542 5. 6.
Correspondence Wang W, et al. Pancreatology 2011;11:16–23. Ueda J, et al. Surgery 2013;153:357–364.
Acknowledgments H.L.H. and L.B.R. contributed equally to this work. Conflicts of interest The authors disclose no conflicts.
http://dx.doi.org/10.1053/j.gastro.2014.03.054
Reply. Thanks to Li et al for their interesting comments. The authors raise some important points regarding retrospective database studies on pancreatic cancer incidence among patients with chronic pancreatitis (CP). The key question is whether patients with pancreatic cancer in our cohort actually suffered from CP or may have been misdiagnosed with CP during examinations that finally demonstrated a pancreatic cancer. This is a general concern in retrospective studies using databases and the method to account for that uncertainty is to disregard cases of pancreatic cancer that are diagnosed within a certain period of time after the diagnose of CP. The preferable latency period has been 2 years, which to our knowledge was introduced by Lowenfels et al1 and has been used in later studies as well.2–5 The background for selection of 2 years of latency period seems not to be evidence based and more likely arbitrary. Furthermore, we do not know whether the excluded patients in these studies actually did also suffer from CP. It should also be remembered that CP patients may go undiagnosed for years, which could shorten the observed latency period between CP and pancreatic cancer diagnosis. According to Danish data, approximately 1000 persons are diagnosed with pancreatic cancer annually and the 1-year survival is 26% (www.cancer.dk). In our material the median survival time with pancreatic cancer without surgery was 86 days (Q1-Q3, 35–235). The observed survival time was independent of time since CP diagnoses: 0–1 year, 104 (39–280); 1–2 years, 67 (19–168); and >2 years, 117 (34–362) days. Hence, it is less likely that patients survive pancreatic cancer for >1 year. We think these considerations justify our approach to exclude the patients with pancreatic cancer within only 1 year of the diagnosis of CP. Furthermore, the results from retrospective studies should be interpreted with precaution; however, post hoc exclusion of patients based on assumptions could be hazardous. To address the request from Li et al, we have excluded the 338 patients with pancreatic cancer within 1 year of CP, and recalculated the hazard ratio (HR) of pancreatic cancer among patients with CP compared with our controls. We then found that 1.48% of the patients with CP and 0.21% of our controls developed pancreatic cancer yielding a HR of 4.5 (95% CI, 3.6–5.7). For other types of cancer, only small changes in the results were observed, which did not change the overall conclusion (not reported). Finally, we want to draw attention to the 388 patients in our study who were diagnosed with pancreatic cancer within 1 year of CP diagnosis. Whether CP was truly present or not should not change the conclusion that diagnostic
Gastroenterology Vol. 147, No. 2
attention should be given especially in the early phase of CP because 2.9% of patients with newly diagnosis of CP are diagnosed with a pancreatic cancer within 1 year. ULRICH CHRISTIAN BANG Department of Endocrinology Copenhagen University Hospital of Hvidovre Hvidovre, Denmark THOMAS BENFIELD Department of Infectious Diseases University Hospital of Hvidovre and Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Hvidovre, Denmark LARS HYLDSTRUP Department of Endocrinology Copenhagen University Hospital of Hvidovre and Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Hvidovre, Denmark FLEMMING BENDTSEN Department of Gastroenterology University Hospital of Hvidovre and Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Hvidovre, Denmark JENS-ERIK BECK JENSEN Department of Endocrinology Copenhagen University Hospital of Hvidovre and Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Hvidovre, Denmark
References 1. 2. 3. 4. 5.
Lowenfels AB, et al. N Engl J Med 1993;328:1433–1437. Ekbom A, et al. J Natl Cancer Inst 1994;86:625–627. Malka D, et al. Gut 2002;51:849–852. Talamini G, et al. Am J Gastroenterol 1999;94:1253–1260. Wang W, et al. Pancreatology 2011;11:16–23.
Conflicts of interest The authors disclose no conflicts.
http://dx.doi.org/10.1053/j.gastro.2014.06.032
Transient Elastography in Primary Sclerosing Cholangitis—the Value as a Prognostic Factor and Limitations Dear Editor: We read with interest the recent work by Corpechot et al1 describing the diagnostic and prognostic value of transient
August 2014
elastography (TE) for patients with primary sclerosing cholangitis (PSC). We congratulate the authors for this important work; the establishment of TE as a noninvasive marker of risk assessment in PSC is a valuable tool for clinicians as well as researchers aiming to design clinical trials. As suggested in the accompanying editorial by Vuppalanchi and Lindor,2 these findings need to be confirmed by independent studies and our own findings are supportive (data not shown). TE has been established as a prognostic tool for other chronic liver diseases. There are several confounding factors that may influence liver stiffness. With respect to PSC and the work presented by Carpechot et al, there is an important limitation that we would like to underline. In our cohort of patients, approximately 25% of patients have abnormal serum bilirubin levels at the time of the first evaluation (approximately 5% of patients had levels >2.5 mg/dL). These patients often present with dominant strictures of the common or main hepatic ducts. As exemplified by one of our patients, the presence of biliary strictures may significantly influence liver stiffness in PSC: When the patient was first evaluated for liver stiffness, the result of the measurement was 43.8 kPa. At this time point, he had a serum bilirubin of 8.7 mg/dL and suffered from a dominant stricture of the common bile duct. After biliary endoscopy with dilatation and stenting of the stenosis, the TE value measured 4 weeks later had decreased to 11.6 kPa (serum bilirubin was 1.0 mg/dL then). Another 6 weeks later, his TE measurement was 9.2 kPa and the serum bilirubin was 0.5 mg/dL. This decline in liver stiffness after sufficient biliary drainage is in accord with findings in other cholestatic diseases3 and indicates that liver stiffness can be significantly influenced by biliary obstruction and stasis in PSC. Patients with dominant strictures were excluded in the study by Corpechot et al. We would like to underline that hepatic imaging must be performed before TE measurement in patients with PSC to correctly interpret the results obtained. HANNO EHLKEN ANSGAR W. LOHSE CHRISTOPH SCHRAMM University Medical Center Hamburg-Eppendorf I. Department of Internal Medicine Hamburg, Germany
References 1. 2. 3.
Corpechot C, et al. Gastroenterology 2014;146:970–979. Vuppalanchi R, et al. Gastroenterology 2014;146: 890–892. Millonig G, et al. Hepatology 2008;48:1718–1723.
Conflicts of interest The authors disclose no conflicts.
Correspondence
543
similar findings in their own patient population, thus confirming in an independent cohort the usefulness of liver stiffness measurement (LSM) as assessed by transient elastography as a noninvasive marker of risk assessment in primary sclerosing cholangitis. Ehlken et al point out an important issue, highlighting the fact that transient elastography results should always be interpreted within a given clinical, biochemical, and radiologic context, taking into account all factors (food intake, weight change, acute hepatitis, acute cholangitis, right heart failure, etc) capable of altering liver stiffness transiently. In primary sclerosing cholangitis, specifically, as rightly underlined by our colleagues, special attention must be paid to exclude biliary obstruction amenable to endoscopic treatment, because dominant stenoses of major bile ducts can occur in up to 40%–50% of patients and, in most of these patients, lead to worsening of cholestasis.1 The striking observation reported by our colleagues of a marked LSM improvement after the endoscopic treatment of a dominant stricture in one of their patients is particularly illustrative of this issue. Most patients with primary sclerosing cholangitis who develop dominant strictures have elevated serum total bilirubin whose mean level before treatment exceeds 2.5 mg/dL in most series.1,2 In our cohort, 7 of the 157 patients (4.5%) with documented biochemical liver tests at the time of first transient elastography had a total bilirubin level of >2.5 mg/dL, in line with our colleagues’ report. Among them, one was excluded from the study because of concomitant features of severe acute cholangitis (total serum bilirubin, 25.5 mg/dL) associated with a dominant stricture of the common bile duct. His LSM before treatment was 14.5 1.6 kPa. He was successfully treated with short-term stenting of the stenosis and antibiotic therapy. One year later (we were unfortunately unable to document follow-up data earlier), his total bilirubin was nearly normal (1.2 mg/dL) and his LSM was 8.3 1.5 kPa. Although initial cholestasis in this patient was likely to be mixed, resulting from both intrahepatic inflammatory cholestasis and extrahepatic mechanical biliary obstruction, this observation supports the findings of our German colleagues and highlights the strong correlation between LSM and bilirubin level in condition of extrahepatic cholestasis.3,4 CHRISTOPHE CORPECHOT OLIVIER CHAZOUILLÈRES Service d’Hépatologie Centre de Référence des Maladies Inflammatoires des Voies Biliaires Hôpital Saint-Antoine Assistance-Publique Hôpitaux de Paris (APHP) & INSERM UMR_S938 Université Pierre et Marie Curie Paris 6 Paris, France
http://dx.doi.org/10.1053/j.gastro.2014.04.058
References Reply. We thank our German colleagues for their judicious comments and are pleased to note that they obtained
1. 2.
Stiehl A, et al. J Hepatol 2002;36:151–156. Baluyut AR, et al. Gastrointest Endosc 2001;53:308–312.
Correspondence Wang W, et al. Pancreatology 2011;11:16–23. Ueda J, et al. Surgery 2013;153:357–364.
Acknowledgments H.L.H. and L.B.R. contributed equally to this work. Conflicts of interest The authors disclose no conflicts.
http://dx.doi.org/10.1053/j.gastro.2014.03.054
Reply. Thanks to Li et al for their interesting comments. The authors raise some important points regarding retrospective database studies on pancreatic cancer incidence among patients with chronic pancreatitis (CP). The key question is whether patients with pancreatic cancer in our cohort actually suffered from CP or may have been misdiagnosed with CP during examinations that finally demonstrated a pancreatic cancer. This is a general concern in retrospective studies using databases and the method to account for that uncertainty is to disregard cases of pancreatic cancer that are diagnosed within a certain period of time after the diagnose of CP. The preferable latency period has been 2 years, which to our knowledge was introduced by Lowenfels et al1 and has been used in later studies as well.2–5 The background for selection of 2 years of latency period seems not to be evidence based and more likely arbitrary. Furthermore, we do not know whether the excluded patients in these studies actually did also suffer from CP. It should also be remembered that CP patients may go undiagnosed for years, which could shorten the observed latency period between CP and pancreatic cancer diagnosis. According to Danish data, approximately 1000 persons are diagnosed with pancreatic cancer annually and the 1-year survival is 26% (www.cancer.dk). In our material the median survival time with pancreatic cancer without surgery was 86 days (Q1-Q3, 35–235). The observed survival time was independent of time since CP diagnoses: 0–1 year, 104 (39–280); 1–2 years, 67 (19–168); and >2 years, 117 (34–362) days. Hence, it is less likely that patients survive pancreatic cancer for >1 year. We think these considerations justify our approach to exclude the patients with pancreatic cancer within only 1 year of the diagnosis of CP. Furthermore, the results from retrospective studies should be interpreted with precaution; however, post hoc exclusion of patients based on assumptions could be hazardous. To address the request from Li et al, we have excluded the 338 patients with pancreatic cancer within 1 year of CP, and recalculated the hazard ratio (HR) of pancreatic cancer among patients with CP compared with our controls. We then found that 1.48% of the patients with CP and 0.21% of our controls developed pancreatic cancer yielding a HR of 4.5 (95% CI, 3.6–5.7). For other types of cancer, only small changes in the results were observed, which did not change the overall conclusion (not reported). Finally, we want to draw attention to the 388 patients in our study who were diagnosed with pancreatic cancer within 1 year of CP diagnosis. Whether CP was truly present or not should not change the conclusion that diagnostic
Gastroenterology Vol. 147, No. 2
attention should be given especially in the early phase of CP because 2.9% of patients with newly diagnosis of CP are diagnosed with a pancreatic cancer within 1 year. ULRICH CHRISTIAN BANG Department of Endocrinology Copenhagen University Hospital of Hvidovre Hvidovre, Denmark THOMAS BENFIELD Department of Infectious Diseases University Hospital of Hvidovre and Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Hvidovre, Denmark LARS HYLDSTRUP Department of Endocrinology Copenhagen University Hospital of Hvidovre and Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Hvidovre, Denmark FLEMMING BENDTSEN Department of Gastroenterology University Hospital of Hvidovre and Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Hvidovre, Denmark JENS-ERIK BECK JENSEN Department of Endocrinology Copenhagen University Hospital of Hvidovre and Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Hvidovre, Denmark
References 1. 2. 3. 4. 5.
Lowenfels AB, et al. N Engl J Med 1993;328:1433–1437. Ekbom A, et al. J Natl Cancer Inst 1994;86:625–627. Malka D, et al. Gut 2002;51:849–852. Talamini G, et al. Am J Gastroenterol 1999;94:1253–1260. Wang W, et al. Pancreatology 2011;11:16–23.
Conflicts of interest The authors disclose no conflicts.
http://dx.doi.org/10.1053/j.gastro.2014.06.032
Transient Elastography in Primary Sclerosing Cholangitis—the Value as a Prognostic Factor and Limitations Dear Editor: We read with interest the recent work by Corpechot et al1 describing the diagnostic and prognostic value of transient
August 2014
elastography (TE) for patients with primary sclerosing cholangitis (PSC). We congratulate the authors for this important work; the establishment of TE as a noninvasive marker of risk assessment in PSC is a valuable tool for clinicians as well as researchers aiming to design clinical trials. As suggested in the accompanying editorial by Vuppalanchi and Lindor,2 these findings need to be confirmed by independent studies and our own findings are supportive (data not shown). TE has been established as a prognostic tool for other chronic liver diseases. There are several confounding factors that may influence liver stiffness. With respect to PSC and the work presented by Carpechot et al, there is an important limitation that we would like to underline. In our cohort of patients, approximately 25% of patients have abnormal serum bilirubin levels at the time of the first evaluation (approximately 5% of patients had levels >2.5 mg/dL). These patients often present with dominant strictures of the common or main hepatic ducts. As exemplified by one of our patients, the presence of biliary strictures may significantly influence liver stiffness in PSC: When the patient was first evaluated for liver stiffness, the result of the measurement was 43.8 kPa. At this time point, he had a serum bilirubin of 8.7 mg/dL and suffered from a dominant stricture of the common bile duct. After biliary endoscopy with dilatation and stenting of the stenosis, the TE value measured 4 weeks later had decreased to 11.6 kPa (serum bilirubin was 1.0 mg/dL then). Another 6 weeks later, his TE measurement was 9.2 kPa and the serum bilirubin was 0.5 mg/dL. This decline in liver stiffness after sufficient biliary drainage is in accord with findings in other cholestatic diseases3 and indicates that liver stiffness can be significantly influenced by biliary obstruction and stasis in PSC. Patients with dominant strictures were excluded in the study by Corpechot et al. We would like to underline that hepatic imaging must be performed before TE measurement in patients with PSC to correctly interpret the results obtained. HANNO EHLKEN ANSGAR W. LOHSE CHRISTOPH SCHRAMM University Medical Center Hamburg-Eppendorf I. Department of Internal Medicine Hamburg, Germany
References 1. 2. 3.
Corpechot C, et al. Gastroenterology 2014;146:970–979. Vuppalanchi R, et al. Gastroenterology 2014;146: 890–892. Millonig G, et al. Hepatology 2008;48:1718–1723.
Conflicts of interest The authors disclose no conflicts.
Correspondence
543
similar findings in their own patient population, thus confirming in an independent cohort the usefulness of liver stiffness measurement (LSM) as assessed by transient elastography as a noninvasive marker of risk assessment in primary sclerosing cholangitis. Ehlken et al point out an important issue, highlighting the fact that transient elastography results should always be interpreted within a given clinical, biochemical, and radiologic context, taking into account all factors (food intake, weight change, acute hepatitis, acute cholangitis, right heart failure, etc) capable of altering liver stiffness transiently. In primary sclerosing cholangitis, specifically, as rightly underlined by our colleagues, special attention must be paid to exclude biliary obstruction amenable to endoscopic treatment, because dominant stenoses of major bile ducts can occur in up to 40%–50% of patients and, in most of these patients, lead to worsening of cholestasis.1 The striking observation reported by our colleagues of a marked LSM improvement after the endoscopic treatment of a dominant stricture in one of their patients is particularly illustrative of this issue. Most patients with primary sclerosing cholangitis who develop dominant strictures have elevated serum total bilirubin whose mean level before treatment exceeds 2.5 mg/dL in most series.1,2 In our cohort, 7 of the 157 patients (4.5%) with documented biochemical liver tests at the time of first transient elastography had a total bilirubin level of >2.5 mg/dL, in line with our colleagues’ report. Among them, one was excluded from the study because of concomitant features of severe acute cholangitis (total serum bilirubin, 25.5 mg/dL) associated with a dominant stricture of the common bile duct. His LSM before treatment was 14.5 1.6 kPa. He was successfully treated with short-term stenting of the stenosis and antibiotic therapy. One year later (we were unfortunately unable to document follow-up data earlier), his total bilirubin was nearly normal (1.2 mg/dL) and his LSM was 8.3 1.5 kPa. Although initial cholestasis in this patient was likely to be mixed, resulting from both intrahepatic inflammatory cholestasis and extrahepatic mechanical biliary obstruction, this observation supports the findings of our German colleagues and highlights the strong correlation between LSM and bilirubin level in condition of extrahepatic cholestasis.3,4 CHRISTOPHE CORPECHOT OLIVIER CHAZOUILLÈRES Service d’Hépatologie Centre de Référence des Maladies Inflammatoires des Voies Biliaires Hôpital Saint-Antoine Assistance-Publique Hôpitaux de Paris (APHP) & INSERM UMR_S938 Université Pierre et Marie Curie Paris 6 Paris, France
http://dx.doi.org/10.1053/j.gastro.2014.04.058
References Reply. We thank our German colleagues for their judicious comments and are pleased to note that they obtained
1. 2.
Stiehl A, et al. J Hepatol 2002;36:151–156. Baluyut AR, et al. Gastrointest Endosc 2001;53:308–312.
