Clinical Gastroenterology and Hepatology 2014;-:-–-
Low Risk of Hepatocellular Carcinoma in Patients With Primary Sclerosing Cholangitis With Cirrhosis Roman Zenouzi,*,a Tobias J. Weismüller,‡,§,a Peter Hübener,* Kornelius Schulze,* Michael Bubenheim,jj Nadine Pannicke,* Christina Weiler–Normann,* Henrike Lenzen,§ Michael P. Manns,§ Ansgar W. Lohse,* and Christoph Schramm* *First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; ‡Department of Internal Medicine 1, University of Bonn, Bonn, Germany; §Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; and jjBiostatistics Department, Rouen University Hospital-Charles Nicolle, Rouen, France BACKGROUND & AIMS:
Primary sclerosing cholangitis (PSC) is associated with an increased risk of hepatobiliary malignancies. However, little is known about the incidence of hepatocellular carcinoma (HCC) among patients with PSC; current recommendations on screening these patients for HCC are conflicting. We investigated the risk of HCC in patients with PSC with cirrhosis.
METHODS:
We performed a retrospective study of patients with well-defined PSC from 2 large-volume tertiary care centers in Germany; data were collected from periods of up to 33 years. Liver cirrhosis was based on histology results or the presence of ascites, esophageal varices, or transient elastography values greater than 14 kPa. Statistical analysis was performed using the Kaplan–Meier method and the Cox proportional hazard model. Data from 509 patients (67% male), with a total of 4202 patients-years, were included in the final analysis.
RESULTS:
We identified 119 patients with cirrhosis. During 292 patient-years, none of these patients developed HCC. Most HCCs were identified incidentally at the time of liver transplantation. We therefore reviewed data on liver explants from 140 patients who underwent transplantation; none were found to contain HCC. In contrast to the low numbers of HCCs among patients with PSC, 35 patients developed cholangiocarcinoma, 3 patients developed gallbladder cancer, and 9 patients developed colorectal cancer.
CONCLUSIONS:
Based on a retrospective analysis of more than 500 patients with PSC, we confirm their high risk for hepatobiliary malignancies. However, the risk of HCC, even among patients with cirrhosis, seems to be low—regular HCC surveillance may not be warranted.
Keywords: Cholangiocarcinoma; Liver Cancer; Screening; Population.
rimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by the progressive fibrosis of intrahepatic and/or extrahepatic bile ducts. End-stage liver disease develops in the majority of patients within 10 to 20 years.1,2 In addition, patients are at greatly increased risk for hepatobiliary malignancy.3 The major clinical challenge with regard to malignancy in PSC is the development of cholangiocarcinoma (CCA), which develops in approximately 15% of patients.4 CCA in PSC is difficult to diagnose in early stages and has a major impact on patient survival.3–5 In addition, gallbladder polyps harbor an increased risk of malignancy, which has led to the recommendation to perform cholecystectomy in patients with gallbladder polyps smaller than even 1 cm in diameter.1,6 Approximately 60% to 80% of patients also suffer from inflammatory bowel disease (IBD), mostly an ulcerative colitis (UC)-like disease. These patients in
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addition are at increased risk to develop colorectal cancer (CRC), which is higher than in patients with UC alone.4,7,8 PSC is a progressive disease leading to a biliary type of cirrhosis. Cirrhosis of different etiologies mediates a variable risk to develop hepatocellular carcinoma (HCC). A high risk of HCC is evident in chronic viral hepatitis B and C9,10 as well as hereditary hemochromatosis11,12
a
Authors share co-first authorship.
Abbreviations used in this paper: AIH, autoimmune hepatitis; CCA, cholangiocarcinoma; CI, confidence interval; CRC, colorectal cancer; GBC, gallbladder cancer; HCC, hepatocellular carcinoma; IBD, inflammatory bowel disease; MRI, magnetic resonance imaging; PSC, primary sclerosing cholangitis; UC, ulcerative colitis. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.02.008
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cirrhosis. Lower risks of HCC have been reported in cirrhosis caused by autoimmune hepatitis (AIH)13,14 or primary biliary cirrhosis.15 Because of a lack of data on the risk of HCC in PSC, recommendations on HCC screening in PSC cirrhosis are conflicting: in contrast to current guidelines,1,16 a recent review article recommended HCC surveillance in patients with PSC cirrhosis.17 Recommendations on HCC screening in PSC cirrhosis, however, are not evidence-based and stem from the assumption that cirrhosis in the setting of PSC harbors a similar risk of HCC development as seen in other cirrhosis etiologies. However, the incidence of HCC in PSC cirrhosis is unknown because data on the occurrence of HCC in PSC has been derived to date from studying the prevalence of HCC in explanted livers and no information was given on the duration of cirrhotic stage disease4,18 (Table 1 contains an overview). The incidence of HCC development in PSC patients at risk (ie, with known cirrhosis) over time therefore remains unclear. Because HCC surveillance may reduce the mortality of patients under sufficiently increased risk of developing HCC,19 this study aimed to determine the risk of HCC in cirrhotic stage PSC in a large and well-characterized cohort of patients with a long observation period and under regular surveillance and to relate this risk to the known cancer risks associated with PSC.
Patients and Methods A total of 515 PSC patients cared for at 2 tertiary care centers in Germany (Hannover and Hamburg) from 1979 until the present were reviewed for this retrospective study. Only patients with well-defined PSC based on biochemical, clinical, and cholangiographic (magnetic resonance imaging [MRI] and/or endoscopic retrograde cholangiopancreatography) features were included.1 The regular surveillance program of PSC patients included ultrasound (at least yearly) and/or MRI (every 1–2 years) of the liver. Ninety-one percent of patients were treated with ursodeoxycholic acid. Except for AIH, concomitant liver diseases were excluded, which led to the exclusion of 6 patients with positive serologic findings for hepatitis B, C, or E. No patient had known alcohol
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abuse. IBD was diagnosed or excluded using colonoscopy in all patients. Follow-up evaluation and calculation of patient-years at risk started at the time of PSC or cirrhosis diagnosis. Cirrhosis was assumed if ascites, esophageal varices, a transient elastography value greater than 14 kPa,20 or a positive liver histology were present. Study end points were death, liver transplantation, or the development of malignancy. All cancers were verified histologically. Survival analyses were performed using the Kaplan–Meier method, for risk analyses the Cox proportional hazard model was used. Because no HCC was observed in PSC patients, the upper limit of the 95% confidence interval (CI) for its instantaneous risk was estimated assuming an exponential model by the negative logarithm (0.05)/patient-years.21
Results Patient Characteristics A total of 509 patients were included in the study, 67% of them were male. The median follow-up period was 7 years (range, 0–33 y), and a total of 4204 patientyears were analyzed. The median age at PSC diagnosis was 32 years (range, 4–73 y). IBD was present in 330 patients (65%), of whom 76% suffered from UC and 15% suffered from Crohn’s disease. In 9% the IBD was classified as indeterminate. In 78 patients (15%) an overlap syndrome with AIH was diagnosed. A total of 460 patients (90%) were treated with ursodeoxycholic acid (Table 2).
Development of Cirrhosis in Primary Sclerosing Cholangitis Overall, in 119 patients, cirrhosis was diagnosed. The diagnosis of cirrhosis was based on esophageal varices in 77 (65%) patients, a positive liver histology in 32 (27%) patients, ascites in 18 (15%) patients, and a transient elastography value greater than 14 kPa in 13 (11%) patients. The median transient elastography value of
Table 1. Literature Review of the Occurrence of HCC in PSC Study
Number of patients with PSC
Number of patients with cirrhosis
Number of HCC in explanted livers
Number of HCC as a result of regular surveillance
Harnois et al, 199718 Bergquist et al, 20024 Demarchi et al, 200726 Tischendorf et al, 20072 Claessen et al, 20097 de Valle et al, 201231 Boonstra et al, 20135
134 604 1 273 211 199 590
Unknown Unknown 1 Unknown 23b Unknown Unknown
2 4 1a -
1 1
a
No information regarding whether HCC was found on regular surveillance or incidentally after liver transplantation. Liver histology was available for 148 patients.
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HCC in PSC
Table 2. Patient Characteristics Total number of patients Male sex Median age at PSC diagnosis, y Patients treated with UDCA therapy Patient diagnosis IBD UC Crohn’s disease Indeterminate AIH overlap Cirrhosis
509 (100%) 343 (67%) 32 460 (90%) 330 251 48 31 78 119
(65%) (49%) (9%) (6%) (15%) (23%)
NOTE. A total of 509 patients were analyzed. UDCA, ursodeoxycholic acid.
those patients with a value greater than 14 kPa was 27.2 kPa (range, 14.3–75 kPa). In 5 patients cirrhosis was diagnosed according to transient elastography only. The rate of cirrhosis was increased in patients with an overlap syndrome with AIH compared with classic PSC patients (35% vs 21%; c2 ¼ 0.01), whereas the rate of cirrhosis was similar in patients with or without IBD (26% vs 20%, c2 ¼ 0.13). Eighteen patients already presented with cirrhosis at the time of initial diagnosis and 101 patients developed cirrhosis during the observation period. To reduce referral bias on the analysis of cirrhosis development, patients presenting with cirrhosis were excluded. By doing so, the estimated median time from the diagnosis of PSC to the development of cirrhosis was 23 years (95% CI, 17–29 y). Overall, a total of 292 patient-years with cirrhosis were analyzed in 119 patients.
Primary Sclerosing Cholangitis Cirrhosis May Not Pose a Significant Risk for the Development of Hepatocellular Carcinoma During follow-up evaluation, 47 patients developed hepatobiliary or gastrointestinal malignancies. However, HCC was not observed in any patient at baseline or during follow-up evaluation. Therefore, the estimated upper 95% CI limit for the instantaneous risk of HCC was 0.07% for the 4204 years covering the entire cohort and 1.03% with regard to the 292 patient-years with cirrhosis. Because current knowledge regarding HCC in PSC is derived mainly from analyzing liver explants, we additionally reviewed the available histopathologic reports of the explanted livers after transplantation for PSC: in 140 transplanted patients not a single HCC was detected, underlining the notion that the incidence of HCC missed by surveillance also may be low in advanced PSC. Furthermore, no mixed hepatocellular/ CCA cases were observed after additional review of the histopathologic reports of all CCA cases, nor were any mixed cancers detected in liver explants from patients with CCA.
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Taken together, these data suggest that the risk of HCC even in the presence of cirrhosis is lower than the limit that generally is accepted for justifying regular surveillance examinations using ultrasound.3,19
Incidence of Cholangiocarcinoma and Gallbladder Cancer With 75% of all tumors, CCA (n ¼ 35) was the most frequent hepatobiliary cancer followed by gallbladder cancer (GBC) (n ¼ 3). It previously was reported that the risk of diagnosing CCA is highest within the first year after diagnosis of PSC.4,22 This could be confirmed in our series, with 20% of patients receiving a diagnosis of CCA at first presentation or within the first year of diagnosis of PSC. Excluding these cases, the cumulative incidence of CCA after 10 and 20 years still was 4.9% and 15.8%, respectively (Figure 1). GBC developed in 3 patients at 3, 10, and 11 years after the diagnosis of PSC. The cumulative incidence of GBC after 10 and 20 years was 0.7% and 1.3%, respectively (Figure 1). Not surprisingly, hepatobiliary malignancy had a major impact on patient survival with a hazard ratio of death for patients developing CCA of 22.29 (95% CI, 11.17–44.51; P < .01) and of 14.16 (95% CI, 3.32–60.33; P < .01) for patients developing GBC.
Colorectal Cancer in Patients With Primary Sclerosing Cholangitis All patients developing CRC suffered from concomitant IBD. In concomitant UC CRC was diagnosed in 8 cases and in concomitant Crohn’s disease in 1 case. Excluding the cases that were diagnosed at first presentation or within the first year of diagnosing PSC (n ¼ 1), the cumulative incidence of CRC after 10 and 20 years in patients with concomitant UC was 1.9% and 7.4%, respectively (Figure 1). CRC was associated with an increased mortality in patients with PSC (hazard ratio, 3.96; 95% CI, 1.20–13.03; P ¼ .02) as compared with patients who did not develop CRC during the observation period.
Transplant-Free and Overall Survival of Patients With Primary Sclerosing Cholangitis A total of 142 patients (28%) underwent liver transplantation, with a 10- and 20-year transplant-free survival rate of 71% (95% CI, 66%–76%) and 37% (95% CI, 30%–45%), respectively. The median transplant-free survival period was 15 years (95% CI, 14–17 y). Thirty-seven patients (7%) died during the observation period, with a 10- and 20-year overall patient survival rate of 94% (95% CI, 91%–97%) and 86% (95% CI, 81%–91%), respectively. Excluding the 21 patients who died of hepatobiliary malignancy, the
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Figure 1. Incidence of hepatobiliary and CRC. Cumulative incidence of developing (A) CCA, (B) CRC, and (C) GBC in patients with PSC. Patients with the diagnosis of CCA (n ¼ 7) or CRC (n ¼ 1) at first presentation or within the first year of follow-up evaluation were excluded from this analysis. Note that the analysis of CRC only included those patients with concomitant UC.
10- and 20-year patient survival was increased to 98% (95% CI, 97%–100%) and 93% (95% CI, 89%–97%), respectively, underlining the idea that hepatobiliary malignancies are the main complications limiting patient survival in PSC.
Discussion The risk of hepatobiliary malignancy is greatly increased in patients with PSC, mainly owing to the high incidence of CCA. Because PSC is a progressive disease leading to cirrhosis in most cases, the risk of HCC in PSC also may be increased. Recommendations on HCC surveillance in cirrhotic stage PSC, however, are conflicting and data on the incidence of HCC in PSC cirrhosis are lacking.7,14,16 Because HCC is one of the cancers that can be cured if detected at early stages, we aimed to determine the incidence of HCC in PSC cirrhosis to assess the potential requirement of HCC screening in PSC. The strength of the study presented here is the large number of patients included with a median observation time of 7 years, and a maximum of up to 33 years. What distinguishes this study from other reports on HCC in
PSC is that we aimed to determine the presence of cirrhosis in PSC before the end point of liver transplantation, thereby enabling us to estimate the incidence of HCC in patients with or without cirrhosis and to compare that risk with the other hepatobiliary malignancies that are known to be associated with PSC. Next to its retrospective nature and a potential underestimation of malignancies owing to competing end points, a possible caveat of our study was the difficulty in defining cirrhosis in PSC patients. PSC is a focal disease and a liver biopsy can be associated with considerable sampling error, especially in PSC. However, in the 2 centers involved in this study, biopsy guidance by minilaparoscopy frequently is performed, reducing the contribution of sampling error.23 We believe that the presence of esophageal varices and ascites indicates cirrhosis in these patients with an acceptable accuracy, but the optimal transient elastography cut-off value defining cirrhosis in PSC is not well defined.20 Our own experience, however, indicates that a cut-off value of 14 kPa has a high positive predictive value for the detection of cirrhosis in PSC (personal unpublished data), and a similar cut-off value of 14.4 kPa was published very recently for the detection of cirrhosis in PSC.24 Still, the
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rate of cirrhosis may have been underestimated in our study. This would imply that the HCC risk estimation presented here may even be too high. The incidence of HCC considerably varies with the etiology of the underlying liver disease. Although HCC is found most frequently in cirrhosis resulting from chronic viral hepatitis B9 and C10 as well as hereditary hemochromatosis,11,12 and recently nonalcoholic steatohepatitis cirrhosis,25 its incidence in cirrhotic-stage autoimmune liver diseases is comparatively low, with an estimated HCC incidence in AIH cirrhosis as low as 0.2% to 1.1%.13,14 Data on the prevalence of HCC in PSC cirrhosis stems mainly from the analysis of liver explants. In the study from the Mayo Clinic, 3 PSC patients with HCC were diagnosed at liver transplantation (point prevalence, 2%), and in only 1 of these cases was the cancer known before transplantation.18 Tischendorf et al2 detected 1 case of HCC in a cohort of 273 patients with PSC. However, it remains unclear whether this cancer was diagnosed on regular surveillance or incidentally after transplantation. In a Swedish cohort, 4 patients with HCC in the explanted liver were mentioned, but no information on the presence or duration of cirrhosis was given (point prevalence, 4%).4 Consistently, case reports on HCC complicating PSC are rare and only 1 case of a patient with PSC and concomitant Crohn’s disease was found in our literature research26 (Table 1 contains an overview of published data). We report here that in analyzing 4204 patient-years and 292 patient-years under cirrhosis risk, there was not a single HCC detected. In addition, in reviewing 140 liver explants of our patients, no incidental HCC was detected in this series. Most centers apply some sort of surveillance strategies using ultrasound and/or MRI for screening patients with PSC, although there is no evidence that this reduces mortality of affected patients. Despite that, to our knowledge there have been only 2 patients with PSC reported by Harnois et al18 and Demarchi et al26 in whom HCC was detected on surveillance. This indicates that the risk of HCC in PSC even in the presence of cirrhosis may be far below the threshold of 1.5% per year that generally is accepted for HCC surveillance.3,19 What are potential explanations for this finding? Fibrosis and chronic inflammation in end-stage liver diseases both are linked to malignant transformation. However, inflammation has been shown not only to promote but also to inhibit hepatic carcinogenesis, which, for example, lately has been shown with regard to the interferon-g/signal transducers and activators of transcription 1 pathway.27 These data suggest that interferon-g also may affect hepatocyte apoptosis and that inflammation may be associated with enhanced cancer immunosurveillance.28 Whether these mechanisms contribute to the comparably low HCC incidence rates in autoimmune liver diseases such as AIH and PSC needs to be elucidated further.
HCC in PSC
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In accordance with the results of other studies, CCA was the most frequent hepatobiliary malignancy in our patient cohort, accounting for the vast majority of deaths observed. Twenty percent of CCA were diagnosed within the first year of follow-up evaluation. These data and data from other studies, which found up to 50% of CCAs to be diagnosed within the first year after diagnosis of PSC,4,22 underline that clinicians should be especially alert at diagnosis and directly after diagnosis of PSC. Excluding this peak of incidence within the first year, a rather constant incidence of 0.5% per year was observed in our patient cohort, resulting in an estimated 20-year cumulative CCA incidence of 15.8% (Figure 1). As has been reported previously, the presence of cirrhosis did not affect CCA development in the study presented here (data not shown).22 PSC has been reported to be an independent risk factor for the development of CRC in patients with UC,29 however, data on the incidence of CRC in PSC are diverging. In some earlier studies the cumulative incidence of CRC or colorectal dysplasia in patients with PSC and concomitant UC after 10 and 20 years was up to 11% and 31%, respectively.8,30 However, in a recently published study of a Swedish cohort only 2 of 199 PSC patients developed a CRC within a median time of 6.5 years.31 This suggests that the risk of CRC may be decreasing, possibly as a consequence of the changing management of IBD over the past decades, including medical treatment and implementation of endoscopic surveillance programs. Accordingly, in our cohort of 251 PSC patients with UC, only 8 cases of CRC occurred and we estimated a cumulative risk of CRC after 10 and 20 years for patients with concomitant UC of 1.9% and 7.4%, respectively. Because our study was not designed to assess colonic neoplasia including dysplasia and because of the relatively short observation time for the assessment of CRC, the frequency of colonic neoplasia may have been underestimated here and the current surveillance strategies of yearly colonoscopies should be followed.1,16 In summary, we confirm the high risk for hepatobiliary malignancy in a large cohort of patients with PSC. However, although CCA was the main complication limiting patient survival, no HCC was observed in a total of 4202 patient-years and 292 patient-years under risk of cirrhosis, or in 140 explanted livers of patients transplanted for PSC. What are the practical implications of this finding? The data reported argue against HCC surveillance in patients with PSC using ultrasound or measurements of a-fetoprotein. Most centers nevertheless will continue to perform regular ultrasound examinations in patients with PSC because of the risk of gallbladder polyps and CCA. At our centers, it is standard of care to recommend ultrasound every 6 months. However, because CCA cannot be detected using transabdominal ultrasound at an early stage and because the incidence of GBC remains very low, ultrasound surveillance for hepatobiliary malignancies remains without
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evidence in patients with PSC. The low risk of HCC may be a comforting piece of information for patients suffering from a progressive disease with a severe prognosis.
References 1. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237–267. 2. Tischendorf JJ, Hecker H, Kruger M, et al. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am J Gastroenterol 2007; 102:107–114. 3. Razumilava N, Gores GJ, Lindor KD. Cancer surveillance in patients with primary sclerosing cholangitis. Hepatology 2011; 54:1842–1852. 4. Bergquist A, Ekbom A, Olsson R, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 2002; 36:321–327. 5. Boonstra K, Weersma RK, van Erpecum KJ, et al. Populationbased epidemiology, malignancy risk and outcome of primary sclerosing cholangitis. Hepatology 2013;58:2045–2055. 6. Schramm C, Lohse AW. Gallbladder polyps in primary sclerosing cholangitis: indication for early intervention. Hepatology 2012;56:396; author reply.
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18. Harnois DM, Gores GJ, Ludwig J, et al. Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer? J Hepatol 1997;27: 512–516. 19. Bruix J, Sherman M. American Association for the Study of Liver Disease: Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020–1022. 20. Corpechot C, El Naggar A, Poujol-Robert A, et al. Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC. Hepatology 2006;43:1118–1124. 21. Piantadosi S. Clinical trials: a methodologic perspective. Hoboken, NJ: Wiley; 2005:262. 22. Boberg KM, Lind GE. Primary sclerosing cholangitis and malignancy. Best Pract Res Clin Gastroenterol 2011;25:753–764. 23. Denzer U, Arnoldy A, Kanzler S, et al. Prospective randomized comparison of minilaparoscopy and percutaneous liver biopsy: diagnosis of cirrhosis and complications. J Clin Gastroenterol 2007;41:103–110. 24. Corpechot C, Gaouar F, El Naggar A, et al. Baseline values and changes in liver stiffness, measured by transient elastography, are associated with fibrosis severity and outcomes of patients with primary sclerosing cholangitis. Gastroenterology 2013: Epub ahead of print.
7. Claessen MM, Vleggaar FP, Tytgat KM, et al. High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol 2009;50: 158–164.
25. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012; 10:1342–1359.e2.
8. Leidenius MH, Farkkila MA, Karkkainen P, et al. Colorectal dysplasia and carcinoma in patients with ulcerative colitis and primary sclerosing cholangitis. Scand J Gastroenterol 1997;32: 706–711.
26. Demarchi B, Bresso F, Novero D, et al. Hepatocellular carcinoma complicating primary sclerosing cholangitis in Crohn’s disease. A case report. Minerva Gastroenterol Dietol 2007;53: 279–283.
9. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295:65–73.
27. Luth S, Schrader J, Zander S, et al. Chronic inflammatory IFNgamma signaling suppresses hepatocarcinogenesis in mice by sensitizing hepatocytes for apoptosis. Cancer Res 2011;71: 3763–3771.
10. Degos F, Christidis C, Ganne-Carrie N, et al. Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death. Gut 2000;47:131–136. 11. Beaton MD, Adams PC. Prognostic factors and survival in patients with hereditary hemochromatosis and cirrhosis. Can J Gastroenterol 2006;20:257–260. 12. Elmberg M, Hultcrantz R, Ekbom A, et al. Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology 2003;125:1733–1741. 13. Teufel A, Weinmann A, Centner C, et al. Hepatocellular carcinoma in patients with autoimmune hepatitis. World J Gastroenterol 2009;15:578–582. 14. Yeoman AD, Al-Chalabi T, Karani JB, et al. Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: implications for follow-up and screening. Hepatology 2008;48:863–870. 15. Farinati F, Floreani A, De Maria N, et al. Hepatocellular carcinoma in primary biliary cirrhosis. J Hepatol 1994;21:315–316.
28. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006;6:836–848. 29. Soetikno RM, Lin OS, Heidenreich PA, et al. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc 2002;56:48–54. 30. Broome U, Lofberg R, Veress B, et al. Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential. Hepatology 1995;22:1404–1408. 31. de Valle MB, Bjornsson E, Lindkvist B. Mortality and cancer risk related to primary sclerosing cholangitis in a Swedish population-based cohort. Liver Int 2012;32:441–448.
Reprint requests Address requests for reprints to: Christoph Schramm, MD, First Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. e-mail: [email protected]; fax: (49) 40-7410-58531.
16. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51: 660–678.
Conflicts of interest The authors disclose no conflicts.
17. Eaton JE, Talwalkar JA, Lazaridis KN, et al. Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology 2013;145:521–536.
Funding Supported by the Sonderforschungsbereich 841, Deutsche Forschungsgemeinschaft (DFG), and by the YAEL foundation.
Low Risk of Hepatocellular Carcinoma in Patients With Primary Sclerosing Cholangitis With Cirrhosis Roman Zenouzi,*,a Tobias J. Weismüller,‡,§,a Peter Hübener,* Kornelius Schulze,* Michael Bubenheim,jj Nadine Pannicke,* Christina Weiler–Normann,* Henrike Lenzen,§ Michael P. Manns,§ Ansgar W. Lohse,* and Christoph Schramm* *First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; ‡Department of Internal Medicine 1, University of Bonn, Bonn, Germany; §Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; and jjBiostatistics Department, Rouen University Hospital-Charles Nicolle, Rouen, France BACKGROUND & AIMS:
Primary sclerosing cholangitis (PSC) is associated with an increased risk of hepatobiliary malignancies. However, little is known about the incidence of hepatocellular carcinoma (HCC) among patients with PSC; current recommendations on screening these patients for HCC are conflicting. We investigated the risk of HCC in patients with PSC with cirrhosis.
METHODS:
We performed a retrospective study of patients with well-defined PSC from 2 large-volume tertiary care centers in Germany; data were collected from periods of up to 33 years. Liver cirrhosis was based on histology results or the presence of ascites, esophageal varices, or transient elastography values greater than 14 kPa. Statistical analysis was performed using the Kaplan–Meier method and the Cox proportional hazard model. Data from 509 patients (67% male), with a total of 4202 patients-years, were included in the final analysis.
RESULTS:
We identified 119 patients with cirrhosis. During 292 patient-years, none of these patients developed HCC. Most HCCs were identified incidentally at the time of liver transplantation. We therefore reviewed data on liver explants from 140 patients who underwent transplantation; none were found to contain HCC. In contrast to the low numbers of HCCs among patients with PSC, 35 patients developed cholangiocarcinoma, 3 patients developed gallbladder cancer, and 9 patients developed colorectal cancer.
CONCLUSIONS:
Based on a retrospective analysis of more than 500 patients with PSC, we confirm their high risk for hepatobiliary malignancies. However, the risk of HCC, even among patients with cirrhosis, seems to be low—regular HCC surveillance may not be warranted.
Keywords: Cholangiocarcinoma; Liver Cancer; Screening; Population.
rimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by the progressive fibrosis of intrahepatic and/or extrahepatic bile ducts. End-stage liver disease develops in the majority of patients within 10 to 20 years.1,2 In addition, patients are at greatly increased risk for hepatobiliary malignancy.3 The major clinical challenge with regard to malignancy in PSC is the development of cholangiocarcinoma (CCA), which develops in approximately 15% of patients.4 CCA in PSC is difficult to diagnose in early stages and has a major impact on patient survival.3–5 In addition, gallbladder polyps harbor an increased risk of malignancy, which has led to the recommendation to perform cholecystectomy in patients with gallbladder polyps smaller than even 1 cm in diameter.1,6 Approximately 60% to 80% of patients also suffer from inflammatory bowel disease (IBD), mostly an ulcerative colitis (UC)-like disease. These patients in
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addition are at increased risk to develop colorectal cancer (CRC), which is higher than in patients with UC alone.4,7,8 PSC is a progressive disease leading to a biliary type of cirrhosis. Cirrhosis of different etiologies mediates a variable risk to develop hepatocellular carcinoma (HCC). A high risk of HCC is evident in chronic viral hepatitis B and C9,10 as well as hereditary hemochromatosis11,12
a
Authors share co-first authorship.
Abbreviations used in this paper: AIH, autoimmune hepatitis; CCA, cholangiocarcinoma; CI, confidence interval; CRC, colorectal cancer; GBC, gallbladder cancer; HCC, hepatocellular carcinoma; IBD, inflammatory bowel disease; MRI, magnetic resonance imaging; PSC, primary sclerosing cholangitis; UC, ulcerative colitis. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.02.008
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cirrhosis. Lower risks of HCC have been reported in cirrhosis caused by autoimmune hepatitis (AIH)13,14 or primary biliary cirrhosis.15 Because of a lack of data on the risk of HCC in PSC, recommendations on HCC screening in PSC cirrhosis are conflicting: in contrast to current guidelines,1,16 a recent review article recommended HCC surveillance in patients with PSC cirrhosis.17 Recommendations on HCC screening in PSC cirrhosis, however, are not evidence-based and stem from the assumption that cirrhosis in the setting of PSC harbors a similar risk of HCC development as seen in other cirrhosis etiologies. However, the incidence of HCC in PSC cirrhosis is unknown because data on the occurrence of HCC in PSC has been derived to date from studying the prevalence of HCC in explanted livers and no information was given on the duration of cirrhotic stage disease4,18 (Table 1 contains an overview). The incidence of HCC development in PSC patients at risk (ie, with known cirrhosis) over time therefore remains unclear. Because HCC surveillance may reduce the mortality of patients under sufficiently increased risk of developing HCC,19 this study aimed to determine the risk of HCC in cirrhotic stage PSC in a large and well-characterized cohort of patients with a long observation period and under regular surveillance and to relate this risk to the known cancer risks associated with PSC.
Patients and Methods A total of 515 PSC patients cared for at 2 tertiary care centers in Germany (Hannover and Hamburg) from 1979 until the present were reviewed for this retrospective study. Only patients with well-defined PSC based on biochemical, clinical, and cholangiographic (magnetic resonance imaging [MRI] and/or endoscopic retrograde cholangiopancreatography) features were included.1 The regular surveillance program of PSC patients included ultrasound (at least yearly) and/or MRI (every 1–2 years) of the liver. Ninety-one percent of patients were treated with ursodeoxycholic acid. Except for AIH, concomitant liver diseases were excluded, which led to the exclusion of 6 patients with positive serologic findings for hepatitis B, C, or E. No patient had known alcohol
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abuse. IBD was diagnosed or excluded using colonoscopy in all patients. Follow-up evaluation and calculation of patient-years at risk started at the time of PSC or cirrhosis diagnosis. Cirrhosis was assumed if ascites, esophageal varices, a transient elastography value greater than 14 kPa,20 or a positive liver histology were present. Study end points were death, liver transplantation, or the development of malignancy. All cancers were verified histologically. Survival analyses were performed using the Kaplan–Meier method, for risk analyses the Cox proportional hazard model was used. Because no HCC was observed in PSC patients, the upper limit of the 95% confidence interval (CI) for its instantaneous risk was estimated assuming an exponential model by the negative logarithm (0.05)/patient-years.21
Results Patient Characteristics A total of 509 patients were included in the study, 67% of them were male. The median follow-up period was 7 years (range, 0–33 y), and a total of 4204 patientyears were analyzed. The median age at PSC diagnosis was 32 years (range, 4–73 y). IBD was present in 330 patients (65%), of whom 76% suffered from UC and 15% suffered from Crohn’s disease. In 9% the IBD was classified as indeterminate. In 78 patients (15%) an overlap syndrome with AIH was diagnosed. A total of 460 patients (90%) were treated with ursodeoxycholic acid (Table 2).
Development of Cirrhosis in Primary Sclerosing Cholangitis Overall, in 119 patients, cirrhosis was diagnosed. The diagnosis of cirrhosis was based on esophageal varices in 77 (65%) patients, a positive liver histology in 32 (27%) patients, ascites in 18 (15%) patients, and a transient elastography value greater than 14 kPa in 13 (11%) patients. The median transient elastography value of
Table 1. Literature Review of the Occurrence of HCC in PSC Study
Number of patients with PSC
Number of patients with cirrhosis
Number of HCC in explanted livers
Number of HCC as a result of regular surveillance
Harnois et al, 199718 Bergquist et al, 20024 Demarchi et al, 200726 Tischendorf et al, 20072 Claessen et al, 20097 de Valle et al, 201231 Boonstra et al, 20135
134 604 1 273 211 199 590
Unknown Unknown 1 Unknown 23b Unknown Unknown
2 4 1a -
1 1
a
No information regarding whether HCC was found on regular surveillance or incidentally after liver transplantation. Liver histology was available for 148 patients.
b
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HCC in PSC
Table 2. Patient Characteristics Total number of patients Male sex Median age at PSC diagnosis, y Patients treated with UDCA therapy Patient diagnosis IBD UC Crohn’s disease Indeterminate AIH overlap Cirrhosis
509 (100%) 343 (67%) 32 460 (90%) 330 251 48 31 78 119
(65%) (49%) (9%) (6%) (15%) (23%)
NOTE. A total of 509 patients were analyzed. UDCA, ursodeoxycholic acid.
those patients with a value greater than 14 kPa was 27.2 kPa (range, 14.3–75 kPa). In 5 patients cirrhosis was diagnosed according to transient elastography only. The rate of cirrhosis was increased in patients with an overlap syndrome with AIH compared with classic PSC patients (35% vs 21%; c2 ¼ 0.01), whereas the rate of cirrhosis was similar in patients with or without IBD (26% vs 20%, c2 ¼ 0.13). Eighteen patients already presented with cirrhosis at the time of initial diagnosis and 101 patients developed cirrhosis during the observation period. To reduce referral bias on the analysis of cirrhosis development, patients presenting with cirrhosis were excluded. By doing so, the estimated median time from the diagnosis of PSC to the development of cirrhosis was 23 years (95% CI, 17–29 y). Overall, a total of 292 patient-years with cirrhosis were analyzed in 119 patients.
Primary Sclerosing Cholangitis Cirrhosis May Not Pose a Significant Risk for the Development of Hepatocellular Carcinoma During follow-up evaluation, 47 patients developed hepatobiliary or gastrointestinal malignancies. However, HCC was not observed in any patient at baseline or during follow-up evaluation. Therefore, the estimated upper 95% CI limit for the instantaneous risk of HCC was 0.07% for the 4204 years covering the entire cohort and 1.03% with regard to the 292 patient-years with cirrhosis. Because current knowledge regarding HCC in PSC is derived mainly from analyzing liver explants, we additionally reviewed the available histopathologic reports of the explanted livers after transplantation for PSC: in 140 transplanted patients not a single HCC was detected, underlining the notion that the incidence of HCC missed by surveillance also may be low in advanced PSC. Furthermore, no mixed hepatocellular/ CCA cases were observed after additional review of the histopathologic reports of all CCA cases, nor were any mixed cancers detected in liver explants from patients with CCA.
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Taken together, these data suggest that the risk of HCC even in the presence of cirrhosis is lower than the limit that generally is accepted for justifying regular surveillance examinations using ultrasound.3,19
Incidence of Cholangiocarcinoma and Gallbladder Cancer With 75% of all tumors, CCA (n ¼ 35) was the most frequent hepatobiliary cancer followed by gallbladder cancer (GBC) (n ¼ 3). It previously was reported that the risk of diagnosing CCA is highest within the first year after diagnosis of PSC.4,22 This could be confirmed in our series, with 20% of patients receiving a diagnosis of CCA at first presentation or within the first year of diagnosis of PSC. Excluding these cases, the cumulative incidence of CCA after 10 and 20 years still was 4.9% and 15.8%, respectively (Figure 1). GBC developed in 3 patients at 3, 10, and 11 years after the diagnosis of PSC. The cumulative incidence of GBC after 10 and 20 years was 0.7% and 1.3%, respectively (Figure 1). Not surprisingly, hepatobiliary malignancy had a major impact on patient survival with a hazard ratio of death for patients developing CCA of 22.29 (95% CI, 11.17–44.51; P < .01) and of 14.16 (95% CI, 3.32–60.33; P < .01) for patients developing GBC.
Colorectal Cancer in Patients With Primary Sclerosing Cholangitis All patients developing CRC suffered from concomitant IBD. In concomitant UC CRC was diagnosed in 8 cases and in concomitant Crohn’s disease in 1 case. Excluding the cases that were diagnosed at first presentation or within the first year of diagnosing PSC (n ¼ 1), the cumulative incidence of CRC after 10 and 20 years in patients with concomitant UC was 1.9% and 7.4%, respectively (Figure 1). CRC was associated with an increased mortality in patients with PSC (hazard ratio, 3.96; 95% CI, 1.20–13.03; P ¼ .02) as compared with patients who did not develop CRC during the observation period.
Transplant-Free and Overall Survival of Patients With Primary Sclerosing Cholangitis A total of 142 patients (28%) underwent liver transplantation, with a 10- and 20-year transplant-free survival rate of 71% (95% CI, 66%–76%) and 37% (95% CI, 30%–45%), respectively. The median transplant-free survival period was 15 years (95% CI, 14–17 y). Thirty-seven patients (7%) died during the observation period, with a 10- and 20-year overall patient survival rate of 94% (95% CI, 91%–97%) and 86% (95% CI, 81%–91%), respectively. Excluding the 21 patients who died of hepatobiliary malignancy, the
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Figure 1. Incidence of hepatobiliary and CRC. Cumulative incidence of developing (A) CCA, (B) CRC, and (C) GBC in patients with PSC. Patients with the diagnosis of CCA (n ¼ 7) or CRC (n ¼ 1) at first presentation or within the first year of follow-up evaluation were excluded from this analysis. Note that the analysis of CRC only included those patients with concomitant UC.
10- and 20-year patient survival was increased to 98% (95% CI, 97%–100%) and 93% (95% CI, 89%–97%), respectively, underlining the idea that hepatobiliary malignancies are the main complications limiting patient survival in PSC.
Discussion The risk of hepatobiliary malignancy is greatly increased in patients with PSC, mainly owing to the high incidence of CCA. Because PSC is a progressive disease leading to cirrhosis in most cases, the risk of HCC in PSC also may be increased. Recommendations on HCC surveillance in cirrhotic stage PSC, however, are conflicting and data on the incidence of HCC in PSC cirrhosis are lacking.7,14,16 Because HCC is one of the cancers that can be cured if detected at early stages, we aimed to determine the incidence of HCC in PSC cirrhosis to assess the potential requirement of HCC screening in PSC. The strength of the study presented here is the large number of patients included with a median observation time of 7 years, and a maximum of up to 33 years. What distinguishes this study from other reports on HCC in
PSC is that we aimed to determine the presence of cirrhosis in PSC before the end point of liver transplantation, thereby enabling us to estimate the incidence of HCC in patients with or without cirrhosis and to compare that risk with the other hepatobiliary malignancies that are known to be associated with PSC. Next to its retrospective nature and a potential underestimation of malignancies owing to competing end points, a possible caveat of our study was the difficulty in defining cirrhosis in PSC patients. PSC is a focal disease and a liver biopsy can be associated with considerable sampling error, especially in PSC. However, in the 2 centers involved in this study, biopsy guidance by minilaparoscopy frequently is performed, reducing the contribution of sampling error.23 We believe that the presence of esophageal varices and ascites indicates cirrhosis in these patients with an acceptable accuracy, but the optimal transient elastography cut-off value defining cirrhosis in PSC is not well defined.20 Our own experience, however, indicates that a cut-off value of 14 kPa has a high positive predictive value for the detection of cirrhosis in PSC (personal unpublished data), and a similar cut-off value of 14.4 kPa was published very recently for the detection of cirrhosis in PSC.24 Still, the
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rate of cirrhosis may have been underestimated in our study. This would imply that the HCC risk estimation presented here may even be too high. The incidence of HCC considerably varies with the etiology of the underlying liver disease. Although HCC is found most frequently in cirrhosis resulting from chronic viral hepatitis B9 and C10 as well as hereditary hemochromatosis,11,12 and recently nonalcoholic steatohepatitis cirrhosis,25 its incidence in cirrhotic-stage autoimmune liver diseases is comparatively low, with an estimated HCC incidence in AIH cirrhosis as low as 0.2% to 1.1%.13,14 Data on the prevalence of HCC in PSC cirrhosis stems mainly from the analysis of liver explants. In the study from the Mayo Clinic, 3 PSC patients with HCC were diagnosed at liver transplantation (point prevalence, 2%), and in only 1 of these cases was the cancer known before transplantation.18 Tischendorf et al2 detected 1 case of HCC in a cohort of 273 patients with PSC. However, it remains unclear whether this cancer was diagnosed on regular surveillance or incidentally after transplantation. In a Swedish cohort, 4 patients with HCC in the explanted liver were mentioned, but no information on the presence or duration of cirrhosis was given (point prevalence, 4%).4 Consistently, case reports on HCC complicating PSC are rare and only 1 case of a patient with PSC and concomitant Crohn’s disease was found in our literature research26 (Table 1 contains an overview of published data). We report here that in analyzing 4204 patient-years and 292 patient-years under cirrhosis risk, there was not a single HCC detected. In addition, in reviewing 140 liver explants of our patients, no incidental HCC was detected in this series. Most centers apply some sort of surveillance strategies using ultrasound and/or MRI for screening patients with PSC, although there is no evidence that this reduces mortality of affected patients. Despite that, to our knowledge there have been only 2 patients with PSC reported by Harnois et al18 and Demarchi et al26 in whom HCC was detected on surveillance. This indicates that the risk of HCC in PSC even in the presence of cirrhosis may be far below the threshold of 1.5% per year that generally is accepted for HCC surveillance.3,19 What are potential explanations for this finding? Fibrosis and chronic inflammation in end-stage liver diseases both are linked to malignant transformation. However, inflammation has been shown not only to promote but also to inhibit hepatic carcinogenesis, which, for example, lately has been shown with regard to the interferon-g/signal transducers and activators of transcription 1 pathway.27 These data suggest that interferon-g also may affect hepatocyte apoptosis and that inflammation may be associated with enhanced cancer immunosurveillance.28 Whether these mechanisms contribute to the comparably low HCC incidence rates in autoimmune liver diseases such as AIH and PSC needs to be elucidated further.
HCC in PSC
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In accordance with the results of other studies, CCA was the most frequent hepatobiliary malignancy in our patient cohort, accounting for the vast majority of deaths observed. Twenty percent of CCA were diagnosed within the first year of follow-up evaluation. These data and data from other studies, which found up to 50% of CCAs to be diagnosed within the first year after diagnosis of PSC,4,22 underline that clinicians should be especially alert at diagnosis and directly after diagnosis of PSC. Excluding this peak of incidence within the first year, a rather constant incidence of 0.5% per year was observed in our patient cohort, resulting in an estimated 20-year cumulative CCA incidence of 15.8% (Figure 1). As has been reported previously, the presence of cirrhosis did not affect CCA development in the study presented here (data not shown).22 PSC has been reported to be an independent risk factor for the development of CRC in patients with UC,29 however, data on the incidence of CRC in PSC are diverging. In some earlier studies the cumulative incidence of CRC or colorectal dysplasia in patients with PSC and concomitant UC after 10 and 20 years was up to 11% and 31%, respectively.8,30 However, in a recently published study of a Swedish cohort only 2 of 199 PSC patients developed a CRC within a median time of 6.5 years.31 This suggests that the risk of CRC may be decreasing, possibly as a consequence of the changing management of IBD over the past decades, including medical treatment and implementation of endoscopic surveillance programs. Accordingly, in our cohort of 251 PSC patients with UC, only 8 cases of CRC occurred and we estimated a cumulative risk of CRC after 10 and 20 years for patients with concomitant UC of 1.9% and 7.4%, respectively. Because our study was not designed to assess colonic neoplasia including dysplasia and because of the relatively short observation time for the assessment of CRC, the frequency of colonic neoplasia may have been underestimated here and the current surveillance strategies of yearly colonoscopies should be followed.1,16 In summary, we confirm the high risk for hepatobiliary malignancy in a large cohort of patients with PSC. However, although CCA was the main complication limiting patient survival, no HCC was observed in a total of 4202 patient-years and 292 patient-years under risk of cirrhosis, or in 140 explanted livers of patients transplanted for PSC. What are the practical implications of this finding? The data reported argue against HCC surveillance in patients with PSC using ultrasound or measurements of a-fetoprotein. Most centers nevertheless will continue to perform regular ultrasound examinations in patients with PSC because of the risk of gallbladder polyps and CCA. At our centers, it is standard of care to recommend ultrasound every 6 months. However, because CCA cannot be detected using transabdominal ultrasound at an early stage and because the incidence of GBC remains very low, ultrasound surveillance for hepatobiliary malignancies remains without
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evidence in patients with PSC. The low risk of HCC may be a comforting piece of information for patients suffering from a progressive disease with a severe prognosis.
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18. Harnois DM, Gores GJ, Ludwig J, et al. Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer? J Hepatol 1997;27: 512–516. 19. Bruix J, Sherman M. American Association for the Study of Liver Disease: Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020–1022. 20. Corpechot C, El Naggar A, Poujol-Robert A, et al. Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC. Hepatology 2006;43:1118–1124. 21. Piantadosi S. Clinical trials: a methodologic perspective. Hoboken, NJ: Wiley; 2005:262. 22. Boberg KM, Lind GE. Primary sclerosing cholangitis and malignancy. Best Pract Res Clin Gastroenterol 2011;25:753–764. 23. Denzer U, Arnoldy A, Kanzler S, et al. Prospective randomized comparison of minilaparoscopy and percutaneous liver biopsy: diagnosis of cirrhosis and complications. J Clin Gastroenterol 2007;41:103–110. 24. Corpechot C, Gaouar F, El Naggar A, et al. Baseline values and changes in liver stiffness, measured by transient elastography, are associated with fibrosis severity and outcomes of patients with primary sclerosing cholangitis. Gastroenterology 2013: Epub ahead of print.
7. Claessen MM, Vleggaar FP, Tytgat KM, et al. High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol 2009;50: 158–164.
25. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012; 10:1342–1359.e2.
8. Leidenius MH, Farkkila MA, Karkkainen P, et al. Colorectal dysplasia and carcinoma in patients with ulcerative colitis and primary sclerosing cholangitis. Scand J Gastroenterol 1997;32: 706–711.
26. Demarchi B, Bresso F, Novero D, et al. Hepatocellular carcinoma complicating primary sclerosing cholangitis in Crohn’s disease. A case report. Minerva Gastroenterol Dietol 2007;53: 279–283.
9. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295:65–73.
27. Luth S, Schrader J, Zander S, et al. Chronic inflammatory IFNgamma signaling suppresses hepatocarcinogenesis in mice by sensitizing hepatocytes for apoptosis. Cancer Res 2011;71: 3763–3771.
10. Degos F, Christidis C, Ganne-Carrie N, et al. Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death. Gut 2000;47:131–136. 11. Beaton MD, Adams PC. Prognostic factors and survival in patients with hereditary hemochromatosis and cirrhosis. Can J Gastroenterol 2006;20:257–260. 12. Elmberg M, Hultcrantz R, Ekbom A, et al. Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology 2003;125:1733–1741. 13. Teufel A, Weinmann A, Centner C, et al. Hepatocellular carcinoma in patients with autoimmune hepatitis. World J Gastroenterol 2009;15:578–582. 14. Yeoman AD, Al-Chalabi T, Karani JB, et al. Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: implications for follow-up and screening. Hepatology 2008;48:863–870. 15. Farinati F, Floreani A, De Maria N, et al. Hepatocellular carcinoma in primary biliary cirrhosis. J Hepatol 1994;21:315–316.
28. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006;6:836–848. 29. Soetikno RM, Lin OS, Heidenreich PA, et al. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc 2002;56:48–54. 30. Broome U, Lofberg R, Veress B, et al. Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential. Hepatology 1995;22:1404–1408. 31. de Valle MB, Bjornsson E, Lindkvist B. Mortality and cancer risk related to primary sclerosing cholangitis in a Swedish population-based cohort. Liver Int 2012;32:441–448.
Reprint requests Address requests for reprints to: Christoph Schramm, MD, First Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. e-mail: [email protected]; fax: (49) 40-7410-58531.
16. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51: 660–678.
Conflicts of interest The authors disclose no conflicts.
17. Eaton JE, Talwalkar JA, Lazaridis KN, et al. Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology 2013;145:521–536.
Funding Supported by the Sonderforschungsbereich 841, Deutsche Forschungsgemeinschaft (DFG), and by the YAEL foundation.
