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Author Manuscript
Liver Transpl. Author manuscript; available in PMC 2014 March 01.

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Published in final edited form as:

Liver Transpl. 2013 March ; 19(3): 250258. doi:10.1002/lt.23587.

Risk of waitlist mortality in patients with primary sclerosing

cholangitis and bacterial cholangitis
David S Goldberg, MD, MSCE1,2, Amanda Camp, MD3, Alvaro Martinez-Camacho, MD3, Lisa
Forman, MD, MSCE3, Brett Fortune, MD, MSc4, and K. Rajender Reddy, MD1
1Division of Gastroenterology, University of Pennsylvania
2Center

for Clinical Epidemiology and Biostatistics, Perelman School of Medicine of the University
of Pennsylvania
3Division

of Gastroenterology, University of Colorado-Denver

4Transplantation

Center, Yale-New Haven Hospital

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Abstract

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Patients with primary sclerosing cholangitis (PSC) are at increased risk of bacterial cholangitis due
to biliary strictures and bile stasis. A subset of PSC patients suffer from repeated episodes of
bacterial cholangitis, leading to frequent hospitalizations and impaired quality of life. Although
PSC waitlist candidates with bacterial cholangitis frequently receive exception points, and/or are
referred for living donor transplantation, the impact of bacterial cholangitis on waitlist mortality is
unknown. We performed a retrospective cohort study of all adult PSC waitlist candidates listed for
initial transplantation from February 27, 2002 to June 1, 2012 at the University of Pennsylvania
and the University of Colorado-Denver. Over this period, 171 PSC patients were waitlisted for
initial transplantation. Prior to waitlisting, 38.6% (66/171) of patients had a history of bacterial
cholangitis, while 28.0% (44/157) of those with at least one MELD update experienced cholangitis
on the waitlist. During follow-up, 30 (17.5%) patients were removed from the waitlist for death or
clinical deterioration, with 46.7% (14/30) developing cholangiocarcinoma. Overall, 12/82 (14.6%)
waitlist candidates who ever had an episode of cholangitis were removed for death or clinical
deterioration, compared with 18/89 (20.2%) without cholangitis (P=0.34 comparing two groups).
No patients were removed due to bacterial cholangitis. In multivariable competing risk models, a
history of bacterial cholangitis was not associated with an increased risk of waitlist removal for
death or clinical deterioration (subhazard ratio=0.67; 95% CI: 0.65-0.70, P<0.001). In summary,
PSC waitlist transplant candidates with bacterial cholangitis do not have an increased risk of
waitlist mortality. The data call into question the systematic granting of exception points or
referral for living donor transplantation due to a perceived risk of increased waitlist mortality.

Keywords
Primary sclerosing cholangitis; bacterial cholangitis; exception points; cholangiocarcinoma;
waitlist mortality

Corresponding Author: David Goldberg, MD, MSCE 3400 Spruce Street 9 Penn Tower Philadelphia, PA 19104 Telephone:
215-349-8222 Fax: 215-349-5915 david.goldberg@uphs.upenn.edu.
Conflicts of Interest: The authors have no conflicts of interest to report as it pertains to this manuscript.

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Introduction
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Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder characterized by

progressive biliary strictures, ultimately leading to the development of liver failure or
cholangiocarcinoma. As a result of biliary strictures and bile stasis, patients with PSC are at
increased risk of bacterial cholangitis. Among PSC patients, bacterial cholangitis is more
commonly seen in those with a history of biliary tract instrumentation (i.e. endoscopic
retrograde cholangiopancreatography; ERCP) and/or dominant bile duct strictures.(1)
Further, bacterial cholangitis may be associated with secondary complications, including
endocarditis and hepatic abscess formation.(2) A subset (<10%) of patients with PSC will
suffer from repeated bouts of bacterial cholangitis, which may result in frequent
hospitalizations and thus impaired quality of life.(3) PSC is clearly associated with a
considerable amount of morbidity, however the impact of bacterial cholangitis on mortality
of patients with PSC is unknown.(4)

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Among patients waitlisted for liver transplantation, prioritization on the waitlist is

determined by a patient's Model for End-Stage Liver Disease (MELD) score. The MELD
score, calculated based on a patient's INR, bilirubin, and creatinine, does not account for
complications of liver disease. As a result, waitlist candidates with PSC, and specifically
those suffering from bacterial cholangitis, are frequently referred for living donor liver
transplantation and/or receive MELD exception points after petition to a regional review
board (RRB).(5, 6) This is despite evidence that even after accounting for exception points,
MELD score, and differences in living donor liver transplantation, waitlist candidates with
PSC have a lower risk of waitlist removal for death or clinical deterioration when compared
to candidates with other forms of end-stage liver disease.(7) Additionally, there is no data
evaluating whether waitlist candidates with PSC who suffer from episodes of bacterial
cholangitis have an increased risk of mortality.(4, 5) While there are published
recommendations to guide RRBs on which patients with PSC and recurrent bacterial
cholangitis should receive exception points, these are not evidence-based.(2)
National transplant registry data available from the United Network for Organ Sharing
(UNOS) do not capture data on episodes of bacterial cholangitis, which limits the ability to
evaluate its association with waitlist mortality. Accordingly, using patient-level data from
two large liver transplant centers, we sought to determine whether: a) waitlist transplant
candidates with PSC and bacterial cholangitis have an increased risk of waitlist mortality;
and b) whether or not current practices of allocation of exception points for patients with
PSC and bacterial cholangitis are justified.

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Methods
We performed a retrospective cohort study of all adult (18 years of age) waitlist transplant
candidates diagnosed with PSC at the University of Pennsylvania (UP) and the University of
Colorado-Denver (UCD) between February 27, 2002 and June 1, 2012. At each center, the
respective transplant databases were queried to identify waitlist candidates with a diagnosis
of PSC. The diagnosis of PSC was confirmed based on the constellation of clinical,
biochemical, radiologic, and histologic features, consistent with published guidelines.(1)
All PSC patients waitlisted for an initial transplant on or after February 27th, 2002 were
included. The start date was chosen to limit the analysis to the MELD era. We excluded
patients listed for re-transplantation.
For each study subject, a detailed medical record review was conducted at each center
(D.G., A.C., and A.M-C.). Relevant demographic and clinical information were recorded
from the chart, including age, self-reported race, gender, date of diagnosis of PSC, history of
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inflammatory bowel disease (IBD; defined by review of medical endoscopy or pathology

reports, and/or documentation of medical record of confirmatory endoscopy and pathology
consistent with ulcerative colitis or Crohn's disease), laboratory data, and presence/absence
of cirrhosis on radiographic imaging.
Subjects were defined as having cirrhosis if a liver biopsy, and/or a radiographic study
(ultrasound, CT, or MRI) had findings consistent with cirrhosis (including a nodular contour
of the liver surface and/or caudate lobe hypertrophy). Detailed data on waitlist removal were
obtained, including the reason for removal (based on UNOS coding criteria), and the
specific cause of death and/or clinical deterioration for those removed from the waitlist
because of death, or being deemed too sick or medically unsuitable for transplantation.

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Given the complexity of the diagnosis of bacterial cholangitis in the setting of PSC, we
chose to define an episode of cholangitis based on any physician medical record
documentation stating the patient had an episode of bacterial cholangitis. We did not use
elevated alkaline phosphatase levels and/or jaundice, or MRICP/ERCP abnormalities to
further define cholangitis episodes as patients with PSC commonly have baseline
abnormalities in one of these parameters.(8) As a result, we defined bacterial cholangitis as
any physician medical record documentation stating the patient had an episode of bacterial
cholangitis. While these episodes were commonly associated with fever, right upper
quadrant pain, worsened jaundice, and/or bacteremia in the absence of an alternative source
of infection, there were no specific criteria used given the retrospective nature of the study.
Outcome
The primary outcome was waitlist removal for death or clinical deterioration, defined as the
patient being deemed too sick or medically unsuitable for transplantation. Outcomes were
initially determined by review of the transplant databases at the respective transplant centers,
but all waitlist removals were subsequently confirmed by detailed medical record review to
verify accuracy of the transplant databases.
Statistical analysis
We used Fisher's exact test and chi-square tests for dichotomous variables and Student t tests
or Wilcoxon rank-sum tests for continuous variables (according to their distributions) to
compare waitlist candidates with vs. without bacterial cholangitis and those who were vs.
were not removed for death or clinical deterioration.

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In evaluating whether bacterial cholangitis impacts the risk of waitlist mortality, one must
consider the competing risk of transplantation, as it influences the probability that a waitlist
candidate will be removed from the waitlist for death or clinical deterioration.(9) Thus we fit
competing risk Cox regression models, with waitlist removal as the outcome, and
transplantation as the competing risk.(9-11) All other outcomes were treated as censors.
Waitlist candidates still on the waitlist at the end of follow-up were censored on that date.
The primary covariate of interest was history of bacterial cholangitis prior to or while on the
waitlist. We grouped together all episodes of bacterial cholangitis as the objective of the
study was to determine if cholangitis, regardless of timing, was associated with worsened
outcomes. In addition, a history of cholangitis, regardless of timing, is commonly used as a
criterion for granting of exception points. Secondary models were used to evaluate the
association between waitlist mortality and a history of bacterial cholangitis prior to listing or
while on the waitlist separately.
Potential covariates included were gender, race (white vs. non-white due to sparse sample
sizes of non-white patients), age at listing, MELD score at listing, and history of a portal
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hypertensive complications (ascites, variceal bleeding, hepatic encephalopathy, or

spontaneous bacterial peritonitis) prior to listing. Covariates were first tested in single-item
fashion; we included any variable with a p-value 0.2 in the final model. The final models
used a stepwise variable-selection process to retain variables with p-values 0.1. Potential
confounders were included if the variable changed the hazard ratio of bacterial cholangitis
by 10%. We used robust standard errors to account for correlation due to patient clustering
by transplant center.(12) Covariates were reported as subhazard ratios, given the use of
competing risk models.(9, 11)
Competing risk survival curves comparing the risk of waitlist removal for death or clinical
deterioration, accounting for the competing risk of transplantation, were constructed using
the stcurve function in Stata.
We chose to exclude the small number of patients with missing data from the final
multivariable models (N=10) given the limited variables that could be used for multiple
imputation.
Institutional Review Board Approval was obtained from both the UP and the UCD. All
statistical analyses were performed using Stata 12.0 (College Station, TX).

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Results
From February 27th, 2002 to June 1st, 2012, 171 patients with PSC were listed for initial
transplantation at the UP (83) and the UCD (88). The median age was 48 years (interquartile
range (IQR): 37-58), with PSC waitlist candidates being predominantly white (83.6%;
143/171) and male (73.1%; 125/171).
At the time of listing, 76.6% (131/171) had a documented history of IBD, with a
significantly greater proportion of waitlist candidates at the UP with IBD (85.5% vs. 68.2%;
P=0.007; Table 1). Of those with IBD, nearly 80% (79.4%, 104/131) had ulcerative colitis.
Listing laboratory and clinical data
The median laboratory MELD score at the time of listing was 14 (IQR: 9-19), with waitlist
candidates at the UP having significantly higher laboratory MELD scores at listing (15 [IQR
10-20] vs. 12 [IQR 7-17]; P=0.008). The median listing serum creatinine was 0.8mg/dL
(IQR: 0.7-1.0), total bilirubin 3.3 mg/dL (IQR: 1.4-10.1), and INR 1.2 (IQR: 1.1-1.4; Table
1).

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Prior to waitlisting, 39.2% (67/171) of waitlist candidates had experienced a hepatic

decompensation (Table 1), with 31.6% (54/171) having ascites, 16.4% (28/171) with
variceal bleeding, 15.2% (26/171) with hepatic encephalopathy, and 1.1% (2/171) with
spontaneous bacterial peritonitis. Based on imaging prior to waitlisting (as few patients had
liver biopsy due to it not being needed for the diagnosis of PSC, the data on radiographic
diagnosis is presented), 53.8% (92/171) of waitlist PSC candidates had documented
cirrhosis. None of these variables differed by center.
Episodes of bacterial cholangitis
Prior to waitlisting, 38.6% (66/171) of waitlist candidates had a reported history of bacterial
cholangitis. A similar proportion of waitlist candidates experienced at least one episode of
bacterial cholangitis across the two centers (Table 2a). At each center, over 50% of waitlist
candidates experienced greater than one episode of bacterial cholangitis prior to waitlisting
(median number of episodes could not be calculated as discrete number of episodes not
available for every patient).
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Among waitlist candidates with at least one UNOS MELD update while waitlisted, 28.0%
(44/157) had an episode of bacterial cholangitis after listing, with a significantly greater
proportion of waitlist candidates at the UCD suffering from bacterial cholangitis (Table 2b).
Overall, 48.0% (82/171) of waitlisted PSC candidates experience at least one episode of
bacterial cholangitis prior to waitlisting and/or while on the waitlist. A significantly greater
proportion of waitlist candidates from the UCD had cholangitis at any point in time (59.8%
[49/88] vs. 40.2% [33/83]; P=0.04).
Waitlist outcomes
Table 3 displays the reasons for waitlist removal for PSC candidates from the two centers.
Median time on the waitlist was similar between the two centers (data not shown). Waitlist
time was also similar for those with a history of cholangitis vs. those without.
At the end of follow-up, 12.3% (21/171) of PSC waitlist candidates listed since 2/27/02
were still listed. During follow-up, 49.7% (85/171) were transplanted at one of the two
centers, with 21.2% (18/85) living donor liver recipients. An additional 8 (4.7%) patients
listed at the UP were transplanted at another center. There was a non-significant increase in
the odds of receiving a decreased donor transplant among those with versus without a
history of cholangitis (35 [49.3%] versus 32 [39.0%]; P=0.20).

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During follow-up, there were 13 waitlist candidates transplanted with exception points (9 at
UC-D and 4 at UP): cholangiocarcinoma (7), recurrent cholangitis (3), hepatocellular
carcinoma (1), fatigue, bone disease, and failure to thrive (1), colon dysplasia requiring
colectomy in a decompensated cirrhotic (1).
Thirty waitlist candidates (17.5%) were removed from waitlist for death or clinical
deterioration, with 53.3% (16/30) of those dying while still waitlisted, and the remaining
46.7% (14/30) removed for clinical deterioration. None of these 30 patients had bacterial
cholangitis immediately preceding delisting or as the inciting event for death or delisting.
Causes of waitlist removal for death or clinical deterioration are listed in Table 3. Notably,
46.7% (14/30) had biopsy proven or presumed (based on imaging or atypical cells on ERCP
brushings) cholangiocarcinoma as the cause of removal for death or clinical deterioration.
Only 16.7% (5/30) were removed due to an infection/sepsis, and none were cholangitisrelated.

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Among those who received a deceased donor liver transplant, the median MELD of those
with a history of cholangitis was 22 (IQR 15-26), compared with 25 (IQR 20-28) in those
without cholangitis (P=0.12). Among those who were removed from the waitlist for death or
clinical deterioration, those with a history of cholangitis had a median MELD score of 27
(IQR 11-31), as compared with 26 (IQR 18-36) in those without cholangitis (P=0.74).
Waitlist time was significantly longer for those who were removed for death or clinical
deterioration (median 341 days; IQR 107-1064) vs. those transplanted (median 151 days;
IQR 41-492; P=0.01). At the time of removal, those who died or clinically deteriorated had
numerically, but not statistically significantly, higher laboratory MELD scores compared
with those who were transplanted (median 26; IQR 18-33 vs. median 21; IQR 16-26;
P=0.06).
During follow-up, 14.6% (25/171) waitlist candidates developed cholangiocarcinoma. Of
these 25, 44% (11/25) were transplanted, while the other 56% were removed for death or
clinical deterioration. The risk of developing cholangiocarcinoma did not differ based on a

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history of bacterial cholangitis (18.3% [15/82] with cholangitis developed

cholangiocarcinoma vs. 11.2% [10/89] without cholangitis; P=0.19).

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Outcomes based on history of cholangitis

We compared the crude risk of waitlist removal for death or clinical deterioration based on:
a) history of cholangitis prior to listing; b) cholangitis while on the waitlist; and c)
cholangitis prior to waitlisting and/or on the waitlist. Within each group, the risk of waitlist
removal for death or clinical deterioration was similar when stratified by center (data not
shown).
Among the 66 waitlist candidates with bacterial cholangitis prior to listing, 18.2% (12/66)
were removed for death or clinical deterioration, compared with 17.1% (18/105; P=0.86
comparing two groups) without cholangitis prior to listing.
Among the 44 waitlist candidates with bacterial cholangitis after listing, 9.1% (4/44) were
removed from the waitlist for death or clinical deterioration, compared with 21.2% (24/113;
P=0.07 comparing groups) without cholangitis (157 total waitlist candidates with at least 1
MELD update).

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Overall, of 82 waitlist candidates who ever had an episode of cholangitis, 14.6% (12/82)
were removed for death or clinical deterioration, compared with 20.2% (18/89) of those
without a history of cholangitis (P=0.34 comparing two groups). Similar unadjusted results
were obtained in time-dependent competing risk analyses (competing risk survival curves;
P=0.26; Figure 1).
Waitlist candidates with a history of cholangitis at any point in time were numerically more
likely to be transplanted during follow-up (59.8% [49/82] vs. 49.4% [44/89]), however this
did not reach statistical significance (P=0.18). Similar results were obtained excluding the 8
patients transplanted at another center.

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In univariable competing risk Cox regression models, a history of cholangitis prior to and/or
on the waitlist and male gender were associated with a decreased hazard of removal for
death or clinical deterioration, while white race, older age, and higher laboratory MELD
score at listing were associated with an increased hazard (Table 4; history of hepatic
decompensation was non-significant and excluded from final model). In multivariable
competing risk models, a history of cholangitis was associated with a significantly decreased
hazard of removal for death or clinical deterioration (subhazard ratio [SHR]=0.67, 95% CI:
0.65-70, P<0.001), while white race and increased age were associated with an increased
risk.
In multivariable competing risk Cox models evaluating each of the bacterial cholangitis
covariates separately, a history of cholangitis prior to waitlisting was not associated with an
increased risk of waitlist removal for death or clinical deterioration (SHR: 1.00, 95% CI:
0.60-1.66; P=0.99), while cholangitis on the waitlist was associated with a decreased risk
(SHR: 0.39, 95% CI: 0.16-0.93; P=0.03).

Discussion
This study is the first to evaluate the risk of waitlist mortality associated with bacterial
cholangitis in waitlisted patients with PSC, using 10 years of data from two large transplant
centers. During a ten year period, nearly half of waitlist candidates with PSC experienced at
least one episode of bacterial cholangitis. A history of bacterial cholangitis was not
associated with an increased risk of waitlist removal for death or clinical deterioration. Most

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importantly, of the 30 patients removed for death or clinical deterioration, none had known
cholangitis as the inciting event. The data call into question the prevailing belief that PSC
patients with bacterial cholangitis are at increased risk of waitlist mortality, and thus merit
exception points and/or referral for living donor transplantation based solely on the risk of
waitlist mortality.
PSC is a progressive disease that has a significant impact on patient morbidity and mortality.
Early natural history studies demonstrated that nearly 75% of PSC patients were
symptomatic at the time of diagnosis.(13) Median survival from the time of diagnosis was
11.9 years.(13) With earlier diagnosis due to increased awareness of the disease, availability
of noninvasive imaging of the biliary tree, increased use of routine liver enzyme evaluation
in asymptomatic patients, and recognition of the association between IBD and PSC, more
asymptomatic cases are detected.(8) Despite this, a significant burden of disease remains,
with approximately 5% of all liver transplants, and 14% of living donor liver transplants
being performed in patients with PSC.(6, 7)
Using UNOS data on all waitlist transplant candidates, we have previously shown that
13.6% of waitlisted candidates with PSC from 2002-2009 were removed from the waitlist
for death or clinical deterioration.(7) This data though does not allow for evaluation of
bacterial cholangitis in waitlist candidates, necessitating the analysis of patient-level data.

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The data presented here demonstrate that in both unadjusted and adjusted analyses, bacterial
cholangitis in PSC waitlist candidates was not associated with an increased risk of mortality
or clinical deterioration. This is underscored by the fact that the causes of death or clinical
deterioration were due to cholangiocarcinoma, portal hypertension, non-cholangitis sepsis,
or other non-hepatic conditions, but not bacterial cholangitis. This data echo early PSC data
from the Mayo Clinic's series from the 1970s. Of 39 PSC patients followed prospectively,
13 (33.3%) died, with 11/13 deaths from liver failure, one due to cholangiocarcinoma, and
one as a complication of colon cancer. Similar to our data, no deaths were directly related to
bacterial cholangitis.(3) More recent data from Norway, Sweden, Finland, and Denmark,
demonstrated that among 255 waitlisted PSC patients followed over an 11 year period, 32
(12.5%) were removed for death or clinical deterioration. None of the waitlist removals were
related to bacterial cholangitis.(14) Our analysis, the first to specifically evaluate the
association between bacterial cholangitis and mortality, validates these earlier studies.

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Although the risk of cholangiocarcinoma in our series is higher than previously published
Scandinavian data (14), when accounting for tumors diagnosed on explant or during the
transplant operation(15), the risk of cholangiocarcinoma in our cohort was not substantially
greater than previously reported. The higher rate of cholangiocarcinoma on the waitlist seen
in our cohort may be related to improved non-invasive imaging techniques (MRI, MRCP)
when compared to the Scandinavian data from 1990-2000, and/or the increased waiting
times in the United States, which may result in an increased risk of developing and/or
detecting cholangiocarcinoma. While there is no specific protocol for surveillance of
cholangiocarcinoma at each center, clinicians typically obtain yearly CT or MRI scans,
along with CA-19-9 tests, or more frequently if clinically indicated. All of the transplants for
cholangiocarcinoma with exception points were at the University of Colorado which follows
the Mayo cholangiocarcinoma transplantation protocol.(16)
An additional notable finding is that infections were rarely a direct cause of waitlist removal
for death or clinical deterioration, unlike what is seen in patients with other forms of endstage liver disease.(17) One potential explanation for this is that at least based on radiologic
imaging pre-waitlisting, a substantial proportion of our patients did not have radiographic
evidence of cirrhosis. Although MRI and CT scans are not 100% sensitive or specific for

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this diagnosis, the data suggest that PSC patients waitlisted for transplantation may not all
have cirrhosis, which may explain the different waitlist risk profile seen in this patient
population.(7)
The issue of the risk of mortality associated with bacterial cholangitis in PSC patients, and
its impact on organ allocation, is important given the limited supply of transplantable
organs. Due to a concern that patients with PSC and bacterial cholangitis potentially have an
increased risk of waitlist mortality, transplant centers frequently apply for exception points
for these patients. In fact, since February 27th, 2002, 337 PSC patients have applied for
MELD exception points for bacterial cholangitis, with the vast majority of these patients
being granted exception points, and ultimately transplanted, despite nearly three-fourths of
them not meeting published recommendations for exception points for PSC and bacterial
cholangitis.(5) Additionally, PSC waitlist candidates are significantly more likely to receive
a living donor transplant, compared to patients with other forms of end-stage liver disease,
with recurrent cholangitis frequently being the indication.(6) While our data does not speak
to the utility or necessity of transplantation due to morbidity and impaired quality of life
related to bacterial cholangitis, it does demonstrate that bacterial cholangitis alone is not
associated with increased mortality.

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Given the non-significant differences in the odds of transplantation in those with versus
without a history of cholangitis, the decreased risk of mortality in patients with a history of
cholangitis is not solely due to an increased rate of transplantation in this cohort, either
through exception points, living donor transplantation, and or increased MELD scores, and
thus increased prioritization for deceased donor organs. Further, the MELD scores at
transplantation and removal were not different in those with versus without cholangitis,
suggesting that cholangitis alone does not result in a significantly increased MELD score
that would change waitlist outcomes.

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Our observations had several limitations. We combined data from two transplant centers for
this analysis. The sample size for this study was small, and only included 171 waitlist
candidates with PSC. The two centers are situated in UNOS regions with above average
MELD scores at transplantation, therefore the data may not be generalizable to all waitlist
candidates with PSC in all UNOS regions. The data was retrospective in nature, and we
were reliant on accurate documentation in the medical record for our data. Further
prospective, multi-center data is needed to confirm our findings. The demographic
distribution of PSC candidates at the two centers was similar. Although patients at the UP
were more likely to have a history of IBD prior to listing, this should not account for our
findings. The laboratory MELD scores at listing at the UP were slightly higher, however we
adjusted for MELD score in our final models. The distribution of portal hypertensive
complications was similar though. We did note that a significantly greater proportion of
waitlist candidates at the UCD had cholangitis on the waitlist. While the reason for this is
unclear, perhaps due to provider differences in the use of prophylactic antibiotics, the risk of
adverse waitlist outcomes did not differ at each center, thus this was not a substantial
limitation.
The definition of cholangitis was based on physician documentation in the medical record,
without definitive corroborating bacteremia or ERCP procedure documentation. We chose to
define cholangitis using physician documentation that is based on expert opinion and
clinical judgment for several reasons. The diagnosis of bacterial cholangitis is difficult in the
setting of PSC. Traditional laboratory abnormalities such as hyperbilirubinemia and elevated
alkaline phosphatase are common at baseline in these patients. Secondly, findings such as
worsening jaundice, fever, and/or right upper quadrant pain or tenderness, in the absence of
another infection, may signify bacterial or non-bacterial cholangitis in this patient

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population, and retrospectively defining an episode of bacterial cholangitis requires use of

prior clinician opinion of treating physicians. Lastly, even with data on blood cultures or
ERCP procedure reports (when performed in the setting of a dominant stricture), there is no
single finding that is confirmatory for bacterial cholangitis in PSC, and the diagnosis (or
presumed diagnosis) is reliant on clinician judgment). Although misclassification may exist,
such that patients were misclassified as cholangitis in the absence of such an infection, we
would not expect this to change our results. Among those categorized as bacterial
cholangitis, only if a significantly greater proportion of those who did not die were
misclassified (leading to an underestimation of the risk of mortality from cholangitis) would
we expect our results to show an increased risk of mortality in patients with cholangitis,
which is extremely unlikely. Additionally, this difficulty in definitively diagnosing
cholangitis in this population also speaks to the challenge of granting exception points or
using this as a basis for increased prioritization. It may in fact be that only those patients
with bacteremia and/or septic complications are at greater risk of mortality, which not only
supports the published consensus recommendations for exception points in PSC, but also
forces us to more stringently define cholangitis in this population to better treat and risk
stratify PSC patients. Due to the retrospective nature of the study, we could not specifically
determine which episodes of cholangitis were associated with bacteremia, with or without
sepsis. However, as no waitlist removals for death or clinical deterioration were directly due
to cholangitis, this suggests that even among the subset of patients with cholangitis
complicated by bacteremia, the risk of waitlist mortality may not be significantly increased.
Further multi-center prospective data is needed though to confirm this.

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We were missing data on 10 patients, and excluded them from the final multivariable model.
However, as the univariable and multivariable hazard ratios were similar, and the hazard
ratio was significantly less than 1, this should not have impacted our results. Thirdly, waitlist
candidates with bacterial cholangitis may have received a living donor liver transplant and/
or received MELD exception points to decrease their probability of dying on the waitlist,
thus increasing the likelihood of transplantation. However, as shown, only 10% of PSC
waitlist candidates received a living donor transplant and 9% received exception points. Of
living donor recipients, only 11/18 had a history of cholangitis, while only 3/13 transplant
recipients with MELD exception points were granted exceptions for recurrent cholangitis.
This demonstrates that referral of PSC waitlist candidates with cholangitis for living donor
transplantation and/or MELD exception points do not explain the findings. Even under a
worst-case scenario whereby all living donor recipients and exception point recipients died,
the outcomes of patients with cholangitis would be the same as non-cholangitis patients, but
not worse. We defined cirrhosis based on radiographic imaging, as few patients had liver
biopsies, is not 100% sensitive. Despite this, given the substantial number of patients
without radiographic evidence of cirrhosis, it is still likely that a sizable proportion of the
patients did not in fact have cirrhosis. Lastly, we were unable to accurately determine if
patients were on suppressive antibiotic therapy due to a history of recurrent cholangitis.
Although this may have decreased the risk of complications from cholangitis and/or
prevented the development of non-cholangitis complications, this is unlikely to fully account
for our results.
In summary, we have shown that waitlisted transplant candidates with PSC and bacterial
cholangitis do not have an increased risk of waitlist mortality when compared with those
without cholangitis. Over a 10 year period, no patients died on the waitlist or were removed
for clinical deterioration as a result of bacterial cholangitis. The data calls into question the
systematic granting of exception points for patients with PSC and bacterial cholangitis on
the basis of increased waitlist mortality. Multi-center patient level data is needed to validate
these findings and develop predictors of waitlist mortality to better risk stratify PSC waitlist
candidates in greatest need of exception points and pre-emptive living donor transplantation.
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Acknowledgments
Grants and Financial Support: NIH/NIDDK F32 1-F32-DK-08969401 Grant (D.G.)

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Abbreviations
PSC

Primary sclerosing cholangitis

ERCP

Endoscopic retrograde cholangiopancreatography

MELD

Model for End-Stage Liver Disease

RRB

Regional review board

UNOS

United Network for Organ Sharing

UP

University of Pennsylvania

UCD

University of Colorado-Denver

IBD

Inflammatory bowel disease

IQR

Interquartile range

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References

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Figure 1.

Competing risk regression evaluating risk of waitlist removal for death or clinical
deterioration

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Table 1

Patient characteristics, clinical and laboratory data at the time of listing, N=171

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Variable
Median age at listing, years (IQR)

University of
Pennsylvania, =83

University of ColoradoDenver, N=88

Combined two center

data

48 (32, 58)

38 (37, 58)

48 (37-58)

P-value
0.98

Race, N (%)

0.44

White

67 (80.7)

76 (86.4)

143 (83.6)

Black

14 (16.9)

8 (9.1)

22 (12.9)

Asian

1 (1.2)

2 (2.3)

3 (1.7)

1 (1.2)

2 (2.3)

3 (1.7)

Male gender, N (%)

Other

57 (69.5)

68 (77.3)

125 (73.1)

0.25

History of IBD, N (%)

71 (85.5)

60 (68.2)

131 (76.6)

0.007

IBD subtype, N (%)

0.49

Ulcerative colitis

57 (80.3)

47 (78.3)

104 (79.4)

Crohn's

13 (18.3)

10 (16.7)

23 (17.6)

Indeterminate

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1 (1.4)

3 (5.0)

4 (3.1)

INR

1.2 (1.1, 1.4)

1.14 (1.0, 1.3)

1.2 (1.1-1.4)

0.008

Total bilirubin, mg/dL

3.6 (1.9, 10.6)

2.3 (1.1, 8.2)

3.3 (1.4-10.1)

0.06

Creatinine, mg/dL

0.8 (0.7, 1.0)

0.9 (0.7, 1.0)

0.8 (0.7-1.0)

0.14

Laboratory MELD score

15 (10, 20)

12 (7, 17)

14 (9-19)**

0.01

AST, U/L

110 (73, 161)

85.5 (53, 126)

98 (63-156)

0.01

Platelet count (thousand/l)

173 (101, 238)

180 (121, 287)

178 (110-281)

0.13

18 (21.7)

10 (11.4)

28 (16.4)

0.07

Variceal bleeding, N (%)

SBP, N (%)

1 (1.2)

1 (1.1)

2 (1.1)

0.97

Ascites, N (%)

31 (37.4)

23 (26.1)

54 (31.6)

0.12

Encephalopathy, N (%)

14 (16.9)

12 (13.6)

26 (15.2)

0.56

Radiographic evidence of cirrhosis, N (%)

51 (61.5)

41 (46.6)

92 (53.8)

0.08

P-value compares the values at the two centers, or the distribution across the two centers for race and IBD subtype

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Table 2

Listing and waitlist data on cholangitis of waitlist candidates with PSC

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a) Bacterial cholangitis prior to listing, N=171

Bacterial cholangitis prior to listing, N (%)

66 (38.6)

Number of episodes cholangitis, N (%)

1

30 (45.5)

11 (16.7)

3-6

9 (13.4)

Multiple or several

16 (24.2)

*
b) Bacterial cholangitis while on waitlist, N=157
Bacterial cholangitis while on waitlist, N (%)

44 (28.0)

Number of episodes of cholangitis, N (%)

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26 (59.1)

9 (20.4)

3-6

5 (11.4)

Multiple or several

4 (9.1)

Similar proportions (P=0.52) of patients had bacterial cholangitis prior to listing between two centers

Multiple or several chosen when medical record specified greater than one episode of bacterial cholangitis without the exact number

10 patients removed from waitlist at the University of Pennsylvania prior to having any waitlist MELD updates or interval waitlist data prior to
removal. 4 patients with missing data on history of cholangitis while on the waitlist from the University of Colorado-Denver

P=0.003 comparing proportion of patients with bacterial cholangitis on waitlist (University of Pennsylvania: 16.4% (12/71) vs. University of
Colorado-Denver: 38.1% (32/84)

Multiple or several chosen when medical record specified greater than one episode of bacterial cholangitis without the exact number

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Table 3

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Reasons for waitlist removal, N=150

Deceased donor OLT, N (%)

67 (44.7)

LDLT, N (%)

18 (12.0)

Died, N (%)

16 (10.7)

Medically unsuitable or too sick to transplant, N (%)

14 (9.3)

Other, N (%)

35 (23.3)

Lost to follow-up

12 (8.0)

Transferred to another center

4 (2.7)

Patient request

1 (0.7)

Transplanted at another center

8 (5.3)

Other

10 (6.7)

**Cholangiocarcinoma (9), progressive wasting, sepsis of unknown source, too ill without specification, pancreatic cancer, complications postcoronary artery bypass surgery

12 and 9 patients remained listed at the University of Pennsylvania and the University of Colorado-Denver at the end of follow-up, respectively

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Cholangiocarcinoma (5), bleeding peptic ulcer (2), pneumonia (2), variceal bleed, spontaneous bacterial peritonitis, fungemia, hepatorenal
syndrome, small bowel obstruction, hemorrhagic stroke, intra-abdominal bleed during interventional radiology procedure

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Table 4

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Competing risk Cox regression models evaluating risk of waitlist removal for death or clinical deterioration
associated with bacterial cholangitis
Variable

Univariable subhazard ratio (95% CI)

Multivariable subhazard ratio (95% CI)

P-value

Cholangitis ever

0.66 (0.53, 0.84)

0.67 (0.65, 0.70)

<0.001

Male gender

0.90 (0.85, 0.96)

0.84 (0.61, 1.16)

0.29

White race

1.88 (1.67, 2.12)

2.11 (1.83, 2.43)

<0.001

1.03 (1.02, 1.04)

1.02 (0.99, 1.06)

0.18

1.35 (1.02, 1.80)

1.37 (1.05, 1.79)

0.02

Listing laboratory MELD score

Age at listing

Increments of 1 MELD point

Five year increments

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