Pancreas • Volume 46, Number 9, October 2017
Letters to the Editor
3. Groot VP, van Santvoort HC, Rombouts SJ, et al. Systematic review on the treatment of isolated local recurrence of pancreatic cancer after surgery; re-resection, chemoradiotherapy and SBRT. HPB (Oxford). 2017;19:83–92. 4. Landelijke werkgroep Gastro-intestinale tumoren. IKNL/Oncoline: Landelijke richtlijn Pancreascarcinoom 2.0. 2011. Available at: http://www.oncoline.nl/pancreascarcinoom. Accessed February 1, 2016. 5. Castellanos JA, Merchant NB. Intensity of follow-up after pancreatic cancer resection. Ann Surg Oncol. 2014;21: 747–751. 6. O'Reilly EM, Lowery MA. Postresection surveillance for pancreatic cancer performance status, imaging, and serum markers. Cancer J. 2012;18:609–613. 7. Labori KJ, Brudvik KW. Follow-up after surgery for pancreatic ductal adenocarcinoma: steps toward an international consensus. Pancreas. 2017;46:e2–e3. 8. Meyers MO, Meszoely IM, Hoffman JP, et al. Is reporting of recurrence data important in pancreatic cancer? Ann Surg Oncol. 2004;11: 304–309. 9. Tzeng CW, Fleming JB, Lee JE, et al. Yield of clinical and radiographic surveillance in patients with resected pancreatic adenocarcinoma following multimodal therapy. HPB (Oxford). 2012;14: 365–372. 10. Nordby T, Hugenschmidt H, Fagerland MW, et al. Follow-up after curative surgery for pancreatic ductal adenocarcinoma: asymptomatic recurrence is associated with improved survival. Eur J Surg Oncol. 2013;39: 559–566. 11. Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(suppl 5): v56–v68.
Pancreatic Steatosis Is Not Associated With Exocrine Pancreatic Function in Overweight Type 2 Diabetes Patients To the Editor: xocrine pancreatic insufficiency (EPI) is common in patients with type 2 diabetes mellitus (T2DM), with a reported prevalence ranging from 5% to 36%,1,2 compared with 2 to 8 per 100,000 in the general population.3 The involved mechanisms are unknown but may include
E
FIGURE 1. Association between pancreatic steatosis and exocrine function. The association of pancreatic fat content with (A) fecal elastase-1, (B) fecal chymotrypsin, (C) 13C cumulative recovery, and (D) secreted pancreatic volume. Statistics were performed using univariate linear regression.
pancreatic steatosis. Several studies have proposed that, similar to fat accumulation in other organs, pancreatic steatosis induces dysfunction of the pancreas.4 However, these studies assess endocrine function. Studies assessing the association between pancreatic fat content and exocrine pancreatic function are currently lacking. Possibly, intracellular fat accumulation inhibits cellular processes, for example, the formation of antiapoptotic proteins, whereas adipocyte infiltration may increase local concentrations of free fatty acids and/or unfavorable adipocytokines, thereby affecting neighboring cells. Indeed, chronic exposure of acinar cells to fatty acids induces endoplasmic reticulum stress, cell dysfunction, and apoptosis in several in vitro studies.5,6 Because T2DM patients frequently have pancreatic steatosis,7 we assessed whether pancreatic fat content and exocrine pancreatic function are associated in T2DM patients. Forty-nine insulin-naive T2DM patients (36 men and 13 postmenopausal women, age [mean (standard deviation {SD}), 63 (7) years; body mass index, (BMI) 31.9 (4.0) kg/m2; HbA1c, 7.3% (0.7%)]) were examined, as part of a larger prospective study.8 During 2 separate visits, exocrine pancreatic function was measured by fecal elastase-1 and chymotrypsin, lipase digestive function (13C-mixed triglycerides breath test), and bicarbonate secretion (secretinenhanced magnetic resonance imaging [MRI] scans). Exocrine pancreatic insufficiency was defined as fecal elastase-1 less than 200 μg/g, fecal chymotrypsin less than
6 U/g, 6-hour cumulative 13C recovery of less than 22%, or not reaching matos-3 (duodenal filling beyond the inferior duodenal genu) on MRI scans. Pancreatic fat content was measured by dual gradient-echo inphase/opposed-phase MRI and corrected for the difference between magnetic resonance spectroscopy and in-/opposed-phase MRI in the liver. A detailed description of the study protocol is supplied in Supplemental Digital Content 1 and 2 (http://links.lww. com/MPA/A602, http://links.lww.com/ MPA/A603; Methods and Results). t-Tests were used to assess between-group differences in pancreatic fat content, whereas regression analyses (after transformation in case of non-Gaussian distribution) were performed to assess associations between pancreatic fat content and exocrine function. Mean (SD) pancreatic fat content was 22.2% (10.9%), ranging from 0% to 45.5%. The presence of EPI differed according to the definition used: fecal elastase-1 (n = 2), fecal chymotrypsin (n = 1), cumulative recovery of 13CO2 (n = 1), and matos-3 (n = 4). When combined, 8 patients had EPI, yet none experienced symptoms of steatorrea. Pancreatic fat content was not associated with fecal elastase-1 (β = −0.051, P = 0.733), fecal chymotrypsin (β = −0.080, P = 0.600), lipase digestive function (β = 0.113, P = 0.438), or bicarbonate secretion (β = −0.110, P = 0.473) (Fig. 1). Adjustments for sex and body mass index, both known to affect exocrine function, did not alter the associations (Supplemental Digital Content 2, Table S1 and Table S2, http:// links.lww.com/MPA/A603). Pancreatic fat
© 2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
www.pancreasjournal.com
e75
Pancreas • Volume 46, Number 9, October 2017
Letters to the Editor
content was not different between patients with EPI (24.4% [SD, 8.6%]) and patients without EPI (21.7% [SD, 11.4%]; P = 0.521). We observed no association between pancreatic fat content and exocrine pancreatic function in overweight patients with T2DM, despite the inclusion of patients with a wide range of pancreatic steatosis and function. These findings suggest that other mechanisms may be involved in the high prevalence of EPI in T2DM patients, such as elevated glucagon or somatostatin levels, diabetic neuropathy, pancreatic arteriopathy, and/or underlying pancreatic disease.1,9 A strength of the study is the measurement of several aspects of exocrine pancreatic function. Unfortunately, we were unable to use the criterion standard tests for measurement of pancreatic steatosis (diaphragm-triggered proton magnetic resonance spectroscopy) and exocrine pancreatic function (duodenal aspiration). However, both the exocrine function tests and the dual echo MRI technique correlate well with the criterion standard techniques (see Supplemental Digital Content 1, http:// links.lww.com/MPA/A602). However, the dual-echo MRI technique is less reliable with fat quantities greater than 50%, and it is therefore unclear whether any of the participants had such an amount of pancreatic fat. Although rare, it is plausible that only in patients with extreme steatosis EPI can occur, given the large functional reserve of the exocrine pancreas. Further studies are needed using criterion standard methods to confirm our findings, especially in patients with greater than 50% pancreatic fat content and in patients with symptoms of EPI.
Diabetes Center, Department of Internal Medicine VU University Medical Center Amsterdam, The Netherlands [email protected]
ACKNOWLEDGMENTS Sanochemia Diagnostics Deutschland GmbH kindly provided the Secrelux vials.
Daniël H. van Raalte, MD, PhD Mark M. Smits, MD
This study was supported by the European Community's Seventh Framework Programme (FP7/2007-2013), under grant agreement number 282521—the SAFEGUARD project. Sanochemia Diagnostics Deutschland GmbH kindly provided the Secrelux vials. Novo Nordisk paid for the fecal chymotrypsin test. The researchers were independent from the funders. Funders had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Through M. Diamant and M.H.H. Kramer, the VU University Medical Center received research grants from AstraZeneca, Novo Nordisk, and Sanofi. The other authors declared no competing interests.
e76
www.pancreasjournal.com
The authors dedicate this research in memory of Prof Michaela Diamant, whose experience and expertise were crucial for the design of this study. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.pancreasjournal.com).
Karuna E.W. Vendrik, MD Lennart Tonneijck, MD Marcel H.A. Muskiet, MD Mark H.H. Kramer, MD, PhD
Petra J.W. Pouwels, PhD Department of Physics and Medical Technology VU University Medical Center Amsterdam, The Netherlands
article/2121028-overview#a9. Accessed February 25, 2016. 4. Smits MM, van Geenen EJ. The clinical significance of pancreatic steatosis. Nat Rev Gastroenterol Hepatol. 2011;8:169–177. 5. Landau Z, Forti E, Alcaly M, et al. Palmitate induced lipoapoptosis of exocrine pancreas AR42J cells. Apoptosis. 2006;11:717–724. 6. Zeng Y, Wang X, Zhang W, et al. Hypertriglyceridemia aggravates ER stress and pathogenesis of acute pancreatitis. Hepatogastroenterology. 2012;59: 2318–2326. 7. Tushuizen ME, Bunck MC, Pouwels PJ, et al. Pancreatic fat content and beta-cell function in men with and without type 2 diabetes. Diabetes Care. 2007;30:2916–2921. 8. Smits MM, Tonneijck L, Muskiet MH, et al. Cardiovascular, renal and gastrointestinal effects of incretin-based therapies: an acute and 12-week randomised, double-blind, placebo-controlled, mechanistic intervention trial in type 2 diabetes. BMJ Open. 2015;5:e009579. 9. Larger E, Philippe MF, Barbot-Trystram L, et al. Pancreatic exocrine function in patients with diabetes. Diabet Med. 2012;29:1047–1054.
Indra C. Pieters-van den Bos, MD, PhD Department of Radiology and Nuclear Medicine VU University Medical Center Amsterdam, The Netherlands
Michaela Diamant, MD, PhD Diabetes Center, Department of Internal Medicine VU University Medical Center Amsterdam, The Netherlands
Djuna L. Cahen, MD, PhD Department of Gastroenterology and Hepatology Erasmus University Medical Center Rotterdam, The Netherlands
Diabetes Center, Department of Internal Medicine VU University Medical Center Amsterdam, The Netherlands
REFERENCES 1. Hardt PD, Ewald N. Exocrine pancreatic insufficiency in diabetes mellitus: a complication of diabetic neuropathy or a different type of diabetes?. Exp Diabetes Res. 2011; 2011:761950. 2. Vujasinovic M, Zaletel J, Tepes B, et al. Low prevalence of exocrine pancreatic insufficiency in patients with diabetes mellitus. Pancreatology. 2013;13:343–346. 3. Al-Kaade S. Exocrine Pancreatic Insufficiency: Background, Anatomy, Pathophysiology. Available at: http://emedicine.medscape.com/
The Characteristics of Aborted Procedures in Total Pancreatectomy With Islet Autotransplantation for Chronic Pancreatitis To the Editor: otal pancreatectomy with islet autotransplantation (TPIAT) is an effective treatment option to control intolerable pain due to chronic pancreatitis (CP) and to treat type 3c diabetes after surgery.1–4 Improvements in pain reduction and glycemic control, as well as quality of life, have been achieved in most patients who undergo TPIAT.5,6 However, it is not uncommon to encounter cases in which the diseased pancreas is hard to dissect owing to severe inflammation, bleeding, or a patient's cardiovascular condition. At our center, 10 of 110 TPIAT cases were aborted before total pancreatectomy. In this study, we analyzed the risk factors in these aborted cases and studied the outcome of salvage TPIAT procedures. The Baylor Simmons Transplant Institute patient database was queried to identify all patients undergoing TPIAT. The retrospective cohort data set included 110 patients who were eligible for and proceeded to surgery for TPIAT between October 2006 and January
T
© 2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editor
3. Groot VP, van Santvoort HC, Rombouts SJ, et al. Systematic review on the treatment of isolated local recurrence of pancreatic cancer after surgery; re-resection, chemoradiotherapy and SBRT. HPB (Oxford). 2017;19:83–92. 4. Landelijke werkgroep Gastro-intestinale tumoren. IKNL/Oncoline: Landelijke richtlijn Pancreascarcinoom 2.0. 2011. Available at: http://www.oncoline.nl/pancreascarcinoom. Accessed February 1, 2016. 5. Castellanos JA, Merchant NB. Intensity of follow-up after pancreatic cancer resection. Ann Surg Oncol. 2014;21: 747–751. 6. O'Reilly EM, Lowery MA. Postresection surveillance for pancreatic cancer performance status, imaging, and serum markers. Cancer J. 2012;18:609–613. 7. Labori KJ, Brudvik KW. Follow-up after surgery for pancreatic ductal adenocarcinoma: steps toward an international consensus. Pancreas. 2017;46:e2–e3. 8. Meyers MO, Meszoely IM, Hoffman JP, et al. Is reporting of recurrence data important in pancreatic cancer? Ann Surg Oncol. 2004;11: 304–309. 9. Tzeng CW, Fleming JB, Lee JE, et al. Yield of clinical and radiographic surveillance in patients with resected pancreatic adenocarcinoma following multimodal therapy. HPB (Oxford). 2012;14: 365–372. 10. Nordby T, Hugenschmidt H, Fagerland MW, et al. Follow-up after curative surgery for pancreatic ductal adenocarcinoma: asymptomatic recurrence is associated with improved survival. Eur J Surg Oncol. 2013;39: 559–566. 11. Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(suppl 5): v56–v68.
Pancreatic Steatosis Is Not Associated With Exocrine Pancreatic Function in Overweight Type 2 Diabetes Patients To the Editor: xocrine pancreatic insufficiency (EPI) is common in patients with type 2 diabetes mellitus (T2DM), with a reported prevalence ranging from 5% to 36%,1,2 compared with 2 to 8 per 100,000 in the general population.3 The involved mechanisms are unknown but may include
E
FIGURE 1. Association between pancreatic steatosis and exocrine function. The association of pancreatic fat content with (A) fecal elastase-1, (B) fecal chymotrypsin, (C) 13C cumulative recovery, and (D) secreted pancreatic volume. Statistics were performed using univariate linear regression.
pancreatic steatosis. Several studies have proposed that, similar to fat accumulation in other organs, pancreatic steatosis induces dysfunction of the pancreas.4 However, these studies assess endocrine function. Studies assessing the association between pancreatic fat content and exocrine pancreatic function are currently lacking. Possibly, intracellular fat accumulation inhibits cellular processes, for example, the formation of antiapoptotic proteins, whereas adipocyte infiltration may increase local concentrations of free fatty acids and/or unfavorable adipocytokines, thereby affecting neighboring cells. Indeed, chronic exposure of acinar cells to fatty acids induces endoplasmic reticulum stress, cell dysfunction, and apoptosis in several in vitro studies.5,6 Because T2DM patients frequently have pancreatic steatosis,7 we assessed whether pancreatic fat content and exocrine pancreatic function are associated in T2DM patients. Forty-nine insulin-naive T2DM patients (36 men and 13 postmenopausal women, age [mean (standard deviation {SD}), 63 (7) years; body mass index, (BMI) 31.9 (4.0) kg/m2; HbA1c, 7.3% (0.7%)]) were examined, as part of a larger prospective study.8 During 2 separate visits, exocrine pancreatic function was measured by fecal elastase-1 and chymotrypsin, lipase digestive function (13C-mixed triglycerides breath test), and bicarbonate secretion (secretinenhanced magnetic resonance imaging [MRI] scans). Exocrine pancreatic insufficiency was defined as fecal elastase-1 less than 200 μg/g, fecal chymotrypsin less than
6 U/g, 6-hour cumulative 13C recovery of less than 22%, or not reaching matos-3 (duodenal filling beyond the inferior duodenal genu) on MRI scans. Pancreatic fat content was measured by dual gradient-echo inphase/opposed-phase MRI and corrected for the difference between magnetic resonance spectroscopy and in-/opposed-phase MRI in the liver. A detailed description of the study protocol is supplied in Supplemental Digital Content 1 and 2 (http://links.lww. com/MPA/A602, http://links.lww.com/ MPA/A603; Methods and Results). t-Tests were used to assess between-group differences in pancreatic fat content, whereas regression analyses (after transformation in case of non-Gaussian distribution) were performed to assess associations between pancreatic fat content and exocrine function. Mean (SD) pancreatic fat content was 22.2% (10.9%), ranging from 0% to 45.5%. The presence of EPI differed according to the definition used: fecal elastase-1 (n = 2), fecal chymotrypsin (n = 1), cumulative recovery of 13CO2 (n = 1), and matos-3 (n = 4). When combined, 8 patients had EPI, yet none experienced symptoms of steatorrea. Pancreatic fat content was not associated with fecal elastase-1 (β = −0.051, P = 0.733), fecal chymotrypsin (β = −0.080, P = 0.600), lipase digestive function (β = 0.113, P = 0.438), or bicarbonate secretion (β = −0.110, P = 0.473) (Fig. 1). Adjustments for sex and body mass index, both known to affect exocrine function, did not alter the associations (Supplemental Digital Content 2, Table S1 and Table S2, http:// links.lww.com/MPA/A603). Pancreatic fat
© 2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
www.pancreasjournal.com
e75
Pancreas • Volume 46, Number 9, October 2017
Letters to the Editor
content was not different between patients with EPI (24.4% [SD, 8.6%]) and patients without EPI (21.7% [SD, 11.4%]; P = 0.521). We observed no association between pancreatic fat content and exocrine pancreatic function in overweight patients with T2DM, despite the inclusion of patients with a wide range of pancreatic steatosis and function. These findings suggest that other mechanisms may be involved in the high prevalence of EPI in T2DM patients, such as elevated glucagon or somatostatin levels, diabetic neuropathy, pancreatic arteriopathy, and/or underlying pancreatic disease.1,9 A strength of the study is the measurement of several aspects of exocrine pancreatic function. Unfortunately, we were unable to use the criterion standard tests for measurement of pancreatic steatosis (diaphragm-triggered proton magnetic resonance spectroscopy) and exocrine pancreatic function (duodenal aspiration). However, both the exocrine function tests and the dual echo MRI technique correlate well with the criterion standard techniques (see Supplemental Digital Content 1, http:// links.lww.com/MPA/A602). However, the dual-echo MRI technique is less reliable with fat quantities greater than 50%, and it is therefore unclear whether any of the participants had such an amount of pancreatic fat. Although rare, it is plausible that only in patients with extreme steatosis EPI can occur, given the large functional reserve of the exocrine pancreas. Further studies are needed using criterion standard methods to confirm our findings, especially in patients with greater than 50% pancreatic fat content and in patients with symptoms of EPI.
Diabetes Center, Department of Internal Medicine VU University Medical Center Amsterdam, The Netherlands [email protected]
ACKNOWLEDGMENTS Sanochemia Diagnostics Deutschland GmbH kindly provided the Secrelux vials.
Daniël H. van Raalte, MD, PhD Mark M. Smits, MD
This study was supported by the European Community's Seventh Framework Programme (FP7/2007-2013), under grant agreement number 282521—the SAFEGUARD project. Sanochemia Diagnostics Deutschland GmbH kindly provided the Secrelux vials. Novo Nordisk paid for the fecal chymotrypsin test. The researchers were independent from the funders. Funders had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Through M. Diamant and M.H.H. Kramer, the VU University Medical Center received research grants from AstraZeneca, Novo Nordisk, and Sanofi. The other authors declared no competing interests.
e76
www.pancreasjournal.com
The authors dedicate this research in memory of Prof Michaela Diamant, whose experience and expertise were crucial for the design of this study. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.pancreasjournal.com).
Karuna E.W. Vendrik, MD Lennart Tonneijck, MD Marcel H.A. Muskiet, MD Mark H.H. Kramer, MD, PhD
Petra J.W. Pouwels, PhD Department of Physics and Medical Technology VU University Medical Center Amsterdam, The Netherlands
article/2121028-overview#a9. Accessed February 25, 2016. 4. Smits MM, van Geenen EJ. The clinical significance of pancreatic steatosis. Nat Rev Gastroenterol Hepatol. 2011;8:169–177. 5. Landau Z, Forti E, Alcaly M, et al. Palmitate induced lipoapoptosis of exocrine pancreas AR42J cells. Apoptosis. 2006;11:717–724. 6. Zeng Y, Wang X, Zhang W, et al. Hypertriglyceridemia aggravates ER stress and pathogenesis of acute pancreatitis. Hepatogastroenterology. 2012;59: 2318–2326. 7. Tushuizen ME, Bunck MC, Pouwels PJ, et al. Pancreatic fat content and beta-cell function in men with and without type 2 diabetes. Diabetes Care. 2007;30:2916–2921. 8. Smits MM, Tonneijck L, Muskiet MH, et al. Cardiovascular, renal and gastrointestinal effects of incretin-based therapies: an acute and 12-week randomised, double-blind, placebo-controlled, mechanistic intervention trial in type 2 diabetes. BMJ Open. 2015;5:e009579. 9. Larger E, Philippe MF, Barbot-Trystram L, et al. Pancreatic exocrine function in patients with diabetes. Diabet Med. 2012;29:1047–1054.
Indra C. Pieters-van den Bos, MD, PhD Department of Radiology and Nuclear Medicine VU University Medical Center Amsterdam, The Netherlands
Michaela Diamant, MD, PhD Diabetes Center, Department of Internal Medicine VU University Medical Center Amsterdam, The Netherlands
Djuna L. Cahen, MD, PhD Department of Gastroenterology and Hepatology Erasmus University Medical Center Rotterdam, The Netherlands
Diabetes Center, Department of Internal Medicine VU University Medical Center Amsterdam, The Netherlands
REFERENCES 1. Hardt PD, Ewald N. Exocrine pancreatic insufficiency in diabetes mellitus: a complication of diabetic neuropathy or a different type of diabetes?. Exp Diabetes Res. 2011; 2011:761950. 2. Vujasinovic M, Zaletel J, Tepes B, et al. Low prevalence of exocrine pancreatic insufficiency in patients with diabetes mellitus. Pancreatology. 2013;13:343–346. 3. Al-Kaade S. Exocrine Pancreatic Insufficiency: Background, Anatomy, Pathophysiology. Available at: http://emedicine.medscape.com/
The Characteristics of Aborted Procedures in Total Pancreatectomy With Islet Autotransplantation for Chronic Pancreatitis To the Editor: otal pancreatectomy with islet autotransplantation (TPIAT) is an effective treatment option to control intolerable pain due to chronic pancreatitis (CP) and to treat type 3c diabetes after surgery.1–4 Improvements in pain reduction and glycemic control, as well as quality of life, have been achieved in most patients who undergo TPIAT.5,6 However, it is not uncommon to encounter cases in which the diseased pancreas is hard to dissect owing to severe inflammation, bleeding, or a patient's cardiovascular condition. At our center, 10 of 110 TPIAT cases were aborted before total pancreatectomy. In this study, we analyzed the risk factors in these aborted cases and studied the outcome of salvage TPIAT procedures. The Baylor Simmons Transplant Institute patient database was queried to identify all patients undergoing TPIAT. The retrospective cohort data set included 110 patients who were eligible for and proceeded to surgery for TPIAT between October 2006 and January
T
© 2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
