European Journal of Internal Medicine 25 (2014) 281–285
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Impact of pancreatic comorbidities in patients with end-stage liver disease on outcome after liver transplantation Felix Darstein a, Christina König a, Maria Hoppe-Lotichius b, Daniel Grimm a, Johanna Knapstein a, Jens Mittler b, Hauke Lang b, Peter Robert Galle a, Tim Zimmermann a,⁎ a b
I. Medizinische Klinik der Universitätsmedizin Mainz, Universitätsmedizin Mainz, Langenbeckstraße 1, 55131 Mainz, Germany Viszeral- und Transplantationschirurgie der Universitätsmedizin Mainz, Universitätsmedizin Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
a r t i c l e
i n f o
Article history: Received 11 August 2013 Received in revised form 13 December 2013 Accepted 3 January 2014 Available online 24 January 2014 Keywords: Liver transplantation Intraductal papillary mucinous neoplasm Pancreatic cysts Pancreatic alterations Chronic pancreatitis Survival
a b s t r a c t Background: Diseases leading to end-stage liver disease (ESLD), especially alcoholic liver cirrhosis cause comorbidities of the pancreas, too. The aim of this retrospective study was to determine the impact of pancreatic alterations diagnosed pretransplant on the outcome after liver transplantation (LT). Methods: In total, data from 372 LT patients were analyzed. Patients were followed up for a mean of 4.2 years. Incidence of chronic pancreatitis (CP), pancreatic cysts (PC) and intraductal papillary mucinous neoplasm (IPMN) was acquired retrospectively from patient's charts. Results: CP, IPMN and PC were rarely diagnosed in LT-recipients [CP (3.8%), PC (1.6%) and IPMN (1.6%)]. There was no significant correlation of IPMN, CP, PC and other patient characteristics. The prevalence of CP (log rank: p = 0.315), PC (log rank: p = 0.242) and IPMN (log rank: p = 0.491) did not influence patient survival. Conclusion: Frequency of radiological alterations of the pancreas in LT recipients (such as CP, PC, IPMN) diagnosed by sonography, CT scan or MRI is comparable to the non-transplant population. Short term survival of LT-recipients after transplantation is not reduced for patients with CP, PC and patients with branch-duct IPMN (with a low-risk for malignancy according to international consensus guidelines). © 2014 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
1. Introduction Over the last decades liver transplantation (LT) was established as the last therapeutic option for patients suffering from end stage liver disease (ESLD). Related to reduction of perioperative complications comorbidities become increasingly important for long-term survival after LT. Increased mortality has been described for many diseases associated with liver cirrhosis, for example renal failure due to hepatorenal syndrome [1]. Due to the link between alcohol consumption and pancreatic pathologies (and common ethyltoxic etiology of liver cirrhosis) diseases of the pancreas must be considered as relevant comorbidities in LT recipients [2]. Pancreatic diseases in the general population are chronic pancreatitis (CP) (incidence 4.5/100 000 person years), pancreatic cysts (PC) (prevalence 1.2%) and intraductal papillary mucinous neoplasm (IPMN) (incidence 4.35/100 000 person years) [3–5]. Although alcohol consumption is the most common cause of chronic pancreatitis, surprisingly clinical co-incidence with liver cirrhosis is rarely reported (2.5%) [6]. In autopsy studies an association of the two diseases (35%) is suspected [7]. There are no reports on the frequency and impact of CP in LT cohorts. As complication of CP and as part of its diagnostic criteria (Cambridge classification) cystic alterations of the ⁎ Corresponding author at: I. Medizinische Klinik, Universitätsmedizin Mainz, Langenbeckstraße 1, 55131 Mainz, Germany. Tel.: +49 6131170. E-mail address: [email protected] (T. Zimmermann).
pancreas (pancreatic duct) can occur [8]. Cystic pancreatic pathologies are a heterogeneous disease entity, which is diagnosed increasingly frequent on the basis of widespread use of sonographic/radiologic imaging [9]. Non-malignant pancreatic cysts (such as true cysts, retention cysts, mucinous non-neoplastic cysts or lymphoepithelial cysts) must be distinguished from pancreatic cystic neoplasms (such as serous cystic tumors, mucinous cystic neoplasms, intraductal papillary mucinous neoplasms and solid pseudopapillary neoplasms) [10]. In patients who underwent pancreatic resection for cystic pancreatic neoplasms the most frequent subtype was IPMN (38–49%) [11]. Optimal diagnosis and therapy of IPMN remain a challenge for the treating physician, as grade of dysplasia is not known until resection and clinical guidelines are “consensus” instead of “evidence based” due to low levels of evidence [12]. Surgical resection is recommended in the case of suspected malignancy due to high-risk stigmata in computed tomography or magnetic resonance imaging (obstructive jaundice in a patient with a cystic lesion of the pancreatic head, enhanced solid component, MPD size of ≥10 mm) [12]. Other cysts should undergo further testing or surveillance. Survival of non-LT recipients with invasive carcinoma is significantly decreased even after resection (5-year survival 60%) [13]. On the other hand the annual malignancy rate of IPMN without risk factors in non-LT is rather low. There are no data regarding prevalence or survival of LT-recipients with IPMN. The aim of this study was to determine the clinical relevance of pancreatic alterations in LT recipients.
0953-6205/$ – see front matter © 2014 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine. http://dx.doi.org/10.1016/j.ejim.2014.01.005
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F. Darstein et al. / European Journal of Internal Medicine 25 (2014) 281–285
2. Methods A total of 616 liver transplantations (performed at the Clinic for General, Visceral and Transplantation Surgery of the University of Mainz until June 1, 2011) were evaluated. Patients were identified from an administrative transplant database. In this database all data were prospectively collected. Patients without at least six months of follow-up were excluded from the study. In the case of missing clinical data patients were also excluded from the study. In patients who underwent retransplantation only the first transplantation was included in the study. A total of 372 patients met the inclusion criteria. In addition to usual patient demographics, we reviewed the etiology of ESLD, prevalence of pretransplant diabetes mellitus, ascites, hepatocellular carcinoma (HCC) status, and prevalence of hypertension. Patients' body mass index (BMI), blood pressure, cholesterol and triglycerides were collected prior to transplant as a part of baseline information. Patients who had oral hypoglycemic agent and/or insulin requirement before transplantation were diagnosed as having pretransplant diabetes mellitus. Computed tomography (CT) and sonography were performed routinely in every patient before LT. CP was diagnosed using imaging studies (either computed tomography/magnetic resonance cholangiopancreatography, transabdominal sonography, endosonography, or endoscopic retrograde cholangiopancreatography) according to the “Cambridge Classification” according to the German guidelines for diagnosis of chronic pancreatitis [8]. PC were diagnosed using imaging studies (either computed tomography/magnetic resonance cholangiopancreatography, transabdominal sonography, endosonography, or endoscopic retrograde cholangiopancreatography). In the case of PC N 1 cm with suspected contact to the pancreatic duct further investigations were accomplished: either pancreatic protocol computed tomography or gadolinium-enhanced magnetic resonance imaging with magnetic resonance cholangiopancreatography, endosonography with cytology or endoscopic retrograde cholangiopancreatography according to the international consensus guidelines [12]. All patients were followed up at least every three to six months at our outpatient clinic. Radiologic controls were done on the basis of the individual findings and risk factors according to the guidelines [8,12]. Categorical variables were expressed as means (±standard deviations (SD)). Observations between groups were compared using chisquare test for categorical variables and the unpaired t-test for continuous variables. p-Values less than 0.05 were considered significant. Cumulative survival curves were generated using the Kaplan–Meier method, and survival between groups was compared by log-rank test. In this analysis, death was considered a censoring event. Cox regression was used for multivariate analysis of survival. All statistical analyses were performed using IBM SPSS statistics version 20 (SPSS Inc., Chicago, IL, USA). 3. Results Mean (±SD) age of our 372 patient cohort was 54.8 (±10.1) years (Table 1). Most patients were male (68%). Nearly all patients were of Caucasian origin (98.4%). Nearly half of all patients (39.5%) were transplanted for alcohol related ESLD, other common causes for transplantation were hepatitis C (25.3%) and hepatitis B (13.7%). 39% of the patients had a history of HCC. Mean baseline BMI was 25.9 ± 5.1 kg/m2, mean baseline cholesterol was 138.2 (±57.0) mg/dl, and mean baseline triglyceride was 105.25 (±73.2) mg/dl. 227 patients (61%) had a diagnosis of arterial hypertension. The majority (208 patients; 55.9%) received tacrolimus as their primary immunosuppressive drug, 99 (26.6%) were prescribed cyclosporine and 272 patients (73.1%) received mycophenolate mofetil. Pancreatic alterations (25/372 LT recipients, 6.7%) such as
Table 1 Demographic information on cohort (n = 372). Follow-up (years), mean (±SD) Age (years), mean (±SD) Gender, % (n) - Male - Female Ethnicity, % (n) - Caucasian - Others Etiology of liver disease, % (n) - ETOH - Hepatitis B - Hepatitis C - Autoimmune - Amyloidosis - Cryptogenic - Other causes - Acute liver injury Hepatocellular carcinoma, % (n) - Yes - No Body height (cm), mean (±SD) Body weight (kg), mean (±SD) BMI (kg/m2), mean (±SD) Baseline cholesterol (mg/dl), mean (±SD) Baseline triglycerides (mg/dl), mean (±SD) Hypertension, % (n) - Yes - No Immunosuppression, % (n) - Tacrolimus - Advagraf - Ciclosporin - mTor inhibitor - Mycophenolate mofetil Nicotine, % (n) - Yes - No - Former smoker
4.2 (±3.1) 54.8 (±10.1) 68 (253) 32 (119) 98.4 (366) 1.6 (6) 39.5 (147) 13.7 (51) 25.3 (94) 7.3 (27) 3.8 (14) 4.8 (18) 5.7 (21) 3.2 (12) 39 (145) 61 (227) 172 (±8.3) 77.7 (±16.6) 25.9 (±5.1) 138.2 (±57.0) 105.25 (±73.2) 61 (227) 39 (145) 55.9 (208) 16.4 (61) 26.6 (99) 18.8 (70) 73.1 (272) 21.2 (79) 47.6 (177) 31.2 (116)
Abbreviations: ETOH = ethyltoxic etiology of liver cirrhosis, BMI = body mass index.
CP (3.8%), PC (1.6%) or IPMN (1.6%) were rarely found (Table 2). In one LT-recipient (0.3%) more than one pancreatic alteration was found (CP & IPMN). There was no statistically significant relation between IPMN, CP, PC and patient characteristics. CP was found more often in patients with alcoholic cirrhosis (p = 0.177) and cryptogenic cirrhosis (p = 0.143), however the difference was not significant. In 3/14 (21.4%) patients with chronic pancreatitis endocrine pancreatic insufficiency was diagnosed (while prevalence of diabetes mellitus in all LT-recipients was 26.6%). All diagnosed IPMN were classified as side branch type, no main duct type was found. All diagnosed IPMN showed no “high-risk stigmata” as thickened wall, intraductal mucin or mural nodules and no suspicious findings for malignancy in the imaging. One LT-recipient has already been treated by surgical left pancreatectomy in an extern hospital before being referred to our transplant center. In three out of six LT recipients with IPMN endosonography with fine-needle aspiration (FNA) was performed. We performed cytology of the cyst content, but we did not routinely perform tumor markers of the cyst fluid like carcinoembryonic antigen (CEA). In two out of three FNA no specific results were obtained,
Table 2 Prevalence of pancreatic pathologies in LT recipients. No pathologies, % (n) Pathologic findings, % (n) - Chronic pancreatitis, % (n) - Pancreatic cysts, % (n) - IPMN, % (n) - Multiple findings, % (n)
93.3 (347) 6.7 (25) 3.8 (14) 1.6 (6) 1.6 (6) 0.3 (1)
Abbreviations: IPMN = intraductal papillary mucinous neoplasm.
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Fig. 3. Survival of LT recipients with IPMN. Fig. 1. Survival of LT recipients with CP.
but in one patient atypical epithelial cells with intracytoplasmatic mucin were observed. The size of the IPMN diagnosed did not increase in the CT/MRI during follow-up. No case of pancreatic cancer was detected. Two out of six patients with IPMN died from sepsis, another suffered from recurrence of hepatocellular carcinoma. All pancreatic alterations were diagnosed prior to LT; no new conspicuous features were detected during surveillance after LT. There was no difference in survival according to prevalence of CP (log rank: p = 0.315), PC (log rank: p = 0.242) or IPMN (log rank: p = 0.491) (Figs. 1–3).
4. Discussion LT often remains the last therapeutic option for patients with ESLD. Over 80 000 patients underwent LT in Europe from 1988 till 2009 [14]. Due to better medical care, survival of patients after LT significantly increased in recent years. To further improve long-term survival of these patients, it is important to identify comorbidities relevant for morbidity and mortality after LT. Many comorbidities and possible complications after LT are known today (e.g. renal failure, de novo cancer, cardio vascular diseases) and their therapy is discussed in clinical
Fig. 2. Survival of LT recipients with pancreatic cysts.
guidelines [15]. There are only few reports about pancreatic comorbidities and their influence on prevalence and survival after LT. Our aim was to determine the relevance of pancreatic comorbidities, especially CP, PC and IPMN in LT recipients. In our study CP (3.8%), PC (1.6%) and IPMN (1.6%) were present in up to 6.7% of LT-recipients. Prevalence of CP (3.8%) in our collective is high compared with the healthy general population (0.028%) [16]. This finding could be due to a high prevalence (39.5%) of alcoholic liver disease in our patients, while alcohol consumption is known to be a risk factor for CP [17]. According to this, CP occurred more often (4.9% [8/147] vs. 2.7% [6/225]) (but not statistically significant; p = 0.177) in patients with alcohol use in medical history compared to alcohol abstinent patients in our collective of LT recipients. Development of liver cirrhosis and CP at the same time in alcohol-dependent patients is reported rarely, and the pathophysiological reasons for this are unknown [18]. Another reason for higher prevalence of CP in LT recipients could be caused by routine-examination of LT-recipients with computed tomography: Chronic pancreatitis could be diagnosed without typical clinical symptoms, while in the general population no radiologic imaging would have been done. So CP is a quantitative relevant finding in LT-recipients; it is more frequent than in the general population (probably due to the abovementioned bias of alcohol consumption). The frequency of PC in LT recipients has not been clarified until now. PC are diagnosed more frequently due to a widespread use of radiological imaging. The estimated prevalence of 1.2% is comparable to the prevalence in our cohort of LT recipients (1.6%) [19]. In total, only six patients presented with PC. In one retrospective study of LT recipients a very high incidence of nearly 60% of pancreatic cysts (malignant and non-malignant) was reported [9]. This difference can only in part be explained by a higher sensitivity in detecting IPMN [20] by using magnetic resonance cholangiopancreatography (as used by Girometti et al.) compared to high resolution computed tomography scan (mainly used in our study). Another reason for the rather high incidence of PC reported by Girometti et al. could be due to a sampling bias: authors included only liver-transplanted patients undergoing magnetic resonance cholangiopancreatography suspected for biliary complications in their study [9]. PC seem to occur occasionally in LT-recipients, comparable to their occurrence in the general population. The probably most relevant pancreatic alteration we investigated was IPMN, due to its potential malignant deformation. IPMN is a mucin-producing neoplasm of the pancreas first described in 1982 [24]. IPMN makes 20–50% of all types of pancreatic cysts, which is also confirmed in our study population of LT recipients (1.6% IPMN and 1.6% non-neoplastic cysts) [21]. During the observation period no new cases of IPMN were detected after LT.
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Our second aim was to look for correlations of clinical characteristics with prevalence of pancreatic alterations, in order to identify risk factors for the development of these alterations. In the literature alcohol consumption and smoking are known as potential risk factors for CP [22]. The influence of alcohol was already discussed above; no significant correlation was found in our LT-recipients. The number of smokers was comparable between the groups: 28.6% (4/10) of patients with CP and 20.9% (75/358) without CP. Known complications of CP are endocrine pancreatic insufficiency (DM) and development of PC, but we did not find significant correlations. Because different types of cysts are grouped under the name of nonneoplastic pancreatic cysts it is difficult to make a statement belonging to risk factors or correlations. In our LT recipients no significant correlations with the prevalence of PC were found. Diabetes mellitus, peptic ulcer and CP are reported risk factors for IPMN [23]. In our LT recipients CP was tendentially more frequent (14.3% vs. 1.1%) in patients with IPMN (without statistically significance). So in contrast to the reporting literature we did not find significant correlations or risk factors for CP, PC and IPMN; probably because of low random number of total pancreatic alterations in our cohort. Our third aim was to analyze changes of pancreatic alterations after LT and if there is an influence of pancreatic alterations on mortality of LT recipients. CP results from recurrent episodes of pancreatic inflammation (especially alcohol intoxication); hereditary pancreatitis is a rare disorder. While persistent alcohol consumption is a contraindication for liver transplantation, further pancreatic damage due to alcohol is an uncommon state after LT. So further progress of CP after LT is not expected, but existing damage will remain. According to this hypothesis we did not find any new cases of CP after LT. Survival of (not transplanted) patients with CP is significantly reduced compared to background population [24]. Mortality is even higher in older patients, smokers and in the case of alcohol consumption. In LT-recipients no reduced survival (log-Rank: p = 0.315) of patients with CP was found (possibly limited by the small number of patients). This might be explained by the selection of patients for liver transplantation: Some of the most vulnerable risk groups (alcoholics, elderly and patients with missing social environment) would not be selected as LT-recipients. So the equal survival of patients with CP after LT might in part be due to a selection bias. Maybe differences in survival can be found in the case of longer observation periods and increased random numbers. The term cystic pancreatic lesions includes a large variability of diseases; it is very difficult to make a general statement about progress and mortality. The main concern in the presence of cystic pancreatic lesions is malignant transformation which results in a possibly lethal disease. As immunosuppression after LT is a known risk factor for de novo neoplasia [25] and immunosuppression might accelerate growth of existing neoplasia [26] worse outcome of cystic pancreatic lesions in LT recipients must be considered. On the other hand there are many cystic lesions without malignant potential. In our patients no significant difference (log rank = 0.242) between liver transplant recipients with or without PC was revealed (Fig. 2). One reason for the lack of differences in survival is certainly due to the small case number. Another reason is a careful exclusion of malignant origin of cysts in our transplant cohort according to inclusion criteria to the group PC. The situation is even more difficult in patients with IPMN. On the one hand correct diagnosis is often challenging, on the other hand IPMN has a known risk for malignant transformation. The risk highly varies due to several known factors and increases from 25.5% in branch duct IPMN to 61% in main duct IPMN [12]. For patients with diagnosis of IPMN who underwent surgery reduced survival of only 36 months was reported [27]. The influence of IPMN on long term survival in non-LT recipients is unclear [28]. So it is important to treat patients with IPMN according to their individual risk for malignant transformation, for example evaluated by imaging. We assessed patients according to IPMN consensus guidelines for non-transplant recipients; all of our transplant recipients belonged to a low risk group of branch duct
IPMN (except one who underwent left pancreatectomy before being referred to our hospital) [12]. In our patients no reduced survival (log rank = 0.615) was detected (Fig. 3). No case of pancreatic cancer was detected during follow-up. This result is comparable with reported monitoring of patients with branch duct IPMN without indication for operation: short-term follow-up after solid organ transplant was not associated with any significant change in cyst characteristics suggesting that incidental branch duct IPMN, even in the setting of immunosuppression post-transplant, can be followed conservatively [29]. But the reported study and our results both lack a longer observation period and high patient numbers. A prospective evaluation of this problem with a longer observation period is necessary to rule out an increase in long-term mortality. Since no radiological examination can definitely exclude the potential of malignant transformation careful surveillance after LT is mandatory. 5. Conclusion Frequency of radiological alterations of the pancreas in LT recipients (such as CP, PC, IPMN) diagnosed by sonography, CT scan or MRI is comparable to the non-transplant population. Short term survival of LT-recipients after transplantation is not reduced for patients with CP, PC and patients with branch-duct IPMN (with a low-risk for malignancy according to international consensus guidelines). Prospective evaluation of this problem with a higher number of patients and a long observation period is necessary to rule out an increase in long-term mortality. Learning points • CP, IPMN and PC are rarely diagnosed in LT-recipients. • Prevalence of CP, IPMN and PC did not influence patient survival. • LT recipients with IPMN should be assesed according to consensus guidelines. • Patients with IPMN should be treated according to individual risk for malignant transformation. • Careful evaluation of patients undergoing liver transplantation is necessary. Conflict of interests There are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. Acknowledgments The study contains parts of the doctoral thesis of C. König to be submitted at the Faculty of Medicine at the University of Mainz. References [1] Angeli P, Sanyal A, Moller S, Alessandria C, Gadano A, Kim R, et al. Current limits and future challenges in the management of renal dysfunction in patients with cirrhosis: report from the International Club of Ascites. Liver Int 2013;33:16–23. [2] Braganza JM, Lee SH, McCloy RF, McMahon MJ. Chronic pancreatitis. Lancet 2011;377:1184–97. [3] Yadav D, Timmons L, Benson JT, Dierkhising RA, Chari ST. Incidence, prevalence, and survival of chronic pancreatitis: a population-based study. Am J Gastroenterol 2011;106:2192–9. [4] Klibansky DA, Reid-Lombardo KM, Gordon SR, Gardner TB. The clinical relevance of the increasing incidence of intraductal papillary mucinous neoplasm. Clin Gastroenterol Hepatol 2012;10:555–8. [5] Cowie CC, Rust KF, Ford ES, Eberhardt MS, Byrd-Holt DD, Li C, et al. Full accounting of diabetes and pre-diabetes in the U.S. population in 1988–1994 and 2005–2006. Diabetes Care 2009;32:287–94. [6] Coté GA, Yadav D, Slivka A, Hawes RH, Anderson MA, Burton FR, et al. Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2011;9:266–73 [quiz e27]. [7] Pace A, de Weerth A, Berna M, Hillbricht K, Tsokos M, Bläker M, et al. Pancreas and liver injury are associated in individuals with increased alcohol consumption. Clin Gastroenterol Hepatol 2009;7:1241–6.
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Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Impact of pancreatic comorbidities in patients with end-stage liver disease on outcome after liver transplantation Felix Darstein a, Christina König a, Maria Hoppe-Lotichius b, Daniel Grimm a, Johanna Knapstein a, Jens Mittler b, Hauke Lang b, Peter Robert Galle a, Tim Zimmermann a,⁎ a b
I. Medizinische Klinik der Universitätsmedizin Mainz, Universitätsmedizin Mainz, Langenbeckstraße 1, 55131 Mainz, Germany Viszeral- und Transplantationschirurgie der Universitätsmedizin Mainz, Universitätsmedizin Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
a r t i c l e
i n f o
Article history: Received 11 August 2013 Received in revised form 13 December 2013 Accepted 3 January 2014 Available online 24 January 2014 Keywords: Liver transplantation Intraductal papillary mucinous neoplasm Pancreatic cysts Pancreatic alterations Chronic pancreatitis Survival
a b s t r a c t Background: Diseases leading to end-stage liver disease (ESLD), especially alcoholic liver cirrhosis cause comorbidities of the pancreas, too. The aim of this retrospective study was to determine the impact of pancreatic alterations diagnosed pretransplant on the outcome after liver transplantation (LT). Methods: In total, data from 372 LT patients were analyzed. Patients were followed up for a mean of 4.2 years. Incidence of chronic pancreatitis (CP), pancreatic cysts (PC) and intraductal papillary mucinous neoplasm (IPMN) was acquired retrospectively from patient's charts. Results: CP, IPMN and PC were rarely diagnosed in LT-recipients [CP (3.8%), PC (1.6%) and IPMN (1.6%)]. There was no significant correlation of IPMN, CP, PC and other patient characteristics. The prevalence of CP (log rank: p = 0.315), PC (log rank: p = 0.242) and IPMN (log rank: p = 0.491) did not influence patient survival. Conclusion: Frequency of radiological alterations of the pancreas in LT recipients (such as CP, PC, IPMN) diagnosed by sonography, CT scan or MRI is comparable to the non-transplant population. Short term survival of LT-recipients after transplantation is not reduced for patients with CP, PC and patients with branch-duct IPMN (with a low-risk for malignancy according to international consensus guidelines). © 2014 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
1. Introduction Over the last decades liver transplantation (LT) was established as the last therapeutic option for patients suffering from end stage liver disease (ESLD). Related to reduction of perioperative complications comorbidities become increasingly important for long-term survival after LT. Increased mortality has been described for many diseases associated with liver cirrhosis, for example renal failure due to hepatorenal syndrome [1]. Due to the link between alcohol consumption and pancreatic pathologies (and common ethyltoxic etiology of liver cirrhosis) diseases of the pancreas must be considered as relevant comorbidities in LT recipients [2]. Pancreatic diseases in the general population are chronic pancreatitis (CP) (incidence 4.5/100 000 person years), pancreatic cysts (PC) (prevalence 1.2%) and intraductal papillary mucinous neoplasm (IPMN) (incidence 4.35/100 000 person years) [3–5]. Although alcohol consumption is the most common cause of chronic pancreatitis, surprisingly clinical co-incidence with liver cirrhosis is rarely reported (2.5%) [6]. In autopsy studies an association of the two diseases (35%) is suspected [7]. There are no reports on the frequency and impact of CP in LT cohorts. As complication of CP and as part of its diagnostic criteria (Cambridge classification) cystic alterations of the ⁎ Corresponding author at: I. Medizinische Klinik, Universitätsmedizin Mainz, Langenbeckstraße 1, 55131 Mainz, Germany. Tel.: +49 6131170. E-mail address: [email protected] (T. Zimmermann).
pancreas (pancreatic duct) can occur [8]. Cystic pancreatic pathologies are a heterogeneous disease entity, which is diagnosed increasingly frequent on the basis of widespread use of sonographic/radiologic imaging [9]. Non-malignant pancreatic cysts (such as true cysts, retention cysts, mucinous non-neoplastic cysts or lymphoepithelial cysts) must be distinguished from pancreatic cystic neoplasms (such as serous cystic tumors, mucinous cystic neoplasms, intraductal papillary mucinous neoplasms and solid pseudopapillary neoplasms) [10]. In patients who underwent pancreatic resection for cystic pancreatic neoplasms the most frequent subtype was IPMN (38–49%) [11]. Optimal diagnosis and therapy of IPMN remain a challenge for the treating physician, as grade of dysplasia is not known until resection and clinical guidelines are “consensus” instead of “evidence based” due to low levels of evidence [12]. Surgical resection is recommended in the case of suspected malignancy due to high-risk stigmata in computed tomography or magnetic resonance imaging (obstructive jaundice in a patient with a cystic lesion of the pancreatic head, enhanced solid component, MPD size of ≥10 mm) [12]. Other cysts should undergo further testing or surveillance. Survival of non-LT recipients with invasive carcinoma is significantly decreased even after resection (5-year survival 60%) [13]. On the other hand the annual malignancy rate of IPMN without risk factors in non-LT is rather low. There are no data regarding prevalence or survival of LT-recipients with IPMN. The aim of this study was to determine the clinical relevance of pancreatic alterations in LT recipients.
0953-6205/$ – see front matter © 2014 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine. http://dx.doi.org/10.1016/j.ejim.2014.01.005
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2. Methods A total of 616 liver transplantations (performed at the Clinic for General, Visceral and Transplantation Surgery of the University of Mainz until June 1, 2011) were evaluated. Patients were identified from an administrative transplant database. In this database all data were prospectively collected. Patients without at least six months of follow-up were excluded from the study. In the case of missing clinical data patients were also excluded from the study. In patients who underwent retransplantation only the first transplantation was included in the study. A total of 372 patients met the inclusion criteria. In addition to usual patient demographics, we reviewed the etiology of ESLD, prevalence of pretransplant diabetes mellitus, ascites, hepatocellular carcinoma (HCC) status, and prevalence of hypertension. Patients' body mass index (BMI), blood pressure, cholesterol and triglycerides were collected prior to transplant as a part of baseline information. Patients who had oral hypoglycemic agent and/or insulin requirement before transplantation were diagnosed as having pretransplant diabetes mellitus. Computed tomography (CT) and sonography were performed routinely in every patient before LT. CP was diagnosed using imaging studies (either computed tomography/magnetic resonance cholangiopancreatography, transabdominal sonography, endosonography, or endoscopic retrograde cholangiopancreatography) according to the “Cambridge Classification” according to the German guidelines for diagnosis of chronic pancreatitis [8]. PC were diagnosed using imaging studies (either computed tomography/magnetic resonance cholangiopancreatography, transabdominal sonography, endosonography, or endoscopic retrograde cholangiopancreatography). In the case of PC N 1 cm with suspected contact to the pancreatic duct further investigations were accomplished: either pancreatic protocol computed tomography or gadolinium-enhanced magnetic resonance imaging with magnetic resonance cholangiopancreatography, endosonography with cytology or endoscopic retrograde cholangiopancreatography according to the international consensus guidelines [12]. All patients were followed up at least every three to six months at our outpatient clinic. Radiologic controls were done on the basis of the individual findings and risk factors according to the guidelines [8,12]. Categorical variables were expressed as means (±standard deviations (SD)). Observations between groups were compared using chisquare test for categorical variables and the unpaired t-test for continuous variables. p-Values less than 0.05 were considered significant. Cumulative survival curves were generated using the Kaplan–Meier method, and survival between groups was compared by log-rank test. In this analysis, death was considered a censoring event. Cox regression was used for multivariate analysis of survival. All statistical analyses were performed using IBM SPSS statistics version 20 (SPSS Inc., Chicago, IL, USA). 3. Results Mean (±SD) age of our 372 patient cohort was 54.8 (±10.1) years (Table 1). Most patients were male (68%). Nearly all patients were of Caucasian origin (98.4%). Nearly half of all patients (39.5%) were transplanted for alcohol related ESLD, other common causes for transplantation were hepatitis C (25.3%) and hepatitis B (13.7%). 39% of the patients had a history of HCC. Mean baseline BMI was 25.9 ± 5.1 kg/m2, mean baseline cholesterol was 138.2 (±57.0) mg/dl, and mean baseline triglyceride was 105.25 (±73.2) mg/dl. 227 patients (61%) had a diagnosis of arterial hypertension. The majority (208 patients; 55.9%) received tacrolimus as their primary immunosuppressive drug, 99 (26.6%) were prescribed cyclosporine and 272 patients (73.1%) received mycophenolate mofetil. Pancreatic alterations (25/372 LT recipients, 6.7%) such as
Table 1 Demographic information on cohort (n = 372). Follow-up (years), mean (±SD) Age (years), mean (±SD) Gender, % (n) - Male - Female Ethnicity, % (n) - Caucasian - Others Etiology of liver disease, % (n) - ETOH - Hepatitis B - Hepatitis C - Autoimmune - Amyloidosis - Cryptogenic - Other causes - Acute liver injury Hepatocellular carcinoma, % (n) - Yes - No Body height (cm), mean (±SD) Body weight (kg), mean (±SD) BMI (kg/m2), mean (±SD) Baseline cholesterol (mg/dl), mean (±SD) Baseline triglycerides (mg/dl), mean (±SD) Hypertension, % (n) - Yes - No Immunosuppression, % (n) - Tacrolimus - Advagraf - Ciclosporin - mTor inhibitor - Mycophenolate mofetil Nicotine, % (n) - Yes - No - Former smoker
4.2 (±3.1) 54.8 (±10.1) 68 (253) 32 (119) 98.4 (366) 1.6 (6) 39.5 (147) 13.7 (51) 25.3 (94) 7.3 (27) 3.8 (14) 4.8 (18) 5.7 (21) 3.2 (12) 39 (145) 61 (227) 172 (±8.3) 77.7 (±16.6) 25.9 (±5.1) 138.2 (±57.0) 105.25 (±73.2) 61 (227) 39 (145) 55.9 (208) 16.4 (61) 26.6 (99) 18.8 (70) 73.1 (272) 21.2 (79) 47.6 (177) 31.2 (116)
Abbreviations: ETOH = ethyltoxic etiology of liver cirrhosis, BMI = body mass index.
CP (3.8%), PC (1.6%) or IPMN (1.6%) were rarely found (Table 2). In one LT-recipient (0.3%) more than one pancreatic alteration was found (CP & IPMN). There was no statistically significant relation between IPMN, CP, PC and patient characteristics. CP was found more often in patients with alcoholic cirrhosis (p = 0.177) and cryptogenic cirrhosis (p = 0.143), however the difference was not significant. In 3/14 (21.4%) patients with chronic pancreatitis endocrine pancreatic insufficiency was diagnosed (while prevalence of diabetes mellitus in all LT-recipients was 26.6%). All diagnosed IPMN were classified as side branch type, no main duct type was found. All diagnosed IPMN showed no “high-risk stigmata” as thickened wall, intraductal mucin or mural nodules and no suspicious findings for malignancy in the imaging. One LT-recipient has already been treated by surgical left pancreatectomy in an extern hospital before being referred to our transplant center. In three out of six LT recipients with IPMN endosonography with fine-needle aspiration (FNA) was performed. We performed cytology of the cyst content, but we did not routinely perform tumor markers of the cyst fluid like carcinoembryonic antigen (CEA). In two out of three FNA no specific results were obtained,
Table 2 Prevalence of pancreatic pathologies in LT recipients. No pathologies, % (n) Pathologic findings, % (n) - Chronic pancreatitis, % (n) - Pancreatic cysts, % (n) - IPMN, % (n) - Multiple findings, % (n)
93.3 (347) 6.7 (25) 3.8 (14) 1.6 (6) 1.6 (6) 0.3 (1)
Abbreviations: IPMN = intraductal papillary mucinous neoplasm.
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Fig. 3. Survival of LT recipients with IPMN. Fig. 1. Survival of LT recipients with CP.
but in one patient atypical epithelial cells with intracytoplasmatic mucin were observed. The size of the IPMN diagnosed did not increase in the CT/MRI during follow-up. No case of pancreatic cancer was detected. Two out of six patients with IPMN died from sepsis, another suffered from recurrence of hepatocellular carcinoma. All pancreatic alterations were diagnosed prior to LT; no new conspicuous features were detected during surveillance after LT. There was no difference in survival according to prevalence of CP (log rank: p = 0.315), PC (log rank: p = 0.242) or IPMN (log rank: p = 0.491) (Figs. 1–3).
4. Discussion LT often remains the last therapeutic option for patients with ESLD. Over 80 000 patients underwent LT in Europe from 1988 till 2009 [14]. Due to better medical care, survival of patients after LT significantly increased in recent years. To further improve long-term survival of these patients, it is important to identify comorbidities relevant for morbidity and mortality after LT. Many comorbidities and possible complications after LT are known today (e.g. renal failure, de novo cancer, cardio vascular diseases) and their therapy is discussed in clinical
Fig. 2. Survival of LT recipients with pancreatic cysts.
guidelines [15]. There are only few reports about pancreatic comorbidities and their influence on prevalence and survival after LT. Our aim was to determine the relevance of pancreatic comorbidities, especially CP, PC and IPMN in LT recipients. In our study CP (3.8%), PC (1.6%) and IPMN (1.6%) were present in up to 6.7% of LT-recipients. Prevalence of CP (3.8%) in our collective is high compared with the healthy general population (0.028%) [16]. This finding could be due to a high prevalence (39.5%) of alcoholic liver disease in our patients, while alcohol consumption is known to be a risk factor for CP [17]. According to this, CP occurred more often (4.9% [8/147] vs. 2.7% [6/225]) (but not statistically significant; p = 0.177) in patients with alcohol use in medical history compared to alcohol abstinent patients in our collective of LT recipients. Development of liver cirrhosis and CP at the same time in alcohol-dependent patients is reported rarely, and the pathophysiological reasons for this are unknown [18]. Another reason for higher prevalence of CP in LT recipients could be caused by routine-examination of LT-recipients with computed tomography: Chronic pancreatitis could be diagnosed without typical clinical symptoms, while in the general population no radiologic imaging would have been done. So CP is a quantitative relevant finding in LT-recipients; it is more frequent than in the general population (probably due to the abovementioned bias of alcohol consumption). The frequency of PC in LT recipients has not been clarified until now. PC are diagnosed more frequently due to a widespread use of radiological imaging. The estimated prevalence of 1.2% is comparable to the prevalence in our cohort of LT recipients (1.6%) [19]. In total, only six patients presented with PC. In one retrospective study of LT recipients a very high incidence of nearly 60% of pancreatic cysts (malignant and non-malignant) was reported [9]. This difference can only in part be explained by a higher sensitivity in detecting IPMN [20] by using magnetic resonance cholangiopancreatography (as used by Girometti et al.) compared to high resolution computed tomography scan (mainly used in our study). Another reason for the rather high incidence of PC reported by Girometti et al. could be due to a sampling bias: authors included only liver-transplanted patients undergoing magnetic resonance cholangiopancreatography suspected for biliary complications in their study [9]. PC seem to occur occasionally in LT-recipients, comparable to their occurrence in the general population. The probably most relevant pancreatic alteration we investigated was IPMN, due to its potential malignant deformation. IPMN is a mucin-producing neoplasm of the pancreas first described in 1982 [24]. IPMN makes 20–50% of all types of pancreatic cysts, which is also confirmed in our study population of LT recipients (1.6% IPMN and 1.6% non-neoplastic cysts) [21]. During the observation period no new cases of IPMN were detected after LT.
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Our second aim was to look for correlations of clinical characteristics with prevalence of pancreatic alterations, in order to identify risk factors for the development of these alterations. In the literature alcohol consumption and smoking are known as potential risk factors for CP [22]. The influence of alcohol was already discussed above; no significant correlation was found in our LT-recipients. The number of smokers was comparable between the groups: 28.6% (4/10) of patients with CP and 20.9% (75/358) without CP. Known complications of CP are endocrine pancreatic insufficiency (DM) and development of PC, but we did not find significant correlations. Because different types of cysts are grouped under the name of nonneoplastic pancreatic cysts it is difficult to make a statement belonging to risk factors or correlations. In our LT recipients no significant correlations with the prevalence of PC were found. Diabetes mellitus, peptic ulcer and CP are reported risk factors for IPMN [23]. In our LT recipients CP was tendentially more frequent (14.3% vs. 1.1%) in patients with IPMN (without statistically significance). So in contrast to the reporting literature we did not find significant correlations or risk factors for CP, PC and IPMN; probably because of low random number of total pancreatic alterations in our cohort. Our third aim was to analyze changes of pancreatic alterations after LT and if there is an influence of pancreatic alterations on mortality of LT recipients. CP results from recurrent episodes of pancreatic inflammation (especially alcohol intoxication); hereditary pancreatitis is a rare disorder. While persistent alcohol consumption is a contraindication for liver transplantation, further pancreatic damage due to alcohol is an uncommon state after LT. So further progress of CP after LT is not expected, but existing damage will remain. According to this hypothesis we did not find any new cases of CP after LT. Survival of (not transplanted) patients with CP is significantly reduced compared to background population [24]. Mortality is even higher in older patients, smokers and in the case of alcohol consumption. In LT-recipients no reduced survival (log-Rank: p = 0.315) of patients with CP was found (possibly limited by the small number of patients). This might be explained by the selection of patients for liver transplantation: Some of the most vulnerable risk groups (alcoholics, elderly and patients with missing social environment) would not be selected as LT-recipients. So the equal survival of patients with CP after LT might in part be due to a selection bias. Maybe differences in survival can be found in the case of longer observation periods and increased random numbers. The term cystic pancreatic lesions includes a large variability of diseases; it is very difficult to make a general statement about progress and mortality. The main concern in the presence of cystic pancreatic lesions is malignant transformation which results in a possibly lethal disease. As immunosuppression after LT is a known risk factor for de novo neoplasia [25] and immunosuppression might accelerate growth of existing neoplasia [26] worse outcome of cystic pancreatic lesions in LT recipients must be considered. On the other hand there are many cystic lesions without malignant potential. In our patients no significant difference (log rank = 0.242) between liver transplant recipients with or without PC was revealed (Fig. 2). One reason for the lack of differences in survival is certainly due to the small case number. Another reason is a careful exclusion of malignant origin of cysts in our transplant cohort according to inclusion criteria to the group PC. The situation is even more difficult in patients with IPMN. On the one hand correct diagnosis is often challenging, on the other hand IPMN has a known risk for malignant transformation. The risk highly varies due to several known factors and increases from 25.5% in branch duct IPMN to 61% in main duct IPMN [12]. For patients with diagnosis of IPMN who underwent surgery reduced survival of only 36 months was reported [27]. The influence of IPMN on long term survival in non-LT recipients is unclear [28]. So it is important to treat patients with IPMN according to their individual risk for malignant transformation, for example evaluated by imaging. We assessed patients according to IPMN consensus guidelines for non-transplant recipients; all of our transplant recipients belonged to a low risk group of branch duct
IPMN (except one who underwent left pancreatectomy before being referred to our hospital) [12]. In our patients no reduced survival (log rank = 0.615) was detected (Fig. 3). No case of pancreatic cancer was detected during follow-up. This result is comparable with reported monitoring of patients with branch duct IPMN without indication for operation: short-term follow-up after solid organ transplant was not associated with any significant change in cyst characteristics suggesting that incidental branch duct IPMN, even in the setting of immunosuppression post-transplant, can be followed conservatively [29]. But the reported study and our results both lack a longer observation period and high patient numbers. A prospective evaluation of this problem with a longer observation period is necessary to rule out an increase in long-term mortality. Since no radiological examination can definitely exclude the potential of malignant transformation careful surveillance after LT is mandatory. 5. Conclusion Frequency of radiological alterations of the pancreas in LT recipients (such as CP, PC, IPMN) diagnosed by sonography, CT scan or MRI is comparable to the non-transplant population. Short term survival of LT-recipients after transplantation is not reduced for patients with CP, PC and patients with branch-duct IPMN (with a low-risk for malignancy according to international consensus guidelines). Prospective evaluation of this problem with a higher number of patients and a long observation period is necessary to rule out an increase in long-term mortality. Learning points • CP, IPMN and PC are rarely diagnosed in LT-recipients. • Prevalence of CP, IPMN and PC did not influence patient survival. • LT recipients with IPMN should be assesed according to consensus guidelines. • Patients with IPMN should be treated according to individual risk for malignant transformation. • Careful evaluation of patients undergoing liver transplantation is necessary. Conflict of interests There are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. Acknowledgments The study contains parts of the doctoral thesis of C. König to be submitted at the Faculty of Medicine at the University of Mainz. References [1] Angeli P, Sanyal A, Moller S, Alessandria C, Gadano A, Kim R, et al. Current limits and future challenges in the management of renal dysfunction in patients with cirrhosis: report from the International Club of Ascites. Liver Int 2013;33:16–23. [2] Braganza JM, Lee SH, McCloy RF, McMahon MJ. Chronic pancreatitis. Lancet 2011;377:1184–97. [3] Yadav D, Timmons L, Benson JT, Dierkhising RA, Chari ST. Incidence, prevalence, and survival of chronic pancreatitis: a population-based study. Am J Gastroenterol 2011;106:2192–9. [4] Klibansky DA, Reid-Lombardo KM, Gordon SR, Gardner TB. The clinical relevance of the increasing incidence of intraductal papillary mucinous neoplasm. Clin Gastroenterol Hepatol 2012;10:555–8. [5] Cowie CC, Rust KF, Ford ES, Eberhardt MS, Byrd-Holt DD, Li C, et al. Full accounting of diabetes and pre-diabetes in the U.S. population in 1988–1994 and 2005–2006. Diabetes Care 2009;32:287–94. [6] Coté GA, Yadav D, Slivka A, Hawes RH, Anderson MA, Burton FR, et al. Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2011;9:266–73 [quiz e27]. [7] Pace A, de Weerth A, Berna M, Hillbricht K, Tsokos M, Bläker M, et al. Pancreas and liver injury are associated in individuals with increased alcohol consumption. Clin Gastroenterol Hepatol 2009;7:1241–6.
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