhibitors and anti-TNF agents has been associated with a significant risk of infectious complications among patients with severe UC and raises concerns about the use of anti-TNF agents in the posttransplant PSC-IBD population [122]. Although data is very limited, in three small case series, the use of anti-TNF therapies in combination with calcineurin inhibitors and/or mycophenolate mofetil (MMF) in the posttransplant setting appeared to be safe and similarly effective at managing IBD as in the non-transplant population [123–125]. There is a single case report regarding the use of vedolizumab in the posttransplant setting with no adverse reactions observed after 11 months of treatment, during which the frequency of administration was increased to every 4 weeks [126]. There have been only three case reports in adults and a single case series in children assessing the use of mTOR inhibitors for the management of refractory IBD. While there appears to be some efficacy in a very selective population, their use in treating IBD in the posttransplant setting has not been evaluated [127–129].

The relative risk of colorectal cancer following liver transplant for non-PSC indications is approximately twofold that of the general population [130]. PSC-IBD patients with an intact colon posttransplant have a tenfold increased risk of CRC as compared to non-PSC transplant indications and 20-fold increased risk over the general population [110]. Similar to IBD in general, the colorectal cancer risk among PSC-IBD patients following transplant is related to the extent and duration of colitis [131]. Notably, transplant-related factors such as type of immunosuppression, rates of rejection, and CMV infection have not been shown to affect posttransplant CRC risk [132, 133]. Patients undergoing regular colonoscopic surveillance posttransplant are more likely to be diagnosed with early stage cancer, and therefore PSC-IBD patients should continue to undergo surveillance colonoscopy every 1–2 years following transplant [133].

Summary

IBD is present in approximately two-thirds of patients with PSC. The pathogenesis of this close association remains unclear. Although there is a clear genetic link between the two diseases, PSC-associated IBD likely represents a distinct clinical entity. PSC-IBD is often characterized by pancolitis with right colon predominant inflammation and relative rectal sparing. Importantly, these patients harbor a dramatically increased risk of colorectal cancer and thus require rigorous colonoscopic surveillance to minimize unfavorable outcomes related to colonic dysplasia. Liver disease progression and liver transplantation present additional challenges related to colitis management, which can have important effects on graft outcomes. Understanding the unique diagnostic, prognostic, and management considerations of this patient population provides the opportunity for optimization of patient care and improved outcomes.

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