ORIGINAL ARTICLE

The Phenotypic Expression of Inflammatory Bowel Diseasein Patients with Primary Sclerosing Cholangitis Differsin the Distribution of Colitis

David F. Schaeffer • Lay Lay Win •

Sara Hafezi-Bakhtiari • Maria Cino •

Gideon M. Hirschfield • Hala El-Zimaity

Received: 23 November 2012 / Accepted: 18 April 2013 / Published online: 14 May 2013

� Springer Science+Business Media New York 2013

Abstract

Background Inflammatory bowel disease (IBD) associ-

ated with primary sclerosing cholangitis (PSC) is reported

to be mild and prone to right-side predominance with rectal

sparing. However, no dedicated studies evaluating patterns

of presentation of liver disease with respect to IBD are

available.

Methods We performed a detailed histological examina-

tion of the colonic biopsies in the context of PSC, identi-

fying 97 patients [89 with ulcerative colitis and ten with

Crohn’s disease (CD)] stratified into two groups, based on

their initial disease presentation: hepatic/biliary (group 1—

PSC-IBD; n = 56) versus colonic (group 2—IBD-PSC;

n = 41).

Results Inflammatory bowel disease that preceded PSC

had a tendency to have a ‘‘pan-colitis’’ distribution; this

group included all patients with CD. Inflammatory bowel

disease diagnosis that followed PSC presentation was more

likely to be right-sided, sparing the descending, sigmoid

and rectal regions (p = 0.002). In both groups, colitis was

mild with focal deep plasmacytosis and occasional mild

cryptitis. Active cryptitis with crypt abscesses, surface

erosion and ulceration were not identified in any of the

patients.

Conclusion Colitis associated with PSC shows mild dis-

ease activity and the colitis pattern is associated with dis-

ease presentation, i.e. colitis preceding PSC (IBD-PSC

cohort) typically have a pancolitic distribution, while

colitis following PSC (PSC-IBD cohort) demonstrates

right-sided predominance. Awareness by pathologists and

clinicians of these patterns of inflammatory bowel disease

is important and of use in directing appropriate investiga-

tions for patients.

Keywords Ulcerative colitis � Inflammatory bowel

disease � Primary sclerosing cholangitis � Pancolitis �PSC-IBD � Colitis distribution

Introduction

The association of primary sclerosing cholangitis (PSC)

with ulcerative colitis (UC) is long described [1]. An

association with Crohn’s disease (CD) was also suggested

early on, but was found to be less common than with UC

[2]. More recent studies have proposed consideration of

PSC-IBD as a third IBD phenotype, independent of UC and

CD [2, 3]. This concept has been further strengthened by

the discovery of distinctions in genetic associations for

PSC and UC/CD [4]. A large PSC population-based study

from the Netherlands recently also corroborated findings by

demonstrating that the IBD phenotype was unique in a

cohort of 579 PSC patients [5].

The prevalence rates of PSC-IBD vary considerably

between different series, ranging from 80 % in northern

D. F. Schaeffer � S. Hafezi-Bakhtiari � H. El-Zimaity (&)

Department of Laboratory Medicine and Pathology, Toronto

General Hospital, University of Toronto, 200 Elizabeth Street,

Toronto, ON M5G 2C4, Canada

e-mail: hala.el-zimaity@uhn.ca

L. L. Win � M. Cino

Liver Centre, Toronto Western Hospital, Toronto, ON, Canada

M. Cino � G. M. Hirschfield

Division of Medicine, University of Toronto, Toronto, ON,

Canada

G. M. Hirschfield

Centre for Liver Research, NIHR Biomedical Research Unit,

University of Birmingham, Birmingham, UK

123

Dig Dis Sci (2013) 58:2608–2614

DOI 10.1007/s10620-013-2697-7

Europe and North America [6] as compared to 50 % in

southern Europe [7] and 35 % in Asia [8, 9]. Treatment

guidelines for PSC, such as the American Association for

the Study of the Liver, stress the importance of screening

colonoscopy with histology, if IBD is not already known.

PSC may appear many years after proctocolectomy for

colitis, and the onset of IBD can be seen many years after

liver transplantation for PSC [10–12]. Clinically, backwash

ileitis, rectal sparing and low disease activity seem to

characterize IBD when associated with PSC [13]. The

subtleties of colitis in this context may not however always

be adequately appreciated by clinicians. We sought to

study, through detailed histopathologic review, the nature

of colitis in patients with PSC and to correlate patterns of

hepatic presentation with colonic disease activity and

extent.

Methods

Patient Selection

We identified patients with a diagnosis of PSC and IBD

from the clinical and pathology files of University Health

Network between the years 1995 and 2011. The diagnosis

of PSC required well-characterized clinical features, such

as radiological findings of beading, duct ectasia and/or

structuring of the intrahepatic or extrahepatic ducts. The

diagnosis of IBD required at least one colonoscopy with

segmental biopsies. In this study, as the use of immune-

modulatory agents to control rejection can confound

observations, we considered transplant an endpoint.

We reviewed patients’ medical records retrospectively

to determine primary disease presentation, as either hepa-

tic/biliary or colonic. We excluded patients if primary

disease presentation could not be elucidated with absolute

certainty. We collected demographic information, such as

age at IBD or PSC presentation, gender, duration of IBD,

interval between IBD and PSC or vice versa diagnosis and

history of liver transplant (see Table 1).

Histological Evaluation

All biopsies were fixed in formalin and prepared by routine

hematoxylin and eosin staining. As colitis associated with

primary sclerosing cholangitis is typically mild, we asses-

sed colonic inflammation as well as structural integrity on a

6-point grading system to help us identify small differences

(see Table 2). Assessment was made blinded to the pattern

of liver disease presentation. For the purpose of summa-

rizing disease activity a simplified grading scheme was

employed [negative (0), mild (1), moderate (2) and severe

(3)] to include overall changes in architectural distortion,

crypt destruction, erosion/ulceration, presence of plasma

cells and neutrophils. In short, scores 1 and 2 were com-

bined as mild (grade 1), scores of 3 graded as moderate

(grade 3) and scores 4 and 5 as severe (grade 3). We

considered the presence of neutrophilic inflammation evi-

dence of active disease. The presence of erosions or surface

ulceration was considered severe activity. Criteria for

chronicity included architectural distortion, basal plasma-

cytosis and Paneth cell metaplasia in the left colon. In the

left colon, deep plasmacytosis was defined as plasma cells

in the lower third of crypts (score of 2). Taking the pres-

ence of ‘‘normal’’ deep plasma cells within the cecum into

account, the scoring scale was adjusted accordingly and

only prominent lymphoplasmacytosis was considered to be

positive (score of 3 or higher) (Fig. 1; Table 2).

We separately evaluated biopsies from the terminal

ileum, caecum, ascending colon, transverse colon,

descending colon, sigmoid colon and rectum. For the

purpose of stratifying the extent of the colitis, biopsies

from the caecum and ascending colon were considered to

reflect the ‘‘right side’’. The ‘‘left side’’ was defined as

involving the transverse, descending and sigmoid colon.

An overall score was calculated per endoscopy by adding

all inflammatory scores, including acute and chronic, and

dividing by the number of specimens. The patient’s overall

inflammatory score represented the mean score of all sep-

arate endoscopies performed in this patient. Histologic

evaluation was blinded to clinical presentation, and specific

to this study.

Statistical Analysis

All scores were entered into a database and analyzed using

STATA 11 (StataCorp, College Station, TX). Fisher’s

exact test or, when appropriate the chi-square test, (both

2-tailed) were used for comparison of proportions. Statis-

tical significance of differences and relationships was

determined by p values of less than 0.05.

Ethics Approval

Ethics approval for the study was obtained from the

Research Ethics Board of the University Health Network.

Results

Patient Demographics and Clinical Features

This study included 97 patients with a diagnosis of PSC

and IBD. Of those, 56 developed colitis following the

diagnosis of primary sclerosing cholangitis (designated

PSC-IBD patient cohort). This group included 18 females

Dig Dis Sci (2013) 58:2608–2614 2609

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(32 %) and 38 males (68 %), with an average age of

20 years at the time of PSC diagnosis (age range

11–47 years). Forty-four (79 %) patients underwent sur-

veillance colonoscopies given that there was a strong

relationship between PSC and IBD, but did not have any

GI-related symptoms. The remaining 12 (21 %) patients

presented with lower GI symptoms, such as watery or

bloody diarrhea with or without fever and abdominal pain,

prompting colonoscopic examination. The mean time

interval before the subsequent diagnosis of inflammatory

bowel disease was 1.9 years (range 0–16 years), with 51

patients (91 %) developing ulcerative colitis; only five

patients (9 %) developed Crohn’s disease. At the time of

analysis 26 patients (46 %) subsequently underwent liver

transplant for endstage PSC.

In comparison, 41 of the 97 patients developed colitis

prior to a diagnosis of primary sclerosing cholangitis

(designated the IBD-PSC group). This group had 11

females (27 %) and 30 males (73 %) with a mean age of 19

at colitis diagnosis (age range 1–59 years). Ulcerative

colitis was also more predominant in this group (36 [88 %]

had ulcerative colitis; only five patients [12 %] had Cro-

hn’s disease). The mean time interval between the initial

diagnosis of IBD and subsequent PSC was 6.1 years (range

0–29 years). In this group twenty-six patients (63 %)

underwent liver transplant.

We reviewed 1,153 endoscopic mucosal biopsies from

338 colonoscopies of the 97 patients. The number of col-

onoscopies was relatively similar between the PSC-IBD

and IBD-PSC group, as was the number of retrieved

endoscopic mucosal biopsies (see Table 1). Data on

colectomy specimen was not available for either group.

Pathological Features

Disease Activity

The study cohort showed a low overall grade of colitis. In

the PSC-IBD cohort 48 patients (86 %) displayed mild

colitis (combined grade 1) compared to 39 patients (95 %)

Table 1 Clinical features and

demographics of patient cohort

and subclassification for PSC-

IBD and IBD-PSC patients

PSC primary sclerosing

cholangitis, IBD inflammatory

bowel disease, UC ulcerative

colitis, CD Crohn’s disease, NA

not available

Characteristic Entire PSC-IBD cohort (n = 97)

Gender m:f [n (%)] 68:29 (70:30)

Age at disease onset (y; range) 19.8 (1–59)

Subtype of IBD [n (%)]

Ulcerative colitis 87 (90)

Crohn’s disease 10 (10)

Colonoscopies (n)

Total number 338

Endoscopies/patient [mean ± SD] 3.35 ± 3.25

Endoscopic mucosal biopsies (n)

Total number 1,153

Biopsies/patient (mean ± SD) 15 ± 11

Characteristic Primary liver diagnosis

[PSC-IBD; (n = 56)]

Primary colonic

diagnosis [IBD-PSC;

(n = 41)]

Gender m:f [n (%)] 38:18 (68:32) 30:11 (73:27)

Age at PSC onset (y; range) 20.3 (11–47) –

Age at IBD onset (y; range) – 19.3 (1–59)

Subtype of IBD (UC:CD) [n (%)] 51:5 (91:9) 36:5 (88:12)

Time interval between PSC and IBD

diagnosis (y) [mean (range)]

1.9 (0–16) 1.9 (0–16)

Time interval between IBD and PSC

diagnosis (y; range)

– –

Liver transplant [n (%)] 26 (46) 26 (63)

Colonoscopies (n)

Total number 186 152

Endoscopies/patient (mean ± SD) 3.9 ± 1.9 2.8 ± 4.6

Endoscopic mucosal biopsies (n)

Total number 629 524

Biopsies/patient (mean ± SD) 16 ± 12 13 ± 10

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in the IBD-PSC group. There was no statistically signifi-

cant difference between the groups. Importantly, none of

the study patients showed any severe activity within any

biopsy. The number of eosinophils present within the

lamina propria served as a surrogate marker for the amount

of inflammation present as demonstrated in Table 3.

Extent of Inflammatory Bowel Disease

A statistically significant higher number of IBD-PSC

patients (56 %) had a pancolitic distribution of disease than

localized to the right (20 %) or left side (24 %; p = 0.002).

This distribution was also significant (p = 0.018) when

Fig. 1 Prominent deep plasmacytosis in the lower third of crypts

(score of 3) in ascending colon [H&E 95]

Table 2 Grading scale used for histological assessment of inflam-

mation and structural damage

Grade Description

(1) Architectural change

Architectural distortion

0 Negative

1 10 % of crypts distorted

2 25 % of crypt distorted

3 50 % of crypts distorted

4 75 % of crypts distorted

5 100 % of crypts distorted

Crypt destruction

0 Negative

1 Probable—local excess

of neutrophils in part of

crypt

2 Probable—marked

attenuation

3 Unequivocal crypt

destruction \5 % of

specimen

4 Crypt destruction [5 but

\50 % of crypts

5 Crypt destruction [50 %

of crypts

Erosion or ulceration

0 No erosion The presence of erosions or

surface ulceration was

considered severe activity

1 Recovering

epithelium ? adjacent

inflammation

2 Probable erosion- focally

stripped

3 Unequivocal erosion

4 Granulation tissue or

ulcer \50 % of

specimen

5 Granulation tissue or

ulcer [50 % of

specimen

(2) Inflammatory cells

Plasma cells

0 Negative In the left colon, deep

plasmacytosis was defined as

plasma cells in the lower third

of crypts (score of 2). In the

caecum and ascending colon,

deep plasma cells had to be

more extensive to be

considered positive (score of 3

or higher)

1 Lower 1/3 loose

2 Lower 1/3 compact

3 Lower third and beyond

in \5 % of specimen

Table 2 continued

Grade Description

4 [5 % but \50 %

5 [ 50 %

Neutrophils (PMN)

0 Negative

1 PMNs in lamina propria

or surface epithelium

2 Cryptitis but no crypt

abscess

3 Cryptitis abscesses \5 %

of crypts

4 Cryptitis abscesses[5 but

\50 % of crypts

5 Cryptitis abscesses

[50 % of crypts

Paneth cell metaplasia

1 If present on left side

To summarize the overall disease activity, we converted the 6-point

scale to a 4-point colitis grade as follows: scores 1 and 2 = mild

(grade 1), scores 3 = moderate (grade 2) and scores 4 and 5 = severe

(grade 3)

Dig Dis Sci (2013) 58:2608–2614 2611

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compared to the PSC-IBD group, where only 19 patients

(33 %) had a pancolitic disease extent, as compared to 30

patients (53 %) who displayed only right-sided colitis

(Fig. 2). Only seven patients (12 %) had a left sided colitis.

The prevalence rate of ileitis was 29.5 % in the entire study

cohort, but there was no statistically significant difference

between the two groups; importantly none of the cohort

patients displayed any chronic inactive changes in the

ileum.

Discussion

To our knowledge this is the first study to document spe-

cific histologic changes in PSC-IBD patients based on the

primary disease presentation. It has been well accepted that

PSC-IBD shows characteristic clinical, colonoscopic, and

histopathological findings [2, 5, 13]. Furthermore, it has

been noted that the interval between the onset of the

inflammatory bowel disease and the onset of biliary tract

disease can vary widely. One of the unifying aspects of

PSC associated IBD however has been its relatively mild

histological appearance. This has been demonstrated in

endoscopic studies [2], as well as by histological assess-

ment [14]. To date, in the largest study by Joo et al. [14] to

systematically evaluate PSC-IBD on histological grounds,

the authors showed a very mild inflammatory activity of

the PSC-IBD patients as compared to matched UC control

patients. These histological findings appear to correlate

directly with the clinical course as the number of hospi-

talization and length of steroid treatment was decreased in

PSC-IBD patients in comparison to UC patients [15].

We confirm the histological impression of a very mild

disease phenotype (Fig. 3); however, we also showed that

there is a statistically significant difference in the extent of

colonic disease based on the primary disease presentation.

The ‘classical’ PSC-IBD displayed the known right-sided

colitis, while IBD-PSC patients showed a higher preva-

lence of pancolitis. Pancolitis itself is not a new finding in

PSC-IBD patients. Prevalence rates of up to 87 % as

compared to 54 % in the matched non-PSC UC control

group have been reported in endoscopy studies [2] and by

colleagues in a pathological assessment study [14]. How-

ever, the literature also reports differing findings [16]

which in part may be explained by ‘heterogeneous’ study

groups in terms of primary disease presentation as dem-

onstrated in this current analysis.

Our study certainly has limitations. For one we did not

evaluate the medication profile of our patients. For exam-

ple, it is fair to assume that most PSC patients received

ursodeoxycholic acid therapy, while the IBD-PSC group

may not have. However, there is recent evidence that ur-

sodeoxycholic acid does not improve the course of IBD in

PSC patients [17] and as such it is doubtful whether this

variable may have any impact on our study cohort. We also

did not have IBD medications listed. Secondly, our anal-

ysis was based exclusively on endoscopically obtained

mucosal biopsies and as such we did not have the benefit of

analysis of the entire colon. However, we consider that this

represents a strength of the study since it accurately reflects

Table 3 Pathologic features of colitis in PSC-IBD patients and IBD-

PSC patients

Feature Primary liver

diagnosis [PSC-IBD;

(n = 56)]

Primary colonic

diagnosis [IBD-PSC;

(n = 41)]

Extent of disease [n (%)]

Pancolitis 19 (33)* 23 (56)*

Right sided 30 (53)** 8 (20)**

Left sided 7 (12) 10 (24)

Proctitis 0 (0) 0 (0)

Colitis grade [mean (%)]

Grade 0—negative 0 (0) 0 (0)

Grade 1—mild 48 (86) 39 (95)

Grade 2—moderate 8 (14) 2 (5)

Grade 3—severe 0 (0) 0 (0)

Eosiniophilic infiltratea [mean ± SD]

Right 45 ± 14 29 ± 18

Left 18 ± 9 27 ± 16

Overall 63 ± 25 56 ± 34

Ulcer [mean (0)] 0 (0) 0 (0)

PSC primary sclerosing cholangitis, IBD inflammatory bowel diseasea Eosinophil count/3 hpf

* p = 0.002; ** p = 0.018

Fig. 2 The distribution of colitis depends on primary disease

presentation. If liver disease precedes the colitis (PSC-IBD) the

colitis has a right-sided predominance. When colitis precedes liver

disease (IBD-PSC), the pattern is predominantly pancolitic in

distribution

2612 Dig Dis Sci (2013) 58:2608–2614

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the reality of pathology practice. Finally our hospital-based

practice in a centre of excellence that acts as a tertiary

centre, with liver transplantation as one service, inherently

introduces biases into our population. Overall however our

goal was to clinically describe the histopathology of colitis

in the context of patterns of PSC-IBD presentation, with a

strong emphasis on dedicated histopathological review.

Thus whilst limitations persist, our findings have clinical

utility to practicing clinicians.

In summary, we validate previous studies in reporting a

mild inflammatory activity in PSC-IBD patients, but also

determine that the extent of disease may be quite different

depending on the primary disease presentation. It is well

established that PSC can be present as an asymptomatic

disease with only mild changes in liver biochemistry tests,

which may fluctuate, so that episodes of normal liver

biochemistry may occur. Our study findings highlight the

important role of the pathologist when reporting colonic

histology, particularly if mild patterns of disease are noted.

Appreciating the nuances of PSC-IBD pathologically may

prompt timely hepatic investigations.

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