nihms-425418

Risk of waitlist mortality in patients with primary sclerosingcholangitis and bacterial cholangitis

David S Goldberg, MD, MSCE1,2, Amanda Camp, MD3, Alvaro Martinez-Camacho, MD3, LisaForman, MD, MSCE3, Brett Fortune, MD, MSc4, and K. Rajender Reddy, MD1

1Division of Gastroenterology, University of Pennsylvania2Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine of the Universityof Pennsylvania3Division of Gastroenterology, University of Colorado-Denver4Transplantation Center, Yale-New Haven Hospital

AbstractPatients with primary sclerosing cholangitis (PSC) are at increased risk of bacterial cholangitis dueto biliary strictures and bile stasis. A subset of PSC patients suffer from repeated episodes ofbacterial cholangitis, leading to frequent hospitalizations and impaired quality of life. AlthoughPSC waitlist candidates with bacterial cholangitis frequently receive exception points, and/or arereferred for living donor transplantation, the impact of bacterial cholangitis on waitlist mortality isunknown. We performed a retrospective cohort study of all adult PSC waitlist candidates listed forinitial transplantation from February 27, 2002 to June 1, 2012 at the University of Pennsylvaniaand the University of Colorado-Denver. Over this period, 171 PSC patients were waitlisted forinitial transplantation. Prior to waitlisting, 38.6% (66/171) of patients had a history of bacterialcholangitis, while 28.0% (44/157) of those with at least one MELD update experienced cholangitison the waitlist. During follow-up, 30 (17.5%) patients were removed from the waitlist for death orclinical 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 clinicaldeterioration, 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, ahistory of bacterial cholangitis was not associated with an increased risk of waitlist removal fordeath 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 ofwaitlist mortality. The data call into question the systematic granting of exception points orreferral for living donor transplantation due to a perceived risk of increased waitlist mortality.

KeywordsPrimary 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 [email protected].

Conflicts of Interest: The authors have no conflicts of interest to report as it pertains to this manuscript.

NIH Public AccessAuthor ManuscriptLiver Transpl. Author manuscript; available in PMC 2014 March 01.

Published in final edited form as:Liver Transpl. 2013 March ; 19(3): 250–258. doi:10.1002/lt.23587.

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IntroductionPrimary sclerosing cholangitis (PSC) is a chronic cholestatic disorder characterized byprogressive biliary strictures, ultimately leading to the development of liver failure orcholangiocarcinoma. As a result of biliary strictures and bile stasis, patients with PSC are atincreased risk of bacterial cholangitis. Among PSC patients, bacterial cholangitis is morecommonly seen in those with a history of biliary tract instrumentation (i.e. endoscopicretrograde cholangiopancreatography; ERCP) and/or dominant bile duct strictures.(1)Further, bacterial cholangitis may be associated with secondary complications, includingendocarditis and hepatic abscess formation.(2) A subset (<10%) of patients with PSC willsuffer from repeated bouts of bacterial cholangitis, which may result in frequenthospitalizations and thus impaired quality of life.(3) PSC is clearly associated with aconsiderable amount of morbidity, however the impact of bacterial cholangitis on mortalityof patients with PSC is unknown.(4)

Among patients waitlisted for liver transplantation, prioritization on the waitlist isdetermined by a patient's Model for End-Stage Liver Disease (MELD) score. The MELDscore, calculated based on a patient's INR, bilirubin, and creatinine, does not account forcomplications of liver disease. As a result, waitlist candidates with PSC, and specificallythose suffering from bacterial cholangitis, are frequently referred for living donor livertransplantation and/or receive MELD exception points after petition to a regional reviewboard (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 withPSC have a lower risk of waitlist removal for death or clinical deterioration when comparedto candidates with other forms of end-stage liver disease.(7) Additionally, there is no dataevaluating whether waitlist candidates with PSC who suffer from episodes of bacterialcholangitis have an increased risk of mortality.(4, 5) While there are publishedrecommendations to guide RRBs on which patients with PSC and recurrent bacterialcholangitis 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 toevaluate its association with waitlist mortality. Accordingly, using patient-level data fromtwo large liver transplant centers, we sought to determine whether: a) waitlist transplantcandidates 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 withPSC and bacterial cholangitis are justified.

MethodsWe performed a retrospective cohort study of all adult (≥18 years of age) waitlist transplantcandidates diagnosed with PSC at the University of Pennsylvania (UP) and the University ofColorado-Denver (UCD) between February 27, 2002 and June 1, 2012. At each center, therespective transplant databases were queried to identify waitlist candidates with a diagnosisof 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 wereincluded. The start date was chosen to limit the analysis to the MELD era. We excludedpatients 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 recordedfrom 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 pathologyreports, and/or documentation of medical record of confirmatory endoscopy and pathologyconsistent with ulcerative colitis or Crohn's disease), laboratory data, and presence/absenceof 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 contourof the liver surface and/or caudate lobe hypertrophy). Detailed data on waitlist removal wereobtained, including the reason for removal (based on UNOS coding criteria), and thespecific cause of death and/or clinical deterioration for those removed from the waitlistbecause of death, or being deemed too sick or medically unsuitable for transplantation.

Given the complexity of the diagnosis of bacterial cholangitis in the setting of PSC, wechose to define an episode of cholangitis based on any physician medical recorddocumentation stating the patient had an episode of bacterial cholangitis. We did not useelevated alkaline phosphatase levels and/or jaundice, or MRICP/ERCP abnormalities tofurther define cholangitis episodes as patients with PSC commonly have baselineabnormalities in one of these parameters.(8) As a result, we defined bacterial cholangitis asany physician medical record documentation stating the patient had an episode of bacterialcholangitis. While these episodes were commonly associated with fever, right upperquadrant pain, worsened jaundice, and/or bacteremia in the absence of an alternative sourceof infection, there were no specific criteria used given the retrospective nature of the study.

OutcomeThe primary outcome was waitlist removal for death or clinical deterioration, defined as thepatient being deemed too sick or medically unsuitable for transplantation. Outcomes wereinitially determined by review of the transplant databases at the respective transplant centers,but all waitlist removals were subsequently confirmed by detailed medical record review toverify accuracy of the transplant databases.

Statistical analysisWe used Fisher's exact test and chi-square tests for dichotomous variables and Student t testsor Wilcoxon rank-sum tests for continuous variables (according to their distributions) tocompare waitlist candidates with vs. without bacterial cholangitis and those who were vs.were not removed for death or clinical deterioration.

In evaluating whether bacterial cholangitis impacts the risk of waitlist mortality, one mustconsider the competing risk of transplantation, as it influences the probability that a waitlistcandidate will be removed from the waitlist for death or clinical deterioration.(9) Thus we fitcompeting risk Cox regression models, with waitlist removal as the outcome, andtransplantation 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 thewaitlist. We grouped together all episodes of bacterial cholangitis as the objective of thestudy was to determine if cholangitis, regardless of timing, was associated with worsenedoutcomes. In addition, a history of cholangitis, regardless of timing, is commonly used as acriterion for granting of exception points. Secondary models were used to evaluate theassociation between waitlist mortality and a history of bacterial cholangitis prior to listing orwhile on the waitlist separately.

Potential covariates included were gender, race (white vs. non-white due to sparse samplesizes 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, orspontaneous bacterial peritonitis) prior to listing. Covariates were first tested in single-itemfashion; we included any variable with a p-value ≤0.2 in the final model. The final modelsused a stepwise variable-selection process to retain variables with p-values ≤0.1. Potentialconfounders were included if the variable changed the hazard ratio of bacterial cholangitisby 10%. We used robust standard errors to account for correlation due to patient clusteringby transplant center.(12) Covariates were reported as subhazard ratios, given the use ofcompeting risk models.(9, 11)

Competing risk survival curves comparing the risk of waitlist removal for death or clinicaldeterioration, accounting for the competing risk of transplantation, were constructed usingthe “stcurve” function in Stata.

We chose to exclude the small number of patients with missing data from the finalmultivariable models (N=10) given the limited variables that could be used for multipleimputation.

Institutional Review Board Approval was obtained from both the UP and the UCD. Allstatistical analyses were performed using Stata 12.0 (College Station, TX).

ResultsFrom February 27th, 2002 to June 1st, 2012, 171 patients with PSC were listed for initialtransplantation at the UP (83) and the UCD (88). The median age was 48 years (interquartilerange (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 asignificantly 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 dataThe median laboratory MELD score at the time of listing was 14 (IQR: 9-19), with waitlistcandidates at the UP having significantly higher laboratory MELD scores at listing (15 [IQR10-20] 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; Table1).

Prior to waitlisting, 39.2% (67/171) of waitlist candidates had experienced a hepaticdecompensation (Table 1), with 31.6% (54/171) having ascites, 16.4% (28/171) withvariceal bleeding, 15.2% (26/171) with hepatic encephalopathy, and 1.1% (2/171) withspontaneous bacterial peritonitis. Based on imaging prior to waitlisting (as few patients hadliver biopsy due to it not being needed for the diagnosis of PSC, the data on radiographicdiagnosis is presented), 53.8% (92/171) of waitlist PSC candidates had documentedcirrhosis. None of these variables differed by center.

Episodes of bacterial cholangitisPrior to waitlisting, 38.6% (66/171) of waitlist candidates had a reported history of bacterialcholangitis. A similar proportion of waitlist candidates experienced at least one episode ofbacterial cholangitis across the two centers (Table 2a). At each center, over 50% of waitlistcandidates experienced greater than one episode of bacterial cholangitis prior to waitlisting(median number of episodes could not be calculated as discrete number of episodes notavailable 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 greaterproportion 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 ofbacterial cholangitis prior to waitlisting and/or while on the waitlist. A significantly greaterproportion 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 outcomesTable 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). Waitlisttime 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 2/27/02were still listed. During follow-up, 49.7% (85/171) were transplanted at one of the twocenters, with 21.2% (18/85) living donor liver recipients. An additional 8 (4.7%) patientslisted at the UP were transplanted at another center. There was a non-significant increase inthe odds of receiving a decreased donor transplant among those with versus without ahistory of cholangitis (35 [49.3%] versus 32 [39.0%]; P=0.20).

During follow-up, there were 13 waitlist candidates transplanted with exception points (9 atUC-D and 4 at UP): cholangiocarcinoma (7), recurrent cholangitis (3), hepatocellularcarcinoma (1), fatigue, bone disease, and failure to thrive (1), colon dysplasia requiringcolectomy in a decompensated cirrhotic (1).

Thirty waitlist candidates (17.5%) were removed from waitlist for death or clinicaldeterioration, with 53.3% (16/30) of those dying while still waitlisted, and the remaining46.7% (14/30) removed for clinical deterioration. None of these 30 patients had bacterialcholangitis 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 ERCPbrushings) 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 cholangitis-related.

Among those who received a deceased donor liver transplant, the median MELD of thosewith a history of cholangitis was 22 (IQR 15-26), compared with 25 (IQR 20-28) in thosewithout cholangitis (P=0.12). Among those who were removed from the waitlist for death orclinical 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 clinicaldeterioration (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 hadnumerically, but not statistically significantly, higher laboratory MELD scores comparedwith 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. Ofthese 25, 44% (11/25) were transplanted, while the other 56% were removed for death orclinical 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 developedcholangiocarcinoma vs. 11.2% [10/89] without cholangitis; P=0.19).

Outcomes based on history of cholangitisWe 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 waitlistremoval for death or clinical deterioration was similar when stratified by center (data notshown).

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=0.86comparing two groups) without cholangitis prior to listing.

Among the 44 waitlist candidates with bacterial cholangitis after listing, 9.1% (4/44) wereremoved 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 1MELD update).

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 thosewithout a history of cholangitis (P=0.34 comparing two groups). Similar unadjusted resultswere 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 morelikely to be transplanted during follow-up (59.8% [49/82] vs. 49.4% [44/89]), however thisdid not reach statistical significance (P=0.18). Similar results were obtained excluding the 8patients transplanted at another center.

In univariable competing risk Cox regression models, a history of cholangitis prior to and/oron the waitlist and male gender were associated with a decreased hazard of removal fordeath or clinical deterioration, while white race, older age, and higher laboratory MELDscore at listing were associated with an increased hazard (Table 4; history of hepaticdecompensation was non-significant and excluded from final model). In multivariablecompeting risk models, a history of cholangitis was associated with a significantly decreasedhazard 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 increasedrisk.

In multivariable competing risk Cox models evaluating each of the bacterial cholangitiscovariates separately, a history of cholangitis prior to waitlisting was not associated with anincreased 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).

DiscussionThis study is the first to evaluate the risk of waitlist mortality associated with bacterialcholangitis in waitlisted patients with PSC, using 10 years of data from two large transplantcenters. During a ten year period, nearly half of waitlist candidates with PSC experienced atleast one episode of bacterial cholangitis. A history of bacterial cholangitis was notassociated 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 knowncholangitis as the inciting event. The data call into question the prevailing belief that PSCpatients with bacterial cholangitis are at increased risk of waitlist mortality, and thus meritexception points and/or referral for living donor transplantation based solely on the risk ofwaitlist 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 weresymptomatic at the time of diagnosis.(13) Median survival from the time of diagnosis was11.9 years.(13) With earlier diagnosis due to increased awareness of the disease, availabilityof noninvasive imaging of the biliary tree, increased use of routine liver enzyme evaluationin asymptomatic patients, and recognition of the association between IBD and PSC, moreasymptomatic 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 transplantsbeing performed in patients with PSC.(6, 7)

Using UNOS data on all waitlist transplant candidates, we have previously shown that13.6% of waitlisted candidates with PSC from 2002-2009 were removed from the waitlistfor death or clinical deterioration.(7) This data though does not allow for evaluation ofbacterial cholangitis in waitlist candidates, necessitating the analysis of patient-level data.

The data presented here demonstrate that in both unadjusted and adjusted analyses, bacterialcholangitis in PSC waitlist candidates was not associated with an increased risk of mortalityor clinical deterioration. This is underscored by the fact that the causes of death or clinicaldeterioration were due to cholangiocarcinoma, portal hypertension, non-cholangitis sepsis,or other non-hepatic conditions, but not bacterial cholangitis. This data echo early PSC datafrom 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, andone as a complication of colon cancer. Similar to our data, no deaths were directly related tobacterial 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 wererelated to bacterial cholangitis.(14) Our analysis, the first to specifically evaluate theassociation between bacterial cholangitis and mortality, validates these earlier studies.

Although the risk of cholangiocarcinoma in our series is higher than previously publishedScandinavian data (14), when accounting for tumors diagnosed on explant or during thetransplant operation(15), the risk of cholangiocarcinoma in our cohort was not substantiallygreater than previously reported. The higher rate of cholangiocarcinoma on the waitlist seenin 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 waitingtimes in the United States, which may result in an increased risk of developing and/ordetecting cholangiocarcinoma. While there is no specific protocol for surveillance ofcholangiocarcinoma 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 forcholangiocarcinoma with exception points were at the University of Colorado which followsthe Mayo cholangiocarcinoma transplantation protocol.(16)

An additional notable finding is that infections were rarely a direct cause of waitlist removalfor death or clinical deterioration, unlike what is seen in patients with other forms of end-stage liver disease.(17) One potential explanation for this is that at least based on radiologicimaging pre-waitlisting, a substantial proportion of our patients did not have radiographicevidence 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 allhave cirrhosis, which may explain the different waitlist risk profile seen in this patientpopulation.(7)

The issue of the risk of mortality associated with bacterial cholangitis in PSC patients, andits impact on organ allocation, is important given the limited supply of transplantableorgans. Due to a concern that patients with PSC and bacterial cholangitis potentially have anincreased risk of waitlist mortality, transplant centers frequently apply for exception pointsfor these patients. In fact, since February 27th, 2002, 337 PSC patients have applied forMELD exception points for bacterial cholangitis, with the vast majority of these patientsbeing granted exception points, and ultimately transplanted, despite nearly three-fourths ofthem not meeting published recommendations for exception points for PSC and bacterialcholangitis.(5) Additionally, PSC waitlist candidates are significantly more likely to receivea 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 speakto the utility or necessity of transplantation due to morbidity and impaired quality of liferelated to bacterial cholangitis, it does demonstrate that bacterial cholangitis alone is notassociated with increased mortality.

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

Our observations had several limitations. We combined data from two transplant centers forthis analysis. The sample size for this study was small, and only included 171 waitlistcandidates with PSC. The two centers are situated in UNOS regions with above averageMELD scores at transplantation, therefore the data may not be generalizable to all waitlistcandidates with PSC in all UNOS regions. The data was retrospective in nature, and wewere reliant on accurate documentation in the medical record for our data. Furtherprospective, multi-center data is needed to confirm our findings. The demographicdistribution of PSC candidates at the two centers was similar. Although patients at the UPwere more likely to have a history of IBD prior to listing, this should not account for ourfindings. The laboratory MELD scores at listing at the UP were slightly higher, however weadjusted for MELD score in our final models. The distribution of portal hypertensivecomplications was similar though. We did note that a significantly greater proportion ofwaitlist candidates at the UCD had cholangitis on the waitlist. While the reason for this isunclear, perhaps due to provider differences in the use of prophylactic antibiotics, the risk ofadverse waitlist outcomes did not differ at each center, thus this was not a substantiallimitation.

The definition of cholangitis was based on physician documentation in the medical record,without definitive corroborating bacteremia or ERCP procedure documentation. We chose todefine cholangitis using physician documentation that is based on expert opinion andclinical judgment for several reasons. The diagnosis of bacterial cholangitis is difficult in thesetting of PSC. Traditional laboratory abnormalities such as hyperbilirubinemia and elevatedalkaline phosphatase are common at baseline in these patients. Secondly, findings such asworsening jaundice, fever, and/or right upper quadrant pain or tenderness, in the absence ofanother 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 ofprior clinician opinion of treating physicians. Lastly, even with data on blood cultures orERCP procedure reports (when performed in the setting of a dominant stricture), there is nosingle finding that is confirmatory for bacterial cholangitis in PSC, and the diagnosis (orpresumed diagnosis) is reliant on clinician judgment). Although misclassification may exist,such that patients were misclassified as cholangitis in the absence of such an infection, wewould not expect this to change our results. Among those categorized as bacterialcholangitis, only if a significantly greater proportion of those who did not die weremisclassified (leading to an underestimation of the risk of mortality from cholangitis) wouldwe expect our results to show an increased risk of mortality in patients with cholangitis,which is extremely unlikely. Additionally, this difficulty in definitively diagnosingcholangitis in this population also speaks to the challenge of granting exception points orusing this as a basis for increased prioritization. It may in fact be that only those patientswith bacteremia and/or septic complications are at greater risk of mortality, which not onlysupports the published consensus recommendations for exception points in PSC, but alsoforces us to more stringently define cholangitis in this population to better treat and riskstratify PSC patients. Due to the retrospective nature of the study, we could not specificallydetermine which episodes of cholangitis were associated with bacteremia, with or withoutsepsis. However, as no waitlist removals for death or clinical deterioration were directly dueto cholangitis, this suggests that even among the subset of patients with cholangitiscomplicated by bacteremia, the risk of waitlist mortality may not be significantly increased.Further multi-center prospective data is needed though to confirm this.

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 hazardratio was significantly less than 1, this should not have impacted our results. Thirdly, waitlistcandidates 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 PSCwaitlist candidates received a living donor transplant and 9% received exception points. Ofliving donor recipients, only 11/18 had a history of cholangitis, while only 3/13 transplantrecipients with MELD exception points were granted exceptions for recurrent cholangitis.This demonstrates that referral of PSC waitlist candidates with cholangitis for living donortransplantation and/or MELD exception points do not explain the findings. Even under aworst-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, butnot worse. We defined cirrhosis based on radiographic imaging, as few patients had liverbiopsies, is not 100% sensitive. Despite this, given the substantial number of patientswithout radiographic evidence of cirrhosis, it is still likely that a sizable proportion of thepatients did not in fact have cirrhosis. Lastly, we were unable to accurately determine ifpatients were on suppressive antibiotic therapy due to a history of recurrent cholangitis.Although this may have decreased the risk of complications from cholangitis and/orprevented the development of non-cholangitis complications, this is unlikely to fully accountfor our results.

In summary, we have shown that waitlisted transplant candidates with PSC and bacterialcholangitis do not have an increased risk of waitlist mortality when compared with thosewithout cholangitis. Over a 10 year period, no patients died on the waitlist or were removedfor clinical deterioration as a result of bacterial cholangitis. The data calls into question thesystematic granting of exception points for patients with PSC and bacterial cholangitis onthe basis of increased waitlist mortality. Multi-center patient level data is needed to validatethese findings and develop predictors of waitlist mortality to better risk stratify PSC waitlistcandidates in greatest need of exception points and pre-emptive living donor transplantation.

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AcknowledgmentsGrants and Financial Support: NIH/NIDDK F32 1-F32-DK-089694–01 Grant (D.G.)

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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5. Goldberg D, Bittermann T, Makar G. Lack of Standardization in Exception Points for Patients withPrimary Sclerosing Cholangitis and Bacterial Cholangitis. Am J Transplant. 2012 Epub 2012/02/18.

6. Goldberg DS, French B, Thomasson A, Reddy KR, Halpern SD. Current trends in living donor livertransplantation for primary sclerosing cholangitis. Transplantation. 2011; 91(10):1148–52. Epub2011/05/06. [PubMed: 21544035]

7. Goldberg D, French B, Thomasson A, Reddy KR, Halpern SD. Waitlist survival of patients withprimary sclerosing cholangitis in the model for end-stage liver disease era. Liver Transpl. 2011;17(11):1355–63. Epub 2011/08/13. [PubMed: 21837735]

8. Levy C, Lindor KD. Primary sclerosing cholangitis: epidemiology, natural history, and prognosis.Semin Liver Dis. 2006; 26(1):22–30. Epub 2006/02/24. [PubMed: 16496230]

9. Kim WR, Therneau TM, Benson JT, Kremers WK, Rosen CB, Gores GJ, et al. Deaths on the livertransplant waiting list: an analysis of competing risks. Hepatology. 2006; 43(2):345–51. Epub2006/01/28. [PubMed: 16440361]

10. Satagopan JM, Ben-Porat L, Berwick M, Robson M, Kutler D, Auerbach AD. A note oncompeting risks in survival data analysis. Br J Cancer. 2004; 91(7):1229–35. Epub 2004/08/12.[PubMed: 15305188]

11. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. Journalof the American Statistical Association. 1999; 94(446):496–509.

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12. French B, Heagerty PJ. Analysis of longitudinal data to evaluate a policy change. Stat Med. 2008;27(24):5005–25. Epub 2008/07/12. [PubMed: 18618416]

13. Wiesner RH, Grambsch PM, Dickson ER, Ludwig J, MacCarty RL, Hunter EB, et al. Primarysclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology. 1989;10(4):430–6. Epub 1989/10/01. [PubMed: 2777204]

14. Brandsaeter B, Broome U, Isoniemi H, Friman S, Hansen B, Schrumpf E, et al. Livertransplantation for primary sclerosing cholangitis in the Nordic countries: outcome afteracceptance to the waiting list. Liver Transpl. 2003; 9(9):961–9. Epub 2003/08/28. [PubMed:12942458]

15. Brandsaeter B, Isoniemi H, Broome U, Olausson M, Backman L, Hansen B, et al. Livertransplantation for primary sclerosing cholangitis; predictors and consequences of hepatobiliarymalignancy. J Hepatol. 2004; 40(5):815–22. Epub 2004/04/20. [PubMed: 15094230]

16. Darwish Murad S, Kim WR, Harnois DM, Douglas DD, Burton J, Kulik LM, et al. Efficacy ofneoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at12 US centers. Gastroenterology. 2012; 143(1):88–98. e3. quiz e14. Epub 2012/04/17. [PubMed:22504095]

17. Bajaj JS, O'Leary JG, Reddy KR, Wong F, Olson JC, Subramanian RM, et al. Second infectionsindependently increase mortality in hospitalized cirrhotic patients: The nacseld experience.Hepatology. 2012 Epub 2012/07/19.

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Figure 1.Competing risk regression evaluating risk of waitlist removal for death or clinicaldeterioration

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Table 1

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

Variable University ofPennsylvania, =83

University of Colorado-Denver, N=88

Combined two centerdata P-value

*

Median age at listing, years (IQR) 48 (32, 58) 38 (37, 58) 48 (37-58) 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)

Other 1 (1.2) 2 (2.3) 3 (1.7)

Male gender, N (%) 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 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/μl) 173 (101, 238) 180 (121, 287) 178 (110-281) 0.13

Variceal bleeding, N (%) 18 (21.7) 10 (11.4) 28 (16.4) 0.07

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

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)

2 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 (%)

1 26 (59.1)

2 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

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 post-coronary 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

†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

Competing risk Cox regression models evaluating risk of waitlist removal for death or clinical deteriorationassociated 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

Listing laboratory MELD score* 1.03 (1.02, 1.04) 1.02 (0.99, 1.06) 0.18

Age at listing† 1.35 (1.02, 1.80) 1.37 (1.05, 1.79) 0.02

*Increments of 1 MELD point

†Five year increments


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episode of cholangitis

subset of psc patients

risk of waitlist mortality

adult psc waitlist candidates

waitlist mortality isunknown

result of biliary strictures

university of colorado

bile stasis