Embed Size (px)
Citation preview
1
TITLE PAGE
Risk Factors for Recurrent Primary Sclerosing Cholangitis After Liver
Transplantation
Reena Ravikumar1, Emmanuel Tsochatzis1, Sophie Jose2, Michael Allison3, Anuja
Athale4, Felicity Creamer5, Bridget Gunson6, Vikram Iyer6, Mansoor Madanur4, Derek
Manas7, Andrea Monaco1, Darius Mirza6, Nicola Owen3, Keith Roberts6, Gourab
Sen7, Parthi Srinivasan4, Stephen Wigmore7, Giuseppe Fusai1, Bimbi Fernando1,
Andrew Burroughs1
1 Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal
Free Hospital, London, UK
2Research Department of Infection and Population Health, University College
London
3Cambridge Transplant Unit, Cambridge University Hospitals, Cambridge, UK
4Institute of Liver Studies, Kings College Hospital, London, UK
5Department of HPB and Liver Transplant Surgery, Royal Infirmary of Edinburgh, UK
6The Liver Unit, University Hospital Birmingham
7Institute of Transplantation, Freeman Hospital, Newcastle
Corresponding author:
Dr Reena Ravikumar,
Sheila Sherlock Liver Unit and UCL Institute for Liver and Digestive Health, Royal
Free London Hospital, Pond Street, London NW3 2QG, UK
0044 7748 700702
2
Abstract word count: 248 words
Manuscript word count: 2972 words
Number of figures and tables: 6 (2 tables, 4 figures)
Keywords: recurrent PSC, ulcerative colitis, colectomy, liver transplantation,
patients and graft survival
Conflicts of interest: No conflicts of interest declared.
Financial support: A £2000 grant from the Royal Free Charity was given to fund the
statistical analysis.
Authors contributions:
RR designed the study, interpreted the data, drafted and revised the manuscript. SJ
analysed and interpreted the data, drafted and revised the manuscript. ET and AKB
interpreted the data and revised the manuscript. BF and GF helped design the study.
MA, AA, FC, BG, VI, MM, DM, AM, DM2, NO, KR, GS, PS, SW, GF, BF undertook
data acquisition and revision of the manuscript. ET and AKB provided final approval.
3
Abstract
Background and aims: The association between Primary Sclerosing Cholangitis
(PSC) and Inflammatory Bowel Disease (IBD) is well recognised. However, the
relationship between IBD and recurrent PSC (rPSC) is less well understood. We
assessed the prevalence of rPSC and analysed the factors associated with rPSC
post liver transplantation and its influence on graft and patient survival.
Methods: This is a UK multicentre observational cohort study across six of the
seven national liver transplant (LT) units. All patients undergoing a first LT for PSC
between January 1 1990 and December 31 2010 were included. Prospectively
collected LT data was obtained from NHSBT and colitis data was retrospectively
collected from individual units.
Results: There were 679 (8.8%) first transplants for PSC. 347 patients (61.4%) had
IBD, of which 306 (88.2%) had ulcerative colitis (UC). 81 (14.3%) patients developed
rPSC and 37 (48.7%) of them developed graft failure from rPSC. Presence of UC
post-LT (HR=2,40 95% CI 1.44-4.02) and younger age (HR=0.78, 95% CI 0.66-0.93)
were the only factors significantly associated with rPSC. rPSc was associated with
over a 4-fold increase in the risk of death (HR=4.71, 95% CI 3.39, 6.56) with 1, 5 and
10-year graft survival rates of 98%, 84% and 56% respectively compared to 95%,
88% and 72% in patients who did not develop rPSC.
Conclusion: The presence of UC post LT is associated with a significantly
increased risk of rPSC. Furthermore, the presence of rPSC increases the rate of
graft failure and death, with higher re-transplantation rates.
4
INTRODUCTION
Primary sclerosing cholangitis (PSC) is an autoimmune disease of the intrahepatic
and/or extrahepatic biliary tree with variable clinical course and no curative
treatment.[1] It is a progressive disorder that can lead to cirrhosis and hepatic
decompensation. PSC co-exists with inflammatory bowel disease, mainly ulcerative
colitis (UC), in 60-70% of the patients.[1]
At present, the only effective therapeutic option for patients with PSC and end stage
liver disease is liver transplantation. Nevertheless, PSC can recur after liver
transplantation, with an incidence of 8.6 to 47% depending on the criteria used to
define recurrence.[2] The factors associated with post-transplant recurrence are
unclear but have been assessed in small cohort studies. These have suggested that
gender[3], presence of inflammatory bowel disease (IBD) or an intact colon after liver
transplantation[3-7] and recurrent acute cellular rejection or steroid resistant rejection
[8, 9] are potential risk factors for recurrent PSC (rPSC), although findings were
inconsistent.
The association between the status of colitis and rPSC is of particular interest. This
implied interaction between the bowel and the liver is reinforced by additional
associations; UC in patients with PSC pre-transplant is often clinically quiescent, but
involves the whole of the colon with more right-sided colitis and carries a higher risk
of bowel cancer compared to UC alone.[10, 11] When patients with UC/PSC are
transplanted for PSC, the number and severity of UC flares increase post-transplant.
[12] On the other hand, colectomy in patients with PSC/UC has no effect on liver
biochemistry or patient survival in the pre-transplant setting.[13]
5
This UK multicentre study assessed the rate and analysed the factors associated
with rPSC post liver transplantation. In particular, it aimed to explore the influence of
colitis and the associations of the presence, timing and type of colectomy with
recurrence in patients with PSC/UC. It also assessed the influence of rPSC on graft
and patient survival.
MATERIALS AND METHODS
Patients
This is a UK multicentre observational cohort study that involved six of the seven
national liver transplant units. All patients undergoing a first liver transplant for PSC
between January 1 1990 and December 31 2010 were included. National ethical
approval, National Health Service Blood and Transplant (NHSBT) approval and
National Information Governance Board approval were obtained to perform this
multicentre study. Prospectively collected liver transplant data was obtained from
NHSBT and colitis data was retrospectively collected from individual units.
Retrospective data was obtained from electronic patient records, patient notes and
hospital databases. Individual patient records at each centre were examined to
further establish the presence of rPSC and to determine the modality of diagnosis of
rPSC. The following liver transplant data was collected: indication for transplantation,
cause and date of death, demographic data, presence of associated
cholangiocarcinoma (CCA), initial use and type of immunosuppression, annual follow
up data for the entire follow up period, presence of rPSC, patients and graft survival.
The following colitis data was collected: presence and type of colitis, date of
diagnosis, timing and type of colectomy.
6
Diagnosis of rPSC
Cases of rPSC were identified in the dataset through centre reporting of a rPSC
diagnosis or graft failure due to recurrence reported by NHSBT. After liver
transplantation, patients are investigated by Doppler ultrasonography, CT or MRI,
magnetic resonance cholangiography (MRCP) or liver biopsy if indicated by
abnormal liver function tests. Routine/protocol angiographic imaging or liver biopsies
for the diagnosis of rPSC were not performed in patients with normal liver function
tests in the absence of clinical indications. The diagnosis of rPSC was guided by the
Mayo Clinic criteria.[14, 15] Patients with autoimmune hepatitis overlap were
excluded. The diagnosis of rPSC at centres was based on histological and
radiological features of PSC in the absence of defined causes of secondary
sclerosing cholangitis and non-anastamotic biliary strictures.[15] Histological
evidence of rPSC was based on the findings of periductular fibrosis, obliterative
ductular lesions and bile duct loss in the absence of chronic allograft rejection.[15-
17] Radiological features of rPSC were defined as intra and/or extrahepatic non-
anastomotic biliary strictures in the presence of normal vascular supply.[15]
Dedicated liver radiologists and histopathologists performed all radiological and
histological evaluations.
Statistical analysis
Risk factors for rPSC were assessed using Kaplan-Meier and Cox Proportional
Hazards (CPH) models with baseline and time-updated covariates. For these
analyses, follow up was calculated from date of first LT to recurrence PSC, as
defined above, and censored at graft failure for other reasons, death or 31st
December 2013. Time updated CPH models also investigated the effect of rPSC and
7
presence of UC on patient survival (calculated at a patient level) and both graft
survival and a combined end-point of graft survival or death (calculated at a graft-
level), with follow up calculated from LT until graft failure or death.
RESULTS
Recipient Characteristics
9068 liver transplants were performed in 8186 patients, of which 679 (8.3%) were
first liver transplants for PSC. A total of 114 patients were excluded from the final
analysis (48 patients with hepatic artery thrombosis, 11 with primary graft non-
function and 55 who died within 6 months of transplant), in keeping with other
published series. This left a final cohort of 565 patients in the final analysis.
The leading cause of death within the first 6 months of transplantation was sepsis
(13 patients) and multi-organ failure (12 patients). The median age at transplantation
was 49 years (interquartile range (IQR) 40 - 57), with a greater preponderance of
men to women (71.8% and 28.2% respectively). (Table 1) Median follow up was 9
years (IQR 5 -14 years). 347 patients (61.4%) had inflammatory bowel disease
(IBD), of which 306 (88.2%) had ulcerative colitis (UC), 29 (8.4%) had Crohn’s colitis
and 12 (3.5%) had indeterminate colitis. 235 patients had a diagnosis of UC prior to
transplantation, of whom 35 (14.9%) had a colectomy prior to transplant, 4 (1.7%)
had a colectomy during their transplant and 37 (15.8%) had colectomy post -
transplant. The timing of colitis diagnosis relative to liver transplant was unknown for
43 (12.4%) patients, of which 27 patients had a diagnosis of UC. 36 (11.8%) patients
8
were diagnosed with UC after their liver transplant. 7 (19.4%) of these patients had a
colectomy.
Recurrent PSC Population
115 cases of rPSC were identified within the NHSBT dataset, 81 (14.3%) of which
were subsequently conclusively confirmed as such by the individual centres (11
cases had biliary complications).
37 (48.7%) patients with rPSC developed graft failure secondary to recurrent
disease, of which 17 (45.9%) patients died and 17 (45.9%) patients were re-grafted
at a median (IQR) of 7.4 (5.3-10.5) years after the first transplant (Figure 1). One
patient transplanted for PSC who required a second transplant for non-thrombotic
infarction, underwent a third transplant for graft failure secondary to rPSC. In the 81
patients diagnosed with rPSC on their 1st liver transplant, 17 were diagnosed with
MRCP, 43 with histology from a liver biopsy and 18 with both MRCP and a liver
biopsy. Histology from liver biopsies revealed features typical of rPSC in 33 patients
and compatible with rPSC in 28 patients. No details were available for 3 patients.
Of 484 individuals who did not have rPSC, only 76 (15.7%) experienced graft failure.
16 of these patients were re-transplanted for hepatitis C cirrhosis (n=2), biliary
complications (n=2), non-thrombotic infarction (n=1). No cause was identified for 6
patients. 13 patients with rPSC patients developed anostomotic biliary strictures in
the immediate post-transplant period, of which 3 were successfully treated with
biliary stents and 3 required a biliary reconstruction. The remaining 7 required no
9
intervention. rPSC in these patients developed years after the anastomotic strictures
and was well documented.
Risk Factors for rPSC
In univariable analysis, UC appeared to be the strongest predictor of rPSC (Table 2).
Diagnosis of UC at any stage, before or after liver transplantation was associated
with an increased risk of rPSC (HR= 2.27, 95%CI 1.31-3.94 diagnosed before
transplantation; HR=3.16, 95%CI 1.17-8.54 diagnosed after transplantation).
Presence of UC post-transplant (UC diagnosed pre-transplant with no colectomy or
UC diagnosed post-transplant) was associated with significantly higher rPSC,
compared to absence of post-transplant UC (no UC or colectomy pre-transplant)
(19.2% vs. 8.2%, HR=2.40, 95% CI 1.44-4.02).
The primary immunosuppressive regime was associated with rPSC in the univariable
analysis. Cyclosporine use had a greater than 2-fold increased risk of rPSC
(HR=2.11, 95% CI 1.22, 3.66). 400 patients had no changes to their primary
immunosuppression drug (cyclosporine/tacrolimus) at 12 months post-
transplantation. 12 patients who initiated cyclosporine immunosuppression
immediately after liver transplantation had discontinued by 12 months, 9 of who
initiated tacrolimus in this time frame. A further 12 patients who were started on
tacrolimus had discontinued by 1 year; 3 initiated cyclosporine in the same time
frame. After adjusting for transplantation era, the use of tacrolimus or cyclosporine
was no longer significantly associated with rPSC (HR=2.07, 95% CI (0.97, 4.44)).
10
Transplantation era was also significantly associated with rPSC. Patients
transplanted between 2001 and 2010 were less likely to develop rPSC compared to
patients transplanted between 1990 and 2000 (HR=0.49, 95% CI (0.31, 0.79)).
We also observed evidence of an association between recipient age and rPSC.
There was a 22% reduction in the recurrence of PSC with each 10 year increment in
age at liver transplant: unadjusted HR=0.78, 95% CI 0.66-0.93. A Kaplan-Meier
analysis of age groups demonstrated that younger patients appeared to progress
quicker with a lower recurrence-free survival (p=0.03, Figure 2). Gender, donor
status (DCD or DBD), donor age, cholangiocarcinoma and type of colectomy were
not associated with rPSC. Of the patients who had a colectomy pre/during
transplant, 11.1% developed rPSC whereas 23.3% of those who had a colectomy
post-transplant had a diagnosis of rPSC (Figure 3, HR=1.89, 95% CI 0.61-5.81 in
those with post-transplant colectomy).
Considering timing of colectomy only in those diagnosed with UC prior to transplant,
we observed an approximate 172% increase in the risk of rPSC in those who had a
colectomy post-transplant (HR=2.72, 95% CI 0.75-9.88), and 63% increased risk in
those who did not have a colectomy (HR=1.63, 95% CI 0.58-4.61) compared to
those with pre/during transplant colectomy, though not statistically significant.
In a multivariable model that included, age, presence of UC post-LT, timing of
colectomy, era of transplantation (before or after the year 2000) and
cyclosporine/tacrolimus use, presence of UC post-LT and younger age were the only
factors independently associated with rPSC. A 154% increased risk of rPSC was
11
found where UC was present post-transplant (HR=2.54, 95% CI 1.32, 4.86). A 23%
reduction in the risk of rPSC was found with each 10-year increment in age
(HR=0.77, 95% CI 0.61, 0.99). There was also a trend for a 2-fold increase in the risk
of rPSc with cyclosporine (HR=2.07, 95% CI 0.97-4.44), although this did not reach
statistical significance. Transplantation era was no longer associated with rPSC
(HR=0.73, 95% CI 0.42-1.84). There was no association with post-transplant
colectomy when compared to colectomy pre-transplant (HR=0.69, 95% CI 0.14-
3.42).
Survival Outcome
Patient survival following a first PSC related liver transplant at 1, 5 and 10 years was
97%, 89% and 79% respectively in the study cohort. When including patients with
HAT, PNF and those who died withing 6 months of transplantation (n=679), patient
survival at 1, 5 and 10 years was 87%, 79% and 70%. In univariable analysis, rPSC
was associated with an increased risk of overall patient mortality (HR=2.79, 95% CI
1.87, 4.16) whereas presence of UC post-transplantation was not associated with
patient survival (HR=0.95, 95% CI 0.68, 1.33).
In a multivariable model containing rPSC, presence of UC post-transplant and
whether re-transplant was performed, rPSc was associated with a nearly 4-fold
increase in the risk of graft failure or death (HR=2.17, 95% CI 1.32, 3.57). The
presence of UC post-transplant was not associated with patient survival after first
transplant (HR=0.90, 95% CI 0.64, 1.27).
12
In the rPSC population, 1, 5 and 10-year graft survival rates were 98%, 84% and
56% respectively compared to 95%, 88% and 82% in patients who did not develop
rPSC (Figure 4). 372 (65.8%) grafts were still functioning in surviving patients at the
end of our follow up period. The presence of rPSC increased the risk of graft failure
(HR=8.15, 95% CI 5.59-11.89). rPSC increased the risk of graft failure or death by
4.71 times (95% CI 3.39-6.56). The presence of UC post-LT was not associated with
graft survival or death (HR 1.03, 95% CI 0.73, 1.44 for graft failure; HR=0.92, 95% CI
0.70- 1.21 graft failure or death). In a multivariable model containing UC post-
transplant, rPSC and an indicator for first or re-transplant, rPSC was still associated
with graft survival (HR=8.01, 95% CI 5.34, 12.02)
In those with a diagnosis of rPSC, the time between liver transplantation and rPSC
diagnosis was not associated with patient survival (HR=0.92 95% CI 0.81, 1.03 per
year since transplantation), but was associated with graft survival (HR=0.85, 95% CI
0.78, 0.92) and the combined end-point of graft failure or death (HR=0.84, 95% CI
0.77, 0.92).
DISCUSSION
This study on patients transplanted for PSC, reported on the largest patient cohort
and longest median follow up to date, has demonstrated that the presence of
ulcerative colitis after liver transplantation and age are the only risk factors
independently associated with the development of rPSC. Furthermore, it conclusively
confirmed that rPSC increases the rate of graft failure and death.
13
Our patient cohort compares well to other published cohorts in terms of methodology
and patient characteristics, with the added benefit of cohort size and length of follow-
up. In comparison to Gautam’s systematic review, our cohort had higher median age
(49 years vs. 43.5 years respectively), longer median follow up period (9 years vs.
4.8 years) and longer maximum follow up period (14 years vs. 6.4 years).[18] The
histological and radiological criteria used to diagnose rPSC in the present study are
comparable to those used in other studies.[5, 8, 19, 20] The rate of rPSC in the
present study of 14.3% is comparable to other larger series.[4, 15, 18, 20]
The causative relationship between UC and rPSC remains unresolved and the risk of
rPSC has been hypothesised to be multifactorial and to include factors such as
donor graft status, immunosuppression use, impact of IBD and age.[3-5, 8, 9, 14, 21]
This study has assessed the impact of all potential risk factors for rPSC. Univariate
analysis demonstrated that the presence of pre-liver transplant (in patients without a
pre-liver transplant colectomy) and post-liver transplant (de novo) UC were
associated with an increased risk of rPSC. This finding was similar to the study by
Cholongitas et al which demonstrated that the absence of UC was protective against
rPSC.[5] Alabraba et al identified an association between the timing of colectomy to
transplantation and risk of rPSC. [4] Although this study did not demonstrate the
significance of the timing of colectomy on rPSC, the association of IBD and rPSC
further supports a role for IBD in rPSC. The different rPSC rates between patients
who had a colectomy before/during liver transplantation and those who had a
colectomy after liver transplantation or did not have a colectomy at all, suggest that
the absence of association might be due to a type II error. Although the grouping of
UC into pre-existing and de novo disease has been criticised[4], the association of
14
both with rPSC in this study demonstrates these factors to be important in
determining the impact of disease presence on rPSC. It remains unclear whether
there is any differential benefit of panproctocolectomy over segmental colectomy in
relation to risk of rPSC. If one were to hypothesise that the presence of any intact
colon were linked mechanistically to rPSC, then one would suppose that segmental
colectomy would not have the same beneficial effect as panproctocolectomy.
In a systematic review by Gautam et al, no significant difference in the incidence of
rPSC between patients with and without colitis was observed.[18] However, only 5 of
the 18 studies (364 of a potential 940 patients) provided IBD data and follow up was
shorter than in the present study.[18] It is possible that the short follow up period
reported resulted in a failure to capture further cases of rPSC. This last point is
important as other studies have reported a mean time to rPSc diagnosis of 5 years[5]
and 5.2 years[4]. Kugelmas et al also report a significantly shorter disease free
recurrence time in patients with IBD than in those without.[21] The median time to re-
transplantation in the present series was 7.4 years. The retrospective, multicentre
nature of this study restricted us from accurately reporting an exact time to rPSC
diagnosis.
Existing studies have reported conflicting data regarding the severity of pre- or post-
liver transplant UC and the impact on rPSC. Marelli et al found that PSC requiring
liver transplantation was associated with a milder course of UC.[22] Similarly,
Navaneethan et al reported that UC activity remains quiescent or improves after liver
transplantation.[23] On the contrary, Moncrief et al reported a worsening symptoms
and severity of IBD after liver transplantation.[24] This issue could not be addressed
15
within the present study due to the nature of data collection though there was no
difference in de novo cases of UC between patients with and without rPSC.
The strong association between PSC and UC, and the impact of post liver transplant
colitis on rPSC, may be explained by the gut-liver link and lymphocyte trafficking
from the gut to the liver. Some authors postulate the pathogenesis of rPSC to be
related to the release of bacterial endotoxins from an inflamed colon.[5] The
development of PSC in patients who have undergone a colectomy can be explained
by long-lived memory T cells originally activated in the gut.[25] Liver-infiltrating
lymphocytes in PSC include mucosal T cells recruited to the liver by aberrant
expression of gut-specific chemokines that activates binding to the hepatic
endothelium.[26] Though normally quiescent, these long lived memory T cells, when
activated in the liver, will lead to the development of inflammation and tissue
damage, promoting recruitment of more mucosal lymphocytes resulting in persistent
inflammation and disease.[27] This theory may be important in assessing the role of
colectomy before or at the time of liver transplantation and is in support of our
primary findings.
The finding of younger patients being more likely to develop rPSC has not been
previously described. This might be due to genetic or immune factors and/or a more
severe course of underlying UC and probably reflects a more aggressive disease
course that was already present in the pre-transplant period. Cholongitas et al
suggested that the severity of pre-liver transplant UC was associated with rPSC.[5]
Unfortunately due to the retrospective design of this study we did not have available
data on the pre-LT course of PSC, in particular the disease severity and the time
16
interval between diagnosis and LT. Further detailed patient information on the pre-LT
severity of UC and PSC and disease progression would be important to better inform
this correlation.
The association between immunosuppression and rPSC remains unclear. A lack of
influence of primary immunosuppression with tacrolimus or cyclosporine has been
reported in other studies,[4, 5, 21, 28] though an increased risk of developing rPSC
in patients receiving cyclosporine compared to tacrolimus was observed in one study
(p=0.047).[9]. In our analysis, there was a trend for more rPSC in patients on
cyclosporine, however this did not reach statistical significance. Moreover, there was
an association in the univariate analysis between transplantation era and rPSC, with
patients transplanted between 1990-2000 having a greater risk for recurrent disease.
This again might be explained by the use of cyclosporine in that period. Since the
agent of choice for primary immunosuppression is tacrolimus, these results do not
have implications for current clinical practice.
Furthermore the use of steroids in the present study did not appear to have an effect
on rPSC. However, Cholongitas et al reported the requirement for maintenance
steroids for more than 3 months post liver transplantation was associated with an
increased risk of rPSC.[5] Likewise, Vera et al demonstrated that the duration of
steroid treatment was linked to rPSC [3] although this was not revisited in a
subsequent publication in 2009.[4] Brandsaeter et al found that steroid resistant
rejection was a predictor of rPSC, however the significance was not maintained in
the multiple regression analysis.[8] Kugelmas et al showed that the use of OKT3 but
17
not the length of corticosteroid treatment was associated with greater incidence of
rPSC.
The impact of rPSC on graft survival has been controversial. A UNOS database
study comparing transplantation for PSC and PBC reported higher re-transplantation
rates and significantly lower graft and patient survival in those with PSC compared to
PBC.[29] Similar results have been reported by others.[6, 28] Cholongitas et al in
their series of 53 patients demonstrated that although patients with rPSC underwent
re-transplantation more frequently than those without rPSC (3/7 with rPSC vs. 3/46
without rPSC, p=0.02), long-term patient survival was similar between the 2 groups.
[5] In the present study the occurrence of rPSC was associated with a significantly
reduced rate of graft survival, a higher rate of graft failure and a higher re-
transplantation rate
The diagnosis of rPSC remains difficult. The lack of utilisation of protocol biopsies
and/or MRCP may have resulted in fewer cases of rPSC reported though our
numbers correspond well with others in the published literature. To ensure quality in
this multicentre study, we have utilised data from NHSBT. We further attempted to
abrogate other confounding factors by excluding patients with HAT, PNF and those
who died within 6 months of transplantation in order to have a sufficiently long follow-
up period and to exclude patients who never had time to develop rPSC. Most risk
factors previously associated with rPSC have been investigated except for acute
cellular rejection, CMV status and the use of extended criteria donor livers. The main
limitation of this study is its retrospective nature. However, it represents, to the best
18
of our knowledge, the largest and most comprehensive analysis of risk factors for
rPSC.
This study, the largest to date to review the effects of IBD and rPSC in patients
following liver transplantation, has identified an association between the presence of
UC after liver transplantation and an increased risk of rPSC. Furthermore rPSC is
associated with inferior graft survival and higher retransplantation rates. Potential
roles for various immunosuppression regimes as strategies to decrease the rate of
rPSC following transplantation are not conclusively supported by data from this
multicentre study. To suggest that all patients with UC undergo a pre-liver transplant
colectomy is contentious but it is certainly an option that should be considered.
Further detailed prospective longitudinal observation studies to assess the impact of
severity of colitis on rPSC are required.
Acknowledgements
The authors would like to thank all six UK liver transplant units for providing the data
and all those involved with data acquisition from the National Health Service Blood
and Transplant (NHSBT); and Kerri Barber, lead statistician at NHSBT.
This manuscript is written to honour and is in memory of Professor Andrew K
Burroughs.
19
REFERENCES
[1] LaRusso NF, Shneider BL, Black D, Gores GJ, James SP, Doo E, et al. Primary
sclerosing cholangitis: summary of a workshop. Hepatology 2006;44:746-764.
[2] Kotlyar DS, Campbell MS, Reddy KR. Recurrence of diseases following orthotopic
liver transplantation. The American journal of gastroenterology 2006;101:1370-1378.
[3] Vera A, Moledina S, Gunson B, Hubscher S, Mirza D, Olliff S, et al. Risk factors for
recurrence of primary sclerosing cholangitis of liver allograft. Lancet 2002;360:1943-
1944.
[4] Alabraba E, Nightingale P, Gunson B, Hubscher S, Olliff S, Mirza D, et al. A re-
evaluation of the risk factors for the recurrence of primary sclerosing cholangitis in liver
allografts. Liver transplantation : official publication of the American Association for the
Study of Liver Diseases and the International Liver Transplantation Society
2009;15:330-340.
[5] Cholongitas E, Shusang V, Papatheodoridis GV, Marelli L, Manousou P, Rolando N,
et al. Risk factors for recurrence of primary sclerosing cholangitis after liver
transplantation. Liver transplantation : official publication of the American Association
for the Study of Liver Diseases and the International Liver Transplantation Society
2008;14:138-143.
[6] Rowe IA, Webb K, Gunson BK, Mehta N, Haque S, Neuberger J. The impact of
disease recurrence on graft survival following liver transplantation: a single centre
experience. Transplant international : official journal of the European Society for Organ
Transplantation 2008;21:459-465.
[7] Dvorchik I, Subotin M, Demetris AJ, Fung JJ, Starzl TE, Wieand S, et al. Effect of
liver transplantation on inflammatory bowel disease in patients with primary sclerosing
cholangitis. Hepatology 2002;35:380-384.
20
[8] Brandsaeter B, Schrumpf E, Bentdal O, Brabrand K, Smith HJ, Abildgaard A, et al.
Recurrent primary sclerosing cholangitis after liver transplantation: a magnetic
resonance cholangiography study with analyses of predictive factors. Liver
transplantation : official publication of the American Association for the Study of Liver
Diseases and the International Liver Transplantation Society 2005;11:1361-1369.
[9] Jeyarajah DR, Netto GJ, Lee SP, Testa G, Abbasoglu O, Husberg BS, et al. Recurrent
primary sclerosing cholangitis after orthotopic liver transplantation: is chronic rejection
part of the disease process? Transplantation 1998;66:1300-1306.
[10] Soetikno RM, Lin OS, Heidenreich PA, Young HS, Blackstone MO. Increased risk of
colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative
colitis: a meta-analysis. Gastrointestinal endoscopy 2002;56:48-54.
[11] Loftus EV, Jr., Harewood GC, Loftus CG, Tremaine WJ, Harmsen WS, Zinsmeister
AR, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with
primary sclerosing cholangitis. Gut 2005;54:91-96.
[12] Papatheodoridis GV, Hamilton M, Mistry PK, Davidson B, Rolles K, Burroughs AK.
Ulcerative colitis has an aggressive course after orthotopic liver transplantation for
primary sclerosing cholangitis. Gut 1998;43:639-644.
[13] Cangemi JR, Wiesner RH, Beaver SJ, Ludwig J, MacCarty RL, Dozois RR, et al.
Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary
sclerosing cholangitis. Gastroenterology 1989;96:790-794.
[14] Graziadei IW. Recurrence of primary sclerosing cholangitis after liver
transplantation. Liver transplantation : official publication of the American Association
for the Study of Liver Diseases and the International Liver Transplantation Society
2002;8:575-581.
21
[15] Graziadei IW, Wiesner RH, Batts KP, Marotta PJ, LaRusso NF, Porayko MK, et al.
Recurrence of primary sclerosing cholangitis following liver transplantation.
Hepatology 1999;29:1050-1056.
[16] Demetris AJ. Distinguishing between recurrent primary sclerosing cholangitis
and chronic rejection. Liver transplantation : official publication of the American
Association for the Study of Liver Diseases and the International Liver Transplantation
Society 2006;12:S68-72.
[17] Harrison RF, Davies MH, Neuberger JM, Hubscher SG. Fibrous and obliterative
cholangitis in liver allografts: evidence of recurrent primary sclerosing cholangitis?
Hepatology 1994;20:356-361.
[18] Gautam M, Cheruvattath R, Balan V. Recurrence of autoimmune liver disease
after liver transplantation: a systematic review. Liver transplantation : official
publication of the American Association for the Study of Liver Diseases and the
International Liver Transplantation Society 2006;12:1813-1824.
[19] Graziadei IW, Wiesner RH, Marotta PJ, Porayko MK, Hay JE, Charlton MR, et al.
Long-term results of patients undergoing liver transplantation for primary sclerosing
cholangitis. Hepatology 1999;30:1121-1127.
[20] Gordon F. Recurrent primary sclerosing cholangitis: Clinical diagnosis and long-
term management issues. Liver transplantation : official publication of the American
Association for the Study of Liver Diseases and the International Liver Transplantation
Society 2006;12:S73-75.
[21] Kugelmas M, Spiegelman P, Osgood MJ, Young DA, Trotter JF, Steinberg T, et al.
Different immunosuppressive regimens and recurrence of primary sclerosing
cholangitis after liver transplantation. Liver transplantation : official publication of the
22
American Association for the Study of Liver Diseases and the International Liver
Transplantation Society 2003;9:727-732.
[22] Marelli L, Xirouchakis E, Kalambokis G, Cholongitas E, Hamilton MI, Burroughs
AK. Does the severity of primary sclerosing cholangitis influence the clinical course of
associated ulcerative colitis? Gut 2011;60:1224-1228.
[23] Navaneethan U, Choudhary M, Venkatesh PG, Lashner BA, Remzi FH, Shen B, et
al. The effects of liver transplantation on the clinical course of colitis in ulcerative colitis
patients with primary sclerosing cholangitis. Alimentary pharmacology & therapeutics
2012.
[24] Moncrief KJ, Savu A, Ma MM, Bain VG, Wong WW, Tandon P. The natural history
of inflammatory bowel disease and primary sclerosing cholangitis after liver
transplantation--a single-centre experience. Canadian journal of gastroenterology =
Journal canadien de gastroenterologie 2010;24:40-46.
[25] Grant AJ, Lalor PF, Salmi M, Jalkanen S, Adams DH. Homing of mucosal
lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory
bowel disease. Lancet 2002;359:150-157.
[26] Eksteen B, Grant AJ, Miles A, Curbishley SM, Lalor PF, Hubscher SG, et al. Hepatic
endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the
liver in primary sclerosing cholangitis. The Journal of experimental medicine
2004;200:1511-1517.
[27] Eksteen B, Miles AE, Grant AJ, Adams DH. Lymphocyte homing in the
pathogenesis of extra-intestinal manifestations of inflammatory bowel disease. Clinical
medicine 2004;4:173-180.
[28] Campsen J, Zimmerman MA, Trotter JF, Wachs M, Bak T, Steinberg T, et al.
Clinically recurrent primary sclerosing cholangitis following liver transplantation: a
23
time course. Liver transplantation : official publication of the American Association for
the Study of Liver Diseases and the International Liver Transplantation Society
2008;14:181-185.
[29] Maheshwari A, Yoo HY, Thuluvath PJ. Long-term outcome of liver transplantation
in patients with PSC: a comparative analysis with PBC. The American journal of
gastroenterology 2004;99:538-542.
24
