Review article: colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease

Authors

  • J. Torres,

    1. The Dr. Henry D. Janowitz Division of Gastroenterology, Mount Sinai School of Medicine, New York, NY, USA.
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  • G. Pineton de Chambrun,

    1. Inserm Unit 995, Université Lille Nord de France, Lille, France.
    2. Department of Medicine, School of Medicine, UCSD, San Diego, CA, USA.
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  • S. Itzkowitz,

    1. The Dr. Henry D. Janowitz Division of Gastroenterology, Mount Sinai School of Medicine, New York, NY, USA.
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  • D. B. Sachar,

    1. The Dr. Henry D. Janowitz Division of Gastroenterology, Mount Sinai School of Medicine, New York, NY, USA.
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  • J.-F. Colombel

    1. The Dr. Henry D. Janowitz Division of Gastroenterology, Mount Sinai School of Medicine, New York, NY, USA.
    2. Department of Hepatogastroenterology, Hôpital Claude Huriez and Centre d’Investigation Clinique, Centre Hospitalier Universitaire de Lille, Université Lille Nord de France, Lille, France.
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  • This uncommissioned review article was subject to full peer-review.

Dr J.-F. Colombel, 1 Gustave Levy Place, New York, NY 10029, USA.
E-mail: jean-frederic.colombel@wanadoo.fr

Abstract

Aliment Pharmacol Ther 2011; 34: 497–508

Summary

Background  Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease strongly associated with inflammatory bowel disease (IBD). IBD patients diagnosed with PSC have an increased risk of colorectal dysplasia and cancer.

Aims  To review the available evidence regarding colorectal neoplasia epidemiology, preventive strategies and outcomes in patients with PSC and IBD, and to advance some hypotheses regarding possible mechanisms involved in cancer pathogenesis in these patients.

Methods  A PubMed search was conducted for the English language publications with predetermined search criteria. Reference lists from studies selected were manually searched to identify further relevant reports. Relevant manuscripts considering colorectal neoplasia in patients with PSC-IBD were selected.

Results  Primary sclerosing cholangitis increases the risk of colorectal neoplasia in patients with ulcerative colitis; fewer data are available for Crohn’s disease. PSC-IBD patients tend to be younger at diagnosis of IBD and at diagnosis of colorectal cancer. Colorectal cancer in PSC-IBD patients predominates in the right colon. The increased risk of neoplasia is maintained after liver transplant and proctocolectomy. The role of ursodeoxycholic acid as a chemopreventive agent is controversial. The mechanisms underlying increased risk of colorectal neoplasia in these patients remain unknown.

Conclusions  A more comprehensive understanding of the mechanisms involved in colorectal neoplasia development in PSC-IBD patients is needed. Until then, early cancer detection through enrolment in surveillance programmes is the only available strategy to decrease cancer risk.

Introduction

Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease characterised by progressive inflammation and fibrosis of the intrahepatic and extrahepatic biliary ducts.1 The incidence of PSC seems to be increasing.2 Although it is a rare disease, PSC portends a considerable healthcare burden: it affects young patients; there are no effective medical therapies; and it is associated with a high rate of complications such as cirrhosis, end-stage liver disease and need for liver transplantation. Moreover, it is considered a premalignant condition with an increased risk of cholangiocarcinoma, pancreatic carcinoma and colorectal cancer (CRC).1, 3

PSC is strongly associated with inflammatory bowel disease (IBD). In Western countries, the prevalence of IBD among PSC patients ranges from 60–80%.2, 4, 5 Ulcerative colitis (UC) accounts for the majority (80%) of cases, whereas about 10% have Crohn’s disease (CD) and another 10% are classified as indeterminate colitis.6 Conversely, PSC is present in 3–8% of all patients with UC and 1–3% of patients with CD.7–9 The association with IBD is stronger with more extensive colonic involvement: in patients with pancolitis, the prevalence of PSC is about 6% in contrast to 1% in those with only distal colitis.9 PSC is not believed to complicate isolated small intestinal CD.7

IBD may be diagnosed at any time during the course of PSC, but in most cases the IBD is recognised first. Although both diseases run distinct courses with no direct relationship between their severities, there are some characteristic findings that have been consistently reported; some authors have even suggested that PSC-IBD patients represent a distinct disease phenotype.6, 10 PSC patients typically have mildly symptomatic or asymptomatic pancolitis or extensive colitis, more right-sided inflammation, rectal sparing and backwash ileitis, and they often have prolonged remissions and a quiescent course of their colonic disease.6, 10, 11 Other distinctive findings in PSC-IBD patients are an increased risk of pouchitis in those undergoing restorative proctocolectomy,12 an increased frequency of combined intra- and extrahepatic biliary strictures13 and an increased risk of PSC recurrence after liver transplantation in patients with intact colons at the time of transplantation.14 Finally, a striking observation is that despite having mild colonic disease with little inflammation, patients with PSC-IBD have a significantly increased risk of developing colorectal neoplasia (CRN) as compared with IBD patients without PSC.10, 15–24 The mechanisms by which concomitant PSC further increases the risk of CRN in patients with IBD remain unknown.

In this review, we will survey the available evidence regarding CRN epidemiology, preventive strategies and clinical outcomes in patients with PSC and IBD, and we will suggest some hypotheses regarding possible mechanisms of cancer pathogenesis in these patients.

Materials and methods

A literature search was conducted to identify relevant studies that addressed CRN in patients with PSC and IBD. PubMed was searched for all articles published until March 2011, using the key words: primary sclerosing cholangitis, colon, cancer, neoplasia and inflammatory bowel disease. All studies whose specific aim was to describe CRC or dysplasia incidence, risk, characteristics and outcomes in patients with IBD and PSC were included. Reference lists from studies selected by electronic search were manually searched to identify further relevant reports. Articles published as abstracts, non-English written and review articles were excluded.

Results – part I: facts

Evidence for increased risk of colorectal neoplasia in PSC-IBD patients

Data on the risk of colorectal dysplasia and cancer (CRN) in patients with PSC were conflicting for some years. Studies with small sample sizes, different end points and different comparison groups, as well problems in determining time of onset of IBD in patients with PSC, gave rise to disparate results.

Brooméet al. in 1992 were the first to suggest that patients with IBD and PSC could have an increased risk for developing CRN.15 Three years later, the same group showed that the absolute cumulative risk of developing CRN in PSC-UC patients after 10, 20 and 25 years of disease duration was 9%, 31% and 50%, respectively, compared with 2%, 5% and 10% in those with UC alone (P < 0.001).17 In this landmark study, 40 PSC patients with extensive UC who had been enrolled in a surveillance programme were matched with two control patients of the same age, also with extensive colitis and a comparable duration of disease, but without PSC. Among the 40 PSC patients with UC, 16 developed CRN, vs. only 10 of 80 in the control group (P < 0.001).

These observations have since been reproduced in other studies.19, 22, 25 By now, many publications have confirmed the increased risk of CRN in PSC-IBD patients, even when controlling for location and extent of disease,10, 16, 18–24 although in some series, this increase in risk appeared to be low or even absent.6, 26–30

Increased duration and extent of colitis are well-recognised risk factors for dysplasia and cancer in patients with IBD. PSC-IBD patients tend to have mild or even asymptomatic extensive colonic disease and some authors have suggested that PSC could be associated with an increased risk of cancer just by representing a surrogate marker of long-standing inflammation.29 Some studies have argued against this view by showing a similar duration of IBD in CRC patients with or without PSC.31, 32 However, there are inherent difficulties in being able to accurately date the onset of colitis in patients with PSC; these patients could have a subclinical phase leading to underestimation of disease duration. For example, a study from Sweden found that among 11 PSC patients with no clinical signs or history of IBD, six (64%) had endoscopic or histological signs of IBD, and two already had indefinite or low-grade dysplasia, suggesting that pancolitis had been longstanding, but unrecognised.33

In 2002, Soetikno et al. published a meta-analysis of 11 studies bearing on the issue of increased neoplasia risk conferred by PSC in IBD patients.34 A total of 16 844 patients with UC were included, 564 (3%) of whom had PSC. Overall, 21% of the patients with PSC-UC developed CRN compared with 4% of patients without PSC. The odds ratio (OR) of developing dysplasia or cancer in patients with PSC was thus 4.8 (95% CI 3.6, 6.4). When dysplasia was excluded from the analysis, to reduce possible errors related to interobserver variation, the risk for carcinoma was still increased by approximately fourfold compared with patients with UC alone (OR 4.3; 95% CI 2.8, 6.5).34 Hence, the presence of PSC was an independent risk factor for development of colorectal dysplasia or cancer in UC patients.

PSC can also be associated with Crohn’s colitis or undetermined colitis and it can also carry an increased risk of CRN, especially if the colitis is extensive;10, 21, 23, 25 therefore patients with PSC who have Crohn’s or indeterminate colitis should be surveyed similar to patients with UC.

Clinical characteristics of colorectal cancer in PSC-IBD patients

Age.  Patients with PSC-IBD have been reported to be significantly younger than IBD-only patients at onset of IBD22, 24, 32 and also at the time of diagnosis of CRC.31

Location.  In many studies, cancer and dysplasia have been reported to be more frequently located in the right colon, proximal to the splenic flexure.6, 10, 20, 22, 32, 35, 36 Carcinoma in particular was found located proximal to the splenic flexure in 39–100% of PSC-IBD cases, compared with only 20–50% of IBD-only cases (Table 1). Even if we consider only those studies in which disease location was matched, still 67–100% vs. 0–36% of cancers were found in a proximal location in PSC-IBD vs. IBD-only patients respectively.10, 32, 35 Thus, it was concluded that PSC is an independent risk factor for right-sided tumours with a calculated OR of 4.8 (95% CI 2.0, 11.8).35 This finding supports the concept that colonoscopy rather than sigmoidoscopy should be used for surveillance. Moreover, this higher frequency of right-sided tumours could suggest a different cancer pathogenesis in patients with PSC-IBD from those with IBD alone, and most authors have speculated about alterations in the concentration and composition of colonic bile acids as the basis for this difference.

Table 1.   Colorectal cancer location in patients with PSC-IBD and in control-IBD patients; cancer is considered proximal if located proximally to the splenic flexure
ReferenceColorectal cancer (n)Extensive colitis or pancolitis (%)Cancer located in the right colon (%)
PSC-IBDIBDPSC-IBDIBDPSC-IBDIBD
  1. NR, not reported.

67487543950
108166611000
20449NRNR10041
2217571487620
352712789716736
3233100100100NR

Relation to PSC characteristics.  Rudolph et al. recently studied the influence of IBD on the outcome of patients with and without bile duct dominant stenosis (defined in their report as high-grade stenosis of the extrahepatic bile ducts leading to biliary obstruction). They found that patients with IBD and dominant bile duct stenosis had an increased risk of developing cancer (CRC, gallbladder cancer and cholangiocarcinoma).37 CRC developed in seven patients with IBD in the observation period, six of whom had a dominant stenosis. Although the association between dominant stenosis and CRC could not be statistically demonstrated in this small study, this finding nonetheless alerts clinicians to the possibility that patients with PSC-IBD and dominant stenosis may have a higher risk of CRC and may need especially careful screening.

Increased risk of colon cancer after liver transplantation

Orthotopic liver transplantation (OLT) is the treatment of choice for patients with PSC who have end-stage liver disease, with survivals ranging from 90–97% at 1 year to 83–88% at 5 years.38 The question therefore arises whether OLT could also be protective for CRC in PSC-IBD patients or not, perhaps by correcting cholestasis, which is one of the proposed theoretical mechanisms involved in cancer risk. Unfortunately, there seems to be little evidence to support the concept of decreased colon cancer risk after OLT. There are in fact several studies reporting the development of CRN in patients with IBD after liver transplantation for PSC, some of them claiming an even higher risk of cancer and some not.39–47 In total, around 52 cases (10%) of CRN have been diagnosed post-transplant in 514 PSC patients with IBD and intact colon (Table 2). Many of these cases were diagnosed within 24–30 months of transplantation, though in most cases the duration of the IBD was greater than 10 years. In several of these studies, there was a short post-transplant interval before cancer appeared, even when colonoscopy had been recently performed as a part of the pre-OLT evaluation, raising the possibility of sampling errors, accelerated malignant transformation related to high levels of immunosuppression or other conditions related to transplantation.39, 40, 45, 46

Table 2.   Summary of studies describing colorectal neoplasia after liver transplant (OLT)
ReferenceIBD-PSC Pts transplanted (n)Pts with intact colon after OLT for F-up (n)Age at OLT (years)CRN after OLT (n)IBD duration in pts w/cancer (years)Time interval between OLT and colorectal cancerF-up after OLT (months)
  1. Pts, patients; m, mean; M, median; NR, not reported.

  2. * It includes one patients with ileo-rectal anastomosis developing rectal cancer after OLT.

  3. † No patient developed cancer, results refer only to dysplasia.

394336412m: 1911 months, 21 monthsm: 45
403327463m: 199 months, 12 months, 13 monthsm: 39
41292143.43NR2 years, 4 years, NRNR
42815745.29NR3.5 months, 10 months, 7.8 yearsM: 50.4
437361*46.5 (UC) 50.6 (CD)5*4 pts: 7–23m: 48 months6–132
44192169NR7NRNRm: 70.9
451008344.98m: 22.5m: 46 monthsNR
461817424m: 13.513 months, 20 months62
4773434611†NR54.7

In a report from Mayo Clinic, there was a fourfold increase in the risk of CRC after transplantation (translating into an incidence of approximately 1.3% per patient-year of follow-up) compared with that expected for patients during a comparable period, although this increase was not statistically significant.42 In a study from Birmingham, UK, the cumulative risk of developing CRC after OLT for PSC in patients with an intact colon and IBD was 14% and 17% after 5 and 10 years respectively.45 In this latter study, multivariate analysis showed that risk factors were the same as for CRC in IBD overall: namely, dysplasia, duration of colitis more than 10 years and pancolitis. In both of these studies, the increased risk did not have a significant impact on survival.

In the largest study performed to date,44 comprising 192 PSC-IBD patients, transplantation was not found to affect the incidence of CRC.44 Similarly, a more recent report compared dysplasia rates among patients with PSC-IBD subjected to OLT, patients with PSC-IBD, but without OLT and patients with OLT, but without either PSC or IBD.47 Although there was no dysplasia among the non-IBD cases, the rates were the same for PSC-IBD patients with and without OLT: 34% and 30% respectively.

Hence, it seems clear that the risk of CRN in PSC-IBD patients is maintained after OLT, and that these patients should be kept in a surveillance programme. There is not enough evidence to suggest that OLT itself accelerates cancer development or confers a higher risk of neoplasia.

Increased risk of colorectal neoplasia after restorative proctocolectomy

Malignant transformation following proctocolectomy with ileal pouch-anal anastomosis (IPAA) seems to be a rare event with around 26 cases described in the literature,48 two of whom were patients with PSC and UC. Both patients had had a mucosectomy with hand-sewn ileo-anal anastomosis and both had initially presented either high-grade dysplasia or cancer in the colectomy specimen; in one patient, adenocarcinoma arose in the ileal pouch mucosa 17 years after IPAA;49 and in the other, malignancy developed in residual rectal mucosa 2 years after IPAA had been performed for rectal cancer.50

Patients with PSC who have undergone IPAA have an increased incidence of pouchitis, which is associated with an atrophic pattern of mucosal adaptation. Some authors have shown that severe and persistent atrophy of the pouch mucosa is a risk factor for pouch mucosal neoplastic transformation.51 Investigators have also found, in a small sample of patients, that those with PSC had a significantly higher incidence of moderate or severe atrophy of the ileal pouch mucosa and a higher (albeit not significantly so) incidence of dysplasia in relation to non-PSC patients.52

Preventive strategies: chemoprophylaxis

The predominance of cancers in the right colon has raised the suspicion that secondary bile acids (BA), which may have carcinogenic potential, could play a role in cancer pathogenesis in this group of patients. Ursodeoxycholic acid (UDCA), by modifying bile acid pool and decreasing faecal levels of the secondary bile acid, deoxycholic acid,53 could therefore have a preventive role. In addition, prolonged administration of UDCA in patients with primary biliary cirrhosis, has been shown to significantly decrease the probability of colorectal adenoma recurrence.54

Three reports have evaluated the impact of UDCA on the risk of developing CRN, once again with conflicting results.55–57 Tung et al. were the first to suggest that UDCA was associated with a decreased prevalence of colonic dysplasia [OR 0.18 (95% CI, 0.05, 0.61); P < 0.005]. In their study, dysplasia was found in 32% of the 41 patients treated with UDCA vs. 72% of 18 patients not treated with UDCA.55 This protective effect remained after adjustment for sex, age at onset and duration of colitis, duration and severity of PSC and sulfasalazine use [adjusted OR 0.14 (95% CI 0.03, 0.64); P < 0.01].

Pardi et al., found that 10% of patients treated with UDCA vs. 35% of patients on placebo developed CRN, again suggesting a significant chemoprotective effect for UDCA, with a 74% reduction in the risk for dysplasia or cancer in those assigned to the UDCA group.56

Contrasting results were reported by Wolf et al., who compared 28 patients with PSC and UC treated with UDCA for at least 6 months, with 92 untreated patients. Although UDCA had a benefit in decreasing mortality, it did not appear to decrease the risk of colorectal cancer or dysplasia.57

All three of these studies had limitations and were retrospective. In view of recent data indicating that high doses of UDCA might worsen prognosis in PSC,58 current evidence does not support the use of UDCA for preventing dysplasia or colon cancer in PSC-IBD patients.59

Regarding chemoprophylaxis with 5-ASA, a study by Lindberg et al. showed that the risk of CRN in PSC-UC patients compared with UC patients without PSC remained elevated even when they had been treated with sulfasalazine.32 Likewise, in a study from France, PSC-IBD patients, despite their lower colonic disease activity and a higher use of 5-aminosalicylates still manifested a higher risk of CRC in comparison with non-PSC-IBD patients matched for disease extent and location.10

Therefore, it seems that neither UDCA nor 5-ASA reliably reduce the elevated risk of CRC in PSC-IBD patients; such efforts must still rely mainly on colonoscopic surveillance.

Preventive strategies: colonoscopic surveillance

The awareness of the high risk of CRC in PSC-IBD patients has led to specific recommendations concerning cancer surveillance in PSC-IBD. It is generally recommended that PSC patients with colitis should be enrolled in a surveillance programme with annual colonoscopy and biopsies from the time of diagnosis of PSC, independent of the known duration of the IBD.60, 61 This guideline is endorsed by the main international societies for the study of liver diseases59, 62 and reinforced by a recent study from Mayo Clinic demonstrating that patients with IBD and PSC can develop CRN relatively soon after diagnosis of both diseases.36

In a population-based study by Kaplan et al. published in 2007, the surveillance practices for patients with PSC and IBD in Calgary Health Region, Canada, were found to be sub-optimal. The number of colonoscopies was only one-third of what was expected, and one-third of patients were not screened at all.23 All individuals who developed dysplasia or cancer in this study had been diagnosed with PSC less than 10 years earlier and two had been diagnosed with UC only 7 years before, underscoring once again that patients with PSC and colitis can develop dysplasia in the early course of their disease and that they need to be informed about this risk and encouraged to enrol in an annual surveillance programme.

Outcomes

In a study from Cleveland Clinic, six of 17 CRC patients (35%) with UC and PSC presented at cancer diagnosis with Dukes stage C or D, and six of them died, compared with no advanced stages or deaths among five CRC patients with UC alone.22 However, the patients with PSC in this study may have had suboptimal surveillance and thus poorer outcomes. Similarly, in a retrospective study comparing CRC in 27 PSC-IBD patients with 127 control IBD patients, those with PSC-IBD had significantly more tumours with an American Joint Committee on Cancer stage of 3A or higher (62% vs. 39%), irrespective of colonic surveillance; moreover, the 5-year survival after CRC diagnosis was lower for the PSC-IBD cases (5-year survival: 40% vs. 75%, P = 0.001).35

So, although morbidity and mortality in these patients are due mainly to hepatic complications,63 CRC is also a devastating complication and both the high risk of CRC and its impact on survival emphasise the need for colonic surveillance in PSC-IBD patients.

Mechanisms of increased risk of colon cancer – part II: perspectives

The mechanisms by which patients with PSC-IBD have an increased risk of CRN remain unknown. The higher frequency of right-sided tumours in this group of patients may suggest a different pathogenesis between patients with PSC-IBD and those with IBD alone. In this regard, many investigators have speculated (albeit without direct evidence) about possible alterations in the concentration and/or composition of colonic BA. It has been postulated that an increase in the concentration of secondary BA could play a role in carcinogenesis,22 and this idea was initially supported by the promising results, although still controversial, of UDCA as a chemoprotective agent in some studies of PSC-IBD patients (see above).55, 56 Notably, patients with PSC alone and without IBD do not have an increased risk of developing CRC. In a large cohort from Sweden, where the risk of malignancies in patients with PSC was assessed, CRC was observed only in patients with concomitant IBD,3 suggesting that additional contributions from other factors besides BA must be involved in CRC pathogenesis in PSC-IBD patients.

Genetic factors can potentially have a role. Two genome wide association studies (GWAS) have been performed to date in PSC, and reported the strongest associations to be on chromosome 6p21, close to the HLA complex. Significant associations were also recognised for three non-HLA loci that had previously been established as susceptibility loci in IBD.64, 65 Interestingly, a previous study reported that a single nucleotide polymorphism (SNP) in position −308 (G→A) in the TNFα promoter was associated with susceptibility to PSC.66 This same polymorphism was found to be significantly more frequent among UC-CRC patients compared with a UC-no CRC control group, independently of the presence of concomitant PSC.67 Two large GWASs of PSC are currently underway and will possibly identify genes influencing the immune response and carcinogenesis, shedding some light on the special phenotype and cancer risk observed in PSC-IBD patients.68

Meanwhile, the recent discovery of new nuclear receptors implicated in BA homeostasis and their correlation with gut inflammation and carcinogenesis, as well advances in our knowledge about intestinal microflora and their possible role in cancer pathogenesis, offer new insights into this subject.

A role for bile acids; interaction with inflamed colon?

Exposure of cells of the gastrointestinal tract to sustained high levels of BA appears to be an important risk factor for gastrointestinal cancer. This phenomenon has been widely demonstrated both in animal and in human studies. Patients with colonic adenomas and CRC present higher than normal concentrations of secondary and total BA in serum and faeces.69 BA can induce production of reactive oxygen and nitrogen species leading to DNA damage, mutation and genomic instability in colon cells.70 The hydrophobic secondary BA, especially deoxycholic acid, appears to be the most strongly associated with CRC.71, 72

Normally, most of the BA secreted by the liver are efficiently reabsorbed in the terminal ileum through an active process carried out by the apical sodium-dependent BA transporter (ASBT), leaving only approximately 5% of the total BA to reach the colonic lumen. In the colon, mostly on the right side, primary BA is transformed into secondary BA by bacterially mediated deconjugation. One fraction of these secondary BA is passively absorbed and reaches the portal circulation, whereas another fraction is further transformed and excreted with the faeces.73

Cholestatic liver diseases such as PSC are characterised by defective hepatic excretion of BA and their accumulation in serum and tissues. This excessive build-up results in the activation of anticholestatic responses in the kidneys, intestine and bile duct to provide alternative excretory routes and thus prevent hepatocellular accumulation of toxic components.74 For example, it has been demonstrated, in both animal and human experiments, that during cholestasis, the ileal expression of ASBT is downregulated.75, 76 These data suggest that intestinal BA absorption is reduced during obstructive cholestasis, which could lead to a relative increase of BA in the proximal colon, in turn producing heightened conversion of primary into secondary BA. Indeed, impaired absorption of BA in the small intestine has been related to colonic tumours. In one animal experiment, Kanamoto et al. eliminated ASBT-mediated BA absorption by resecting the terminal ileum in rats. When these rats were then fed with deoxycholic acid they had an increase in the influx of BA into the colon and a concomitant increase in the incidence of colonic tumours compared with controls.77

As concentrations of carcinogenic secondary BA are highest in the proximal colon, the finding of proximal cancers in PSC supports a role for these compounds.35 Moreover, patients with UC and dysplasia or carcinoma have higher faecal BA concentration than do control UC patients without neoplasia.78

Bile acids homeostasis is tightly regulated by the activation of Farnesoid X Receptor (FXR), a nuclear BA receptor, expressed at high levels in liver and intestine.79 BA act as ligands for FRX, which in turn serves as a biological sensor for BA.80 The interaction between BA and FXR has been shown to play a key role not only in the enterohepatic circulation but also in regulation of inflammatory liver and intestinal responses, intestinal barrier function and antibacterial defence.81 In enterocytes, BA-dependent FXR-activation results mainly in two events. First, FXR induces synthesis of fibroblast growth factor-19, which is then secreted into the portal circulation and acts on hepatocytes to supress CYP7A1, the rate-limiting enzyme responsible for BA synthesis.82 Second, FXR-activation increases expression of ileal BA-binding protein (IBABP) and basolateral organic solute transporter (OST), and is coupled to reduced ASBT expression, which results in decreased BA intestinal absorption and prevention of intracellular BA accumulation.73 In hepatocytes, FXR-activation results in inhibition of BA neosynthesis and also in induction of canalicular BA-transport proteins and BA secretion.81 Therefore, FXR-mediated mechanisms prevent the noxious effects of BA accumulation on hepatocytes and on the cells lining the intestinal and biliary tract.81

It has been recently demonstrated that FXR is a regulator of innate intestinal immunity through a regulatory role in macrophages.83, 84 Animal experiments have demonstrated that FXR-knockout mice are more susceptible to a model of chronic induced intestinal inflammation, and conversely that inflammation down-regulates colonic FXR-expression.83 FXR mRNA expression was almost undetectable in colon biopsies from macroscopically-inflamed areas in patients with Crohn’s disease. Actually, activation of FXR by administration of an FXR-agonist has recently been proposed as a potential new therapeutic target in IBD.84 FXR-activation protects against inflammation possibly by repressing the nuclear factor-κB and by counter-regulating the expression of inflammatory cytokines in immune cells.84 Also, the fact that FXR-activation results in choleresis makes it a rational treatment option for cholestatic liver diseases such as PSC or primary biliary cirrhosis. Indeed, the potent synthetic FXR-agonist, 6-ethylchenodeoxycholic acid (6-ECDCA), is currently under evaluation in a phase III trial for primary biliary cirrhosis.85 However, in cholestatic diseases with an obstructive component, such as PSC, upregulation of canalicular transporters by FXR ligands might be deleterious by way of increasing biliary hydrostatic pressure.86

Besides its regulatory role in enterohepatic cycle, intestinal and liver inflammation, FXR has also been involved in colonic carcinogenesis. It has been demonstrated that FXR-knockout mice have an increased colorectal carcinogenesis in inflammation-linked carcinogenesis mice models87 and that FXR is down-regulated in human colon cancer with a reciprocal relationship between the degree of expression and tumour stage.88

These data suggest that in PSC-IBD patients, colonic inflammation, in part by inactivating FXR-mediated mechanisms, could exacerbate the toxic and pro-carcinogenic effects of secondary BA on colonic cells.

A role for gut flora?

The human colon contains around 1011–1012 different bacterial species, with anaerobic bacteria contributing 99% of the total diversity.89 Intestinal microflora are essential for host wellbeing by virtue of their participation in immune and metabolic functions. For example, gut flora are responsible for degradation of complex polysaccharides with subsequent production of short-chain fatty acids, which contribute to salvage of nutrients and to the integrity of the epithelial layer. The flora also have a role in preventing colonisation of harmful pathogenic species, and they can participate in the detoxification of various carcinogens such as heterocyclic aromatic amines and polycyclic aromatic hydrocarbons.90

Although some members of the colonic microbiome promote the host’s health, there is also evidence for a role of intestinal bacteria in the pathogenesis of IBD of CRC.91 Supporting this concept are the striking observations that chronic intestinal inflammation does not occur when animal models are maintained in a germ-free environment92 and that the incidence of both spontaneous and induced tumours is significantly lower in germ-free conditions.93

Although there are many studies providing evidence for gut flora in colon cancer pathogenesis, fewer data are available for the role of the microbiome specifically in colitis-associated cancer.94 Animal studies have shown, for example, that some members of the commensal microbiome are capable of producing metabolites that act as direct-acting mutagens,95 that the incidence of colonic adenomas in mono-associated mice varies according to the colonising species,96 and that bacteria-induced inflammation can drive progression from adenoma to adenocarcinoma.94, 97 Human studies have allowed identification of specific strains of bacteria in colorectal tumour or faecal samples from patients with CRC. For example, Swidsinski et al.98 demonstrated that patients with colorectal neoplasms had intracellular colonisation by E. coli in 82% of cases vs. 69% of controls. In another study,99 faecal samples from patients with CRC had a higher prevalence of enterotoxigenic Bacteroides fragilis, which has also been involved in IBD.100 Although most attention has focused on the carcinogenic potential of bacteria, it is also true that there are some symbionts capable of detoxifying carcinogens and generating protective metabolites, thus inhibiting chronic intestinal inflammation and lowering the risk of cancer.101

There is a close relationship between gut flora and bile salts. Bile salts have antimicrobial properties102 and have recently been shown, through FXR-activation, to regulate the expression of host genes whose products promote innate defence against luminal bacteria.103 Bacteria have different tolerances to the actions of bile salts, and bacterial pathogenic mechanisms can be modified through interaction with bile salts.104 Conversely, bile salt metabolism is a property of the gastrointestinal microflora; secondary BA, lithocolic and deoxycholic acid, are formed exclusively through microbial biotransformations in the large intestine.105 Some of the secondary bile salts generated by microorganisms can be potentially toxic and/or mutagenic or can lead to activation of other carcinogens in intestinal contents.104

The consequences of cholestasis and of a BA pool altered by the diverse bacteria in the inflamed colon are not fully known, but we can hypothesise that a specific alteration of the microbiome in PSC-IBD patients could participate in colorectal carcinogenesis either directly or through BA transformation. Alternatively, changes in BA compositions could select more pro-carcinogenic strains of bacteria in the gut.

PSC associated with IBD therefore represents a unique model in which to study the physiopathology of CRC in terms of bile salt metabolism, inflammation and interactions with gut flora (Figure 1). A better understanding of these processes might provide new insights into the pathogenic mechanisms involved in the increased CRC risk observed in patients with PSC and IBD.

Figure 1.

 Proposed interaction between colonic inflammation, microbiome and bile acid that could explain increased carcinogenesis in individuals with primary sclerosing cholangitis and inflammatory bowel disease.

Conclusions

Most studies agree that IBD patients with concomitant PSC have a higher risk for CRN than those with IBD alone, even after adjusting for differences in disease location and duration. The risk for colonic dysplasia or cancer in patients with PSC-IBD can approach 50% after 25 years of colitis. Cancers developing in PSC-IBD patients are more frequent in the right colon, which could suggest a different pathogenesis.

Given the high cumulative incidence of CRN and short-time interval between PSC diagnosis and development of neoplasia, PSC-IBD patients must be educated about their increased risk and should enter an annual surveillance colonoscopy programme at the time of PSC diagnosis. The increased risk of CRN is maintained after liver transplant and after restorative proctocolectomy, and therefore these patients also should be maintained under surveillance, although optimal surveillance intervals are not defined. Ursodeoxycholic acid remains controversial as a chemopreventive agent.

CRC is a dramatic complication with a profound impact on survival; a more comprehensive knowledge of the mechanisms involved in the development of CRC during IBD and PSC is needed, so that we can better prevent and treat the neoplastic disease in these patients. The better understanding of these mechanisms including host and microbial alterations, could lead to the development of new biological markers or new targeted interventions against the underlying abnormalities of colorectal inflammation-linked carcinogenesis.

Acknowledgements

Declaration of personal interests: None. Declaration of funding interests: Joana Torres has received a Travel Grant from International Organization for the study of Inflammatory Bowel Disease (IOIBD) and a Grant from Burril B. Crohn Research Foundation.

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