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Endoscopic ultrasonography in chronic asymptomatic pancreatic hyperenzymemia: The more we see, the less we know
Accepted Manuscript Title: Endoscopic ultrasonography in chronic asymptomatic pancreatic hyperenzymemia: The more we see, the less we know Author: Luca Frulloni Antonio Amodio PII: DOI: Reference:
S1590-8658(16)30813-1 http://dx.doi.org/doi:10.1016/j.dld.2016.11.009 YDLD 3297
To appear in:
Digestive and Liver Disease
Received date: Accepted date:
27-10-2016 18-11-2016
Please cite this article as: Frulloni Luca, Amodio Antonio.Endoscopic ultrasonography in chronic asymptomatic pancreatic hyperenzymemia: The more we see, the less we know.Digestive and Liver Disease http://dx.doi.org/10.1016/j.dld.2016.11.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Endoscopic ultrasonography in chronic asymptomatic pancreatic hyperenzymemia: The more we see, the less we know
Luca Frulloni, MD, PhD, Antonio Amodio, MD, PhD Department of Medicine, Pancreas Institute, University of Verona, Verona, Italy
Corresponding author: Luca Frulloni Department of Medicine, Pancreas Institute University of Verona, Verona, Italy Email: [email protected] Tel: +39-045-8124466 Fax: +39-045-80274595
Keywords: hyperenzymemia, pancreatic, MR, MRCP, EUS
Elevated serum pancreatic enzymes are a common symptom of pancreatic disease1. However, an increase of serum amylases and/or lipases in asymptomatic patients who undergo routine biochemical tests or tests to investigate non-specific symptoms that are not correlated with pancreatic diseases may be accidentally discovered. This represents a clinical problem because patients undergo many instrumental investigations in the attempt to diagnose a pancreatic disease, which results in a significant increase in costs, and the patient is often over-diagnosed. An increase in serum pancreatic enzyme levels in patients without any evidence of pancreatic disease was described in the 1970s by Warshaw and Lee2. These authors stressed that “The assumption that the pancreas is at fault, especially if there is abdominal pain, may cause morbidity due to gross overtreatment.” Twenty years later, Lucio Gullo introduced the term “benign pancreatic chronic hyperamylasemia” to define a distinct clinical entity that is characterized by a chronic elevation of pancreatic enzymes, in absence of typical pancreatic pain and, particularly, in absence of pancreatic disease3. Later, sporadic and familial forms were described4, often characterized by large and rapid fluctuations in serum amylase and lipase levels, even within the same day5. Gullo’s syndrome was proposed to define the condition of these subjects6. In more recent years, different morphological alterations of the pancreas (ductal abnormalities suggestive of early chronic pancreatitis, dysfunction of the sphincter of Oddi, pancreatic cysts, IPMNs, endocrine neoplasia, and, rarely, ductal adenocarcinoma) were documented in a significant proportion of subjects with chronic asymptomatic pancreatic hyperenzymemia (CAPH) using cholangio-pancreatography magnetic resonance (MRCP) and MRCP with secretin stimulation (s-MRCP)7-11. s-MRCP is suggested to be the most appropriate imaging technique to investigate subjects with CAPH because of its diagnostic yield, reproducibility, and non-invasiveness7, 9, 11. In the present issue, Di Leo et al.12 prospectively studied 68 subjects with CAPH using both endoscopic ultra-sonography (EUS) and s-MRCP. The most significant advance of this study is the presence of a control group of subjects evaluated for gastric disease using EUS and the exclusion of other potential causes of CAPH. EUS detected pancreatic alterations more frequently in the CAPH group (60.3%) than in controls (13.2%), whereas s-MRCP showed pancreatic alterations in 51.5% in the CAPH group. Combining the two imaging modalities, pancreatic abnormalities were detected in 63.3% of
CAPH subjects. The EUS and s-MRCP diagnoses were consistent in most subjects (75%), but the authors claim a higher sensitivity of EUS compared to s-MRCP and recommended using both procedures, with a preference for using EUS before considering CAPH to be a benign condition (or Gullo’s syndrome). Pancreatic asymptomatic hyperenzymemia represents a clinical challenge for physicians because it may represent a biochemical sign of a pancreatic disease but also a chronic benign condition. In the first description of CAPH, Lucio Gullo proposed that “in the absence of any clinical, functional, or imaging evidence of pancreatic disease, we can be confidently assured that no disease is present, thereby avoiding multiple, often costly diagnostic examinations.”3 The implications of this widely accepted statement are: 1) all pancreatic diseases need to be excluded before this condition is diagnosed; and 2) no other investigations are required after the diagnosis. In the presence of ductal or parenchymal alterations, we need to understand the clinical relevance of changes observed at imaging, to better define the diagnostic algorithm and the need for a follow-up. The presence of morphological alterations at s-MRCP or EUS in the pancreas of CAPH subjects ranges between 50% and 60%7-12, but their real meaning in this particular clinical setting is still unknown. The abnormalities found at imaging in these studies are clinically relevant in 10–20% of subjects, because they suggest that surgery (IPMNs, endocrine neoplasia, pancreatic adenocarcinoma) or followup (IPMNs) is required, but it is still unknown if milder changes in the images represent disease. In the present study12, EUS was able to detect signs of chronic pancreatitis, according to the Rosemont classification13, more frequently in the CAPH group (32.4%) than in the control group (4.4%). However, subjects with EUS findings “consistent with chronic pancreatitis” using the Rosemont criteria was observed at a similar percentage in the two groups (5.9% vs. 2.9%). Moderate–severe pancreatic fibrosis has been observed in 15% of autopsy of patients without any evidence of pancreatic diseases and without excessive alcohol intake, at a mean age of 66.1 ± 15.9 years.14 Additionally, the mean age of subjects in the CAPH group with pancreatic alterations was significantly higher than that in the CAPH group with normal EUS, and it has been shown that pancreatic fibrosis increases with age15-17. The impact of mild pancreatic changes on clinical outcomes are not known, but they are likely not clinically relevant and, therefore, do not require followup. However, only prospective studies on long-term outcomes in patients with CAPH and early (mild) chronic pancreatic features at EUS or s-MRCP can explain the true role of these alterations and their clinical impact.
A second key point is how to evaluate the pancreas in patients with CAPH. Di Leo et al.12 proposed EUS as the preferred instrumental investigation in CAPH. EUS seems to better diagnose IPMNs by evaluating the communication between cyst and pancreatic ductal system, and early chronic pancreatitis, with the limitations previously reported. However, negative issues related to EUS compared to MRCP include its higher costs and invasiveness, and it is operator-dependent. Additionally, it is still unknown if the diagnostic gain by EUS compared to s-MRCP is clinically relevant. Finally, some subjects require follow-up and EUS cannot be used as an imaging modality in this setting. Thus, MRI and MRCP remain the current imaging modalities of choice for subjects with CAPH. The uncertainty about the significance of mild pancreatic alterations observed using EUS also allows us to make some considerations on the use of secretin with MRI in patients with CAPH. The use of secretin improves diagnostic accuracy for pancreas divisum and early chronic pancreatitis. Because pancreas divisum in absence of symptoms can be considered only an anatomic abnormality, and the meaning of early (mild) chronic pancreatitis in CAPH is still unknown, MRI with MRCP sequences without secretin stimulation probably represent the first appropriate imaging modality approach (index evaluation), and can be proposed in the follow up of CAPH subjects with pancreatic alterations, to evaluate possible progression of the potential disease. Careful evaluation of patients with CAPH using the most accurate imaging technique seems to confirm that “the more we see, the less we know”.
Conflict of interest: none
References 1.
Frulloni L, Patrizi F, Bernardoni L, et al. Pancreatic hyperenzymemia: clinical significance and diagnostic approach. Jop 2005;6:536-51.
2.
Warshaw AL, Lee KH. Macroamylasemia and other chronic nonspecific hyperamylasemias: chemical oddities or clinical entities? Am J Surg 1978;135:48893.
3.
Gullo
L.
Chronic
nonpathological
hyperamylasemia
of
pancreatic
origin.
Gastroenterology 1996;110:1905-8. 4.
Gullo L. Familial pancreatic hyperenzymemia. Pancreas 2000;20:158-60.
5.
Gullo L. Day-to-day variations of serum pancreatic enzymes in benign pancreatic hyperenzymemia. Clin Gastroenterol Hepatol 2007;5:70-4.
6.
Gullo L. Benign pancreatic hyperenzymemia or Gullo's syndrome. Jop 2006;7:2412; author reply 243-4.
7.
Amodio A, Manfredi R, Katsotourchi AM, et al. Prospective evaluation of subjects with chronic asymptomatic pancreatic hyperenzymemia. Am J Gastroenterol 2012;107:1089-95.
8.
Donati F, Boraschi P, Gigoni R, et al. Secretin-stimulated MR cholangiopancreatography in the evaluation of asymptomatic patients with non-specific pancreatic hyperenzymemia. Eur J Radiol 2010;75:e38-44.
9.
Testoni PA, Mariani A, Curioni S, et al. Pancreatic ductal abnormalities documented by secretin-enhanced MRCP in asymptomatic subjects with chronic pancreatic hyperenzymemia. Am J Gastroenterol 2009;104:1780-6.
10.
Pezzilli R, Morselli-Labate AM, Casadei R, et al. Chronic asymptomatic pancreatic hyperenzymemia is a benign condition in only half of the cases: a prospective study. Scand J Gastroenterol 2009;44:888-93.
11.
Mortele KJ, Wiesner W, Zou KH, et al. Asymptomatic nonspecific serum hyperamylasemia and hyperlipasemia: spectrum of MRCP findings and clinical implications. Abdom Imaging 2004;29:109-14.
12.
Di Leo M, Petrone MC, Zuppardo RA, et al. Pancreatic morpho-functional imaging as a diagnostic approach forchronic asymptomatic pancreatic hyperenzymemia. Dig Liv Dis 2016.
13.
Catalano MF, Sahai A, Levy M, et al. EUS-based criteria for the diagnosis of chronic
pancreatitis:
the
Rosemont
classification.
Gastrointest
Endosc
2009;69:1251-61. 14.
van Geenen EJ, Smits MM, Schreuder TC, et al. Smoking is related to pancreatic fibrosis in humans. Am J Gastroenterol 2011;106:1161-6; quiz 1167.
15.
Detlefsen S, Sipos B, Feyerabend B, et al. Pancreatic fibrosis associated with age and ductal papillary hyperplasia. Virchows Arch 2005;447:800-5.
16.
Stamm BH. Incidence and diagnostic significance of minor pathologic changes in the adult pancreas at autopsy: a systematic study of 112 autopsies in patients without known pancreatic disease. Hum Pathol 1984;15:677-83.
17.
Shimizu M, Hayashi T, Saitoh Y, et al. Interstitial fibrosis in the pancreas. Am J Clin Pathol 1989;91:531-4.
S1590-8658(16)30813-1 http://dx.doi.org/doi:10.1016/j.dld.2016.11.009 YDLD 3297
To appear in:
Digestive and Liver Disease
Received date: Accepted date:
27-10-2016 18-11-2016
Please cite this article as: Frulloni Luca, Amodio Antonio.Endoscopic ultrasonography in chronic asymptomatic pancreatic hyperenzymemia: The more we see, the less we know.Digestive and Liver Disease http://dx.doi.org/10.1016/j.dld.2016.11.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Endoscopic ultrasonography in chronic asymptomatic pancreatic hyperenzymemia: The more we see, the less we know
Luca Frulloni, MD, PhD, Antonio Amodio, MD, PhD Department of Medicine, Pancreas Institute, University of Verona, Verona, Italy
Corresponding author: Luca Frulloni Department of Medicine, Pancreas Institute University of Verona, Verona, Italy Email: [email protected] Tel: +39-045-8124466 Fax: +39-045-80274595
Keywords: hyperenzymemia, pancreatic, MR, MRCP, EUS
Elevated serum pancreatic enzymes are a common symptom of pancreatic disease1. However, an increase of serum amylases and/or lipases in asymptomatic patients who undergo routine biochemical tests or tests to investigate non-specific symptoms that are not correlated with pancreatic diseases may be accidentally discovered. This represents a clinical problem because patients undergo many instrumental investigations in the attempt to diagnose a pancreatic disease, which results in a significant increase in costs, and the patient is often over-diagnosed. An increase in serum pancreatic enzyme levels in patients without any evidence of pancreatic disease was described in the 1970s by Warshaw and Lee2. These authors stressed that “The assumption that the pancreas is at fault, especially if there is abdominal pain, may cause morbidity due to gross overtreatment.” Twenty years later, Lucio Gullo introduced the term “benign pancreatic chronic hyperamylasemia” to define a distinct clinical entity that is characterized by a chronic elevation of pancreatic enzymes, in absence of typical pancreatic pain and, particularly, in absence of pancreatic disease3. Later, sporadic and familial forms were described4, often characterized by large and rapid fluctuations in serum amylase and lipase levels, even within the same day5. Gullo’s syndrome was proposed to define the condition of these subjects6. In more recent years, different morphological alterations of the pancreas (ductal abnormalities suggestive of early chronic pancreatitis, dysfunction of the sphincter of Oddi, pancreatic cysts, IPMNs, endocrine neoplasia, and, rarely, ductal adenocarcinoma) were documented in a significant proportion of subjects with chronic asymptomatic pancreatic hyperenzymemia (CAPH) using cholangio-pancreatography magnetic resonance (MRCP) and MRCP with secretin stimulation (s-MRCP)7-11. s-MRCP is suggested to be the most appropriate imaging technique to investigate subjects with CAPH because of its diagnostic yield, reproducibility, and non-invasiveness7, 9, 11. In the present issue, Di Leo et al.12 prospectively studied 68 subjects with CAPH using both endoscopic ultra-sonography (EUS) and s-MRCP. The most significant advance of this study is the presence of a control group of subjects evaluated for gastric disease using EUS and the exclusion of other potential causes of CAPH. EUS detected pancreatic alterations more frequently in the CAPH group (60.3%) than in controls (13.2%), whereas s-MRCP showed pancreatic alterations in 51.5% in the CAPH group. Combining the two imaging modalities, pancreatic abnormalities were detected in 63.3% of
CAPH subjects. The EUS and s-MRCP diagnoses were consistent in most subjects (75%), but the authors claim a higher sensitivity of EUS compared to s-MRCP and recommended using both procedures, with a preference for using EUS before considering CAPH to be a benign condition (or Gullo’s syndrome). Pancreatic asymptomatic hyperenzymemia represents a clinical challenge for physicians because it may represent a biochemical sign of a pancreatic disease but also a chronic benign condition. In the first description of CAPH, Lucio Gullo proposed that “in the absence of any clinical, functional, or imaging evidence of pancreatic disease, we can be confidently assured that no disease is present, thereby avoiding multiple, often costly diagnostic examinations.”3 The implications of this widely accepted statement are: 1) all pancreatic diseases need to be excluded before this condition is diagnosed; and 2) no other investigations are required after the diagnosis. In the presence of ductal or parenchymal alterations, we need to understand the clinical relevance of changes observed at imaging, to better define the diagnostic algorithm and the need for a follow-up. The presence of morphological alterations at s-MRCP or EUS in the pancreas of CAPH subjects ranges between 50% and 60%7-12, but their real meaning in this particular clinical setting is still unknown. The abnormalities found at imaging in these studies are clinically relevant in 10–20% of subjects, because they suggest that surgery (IPMNs, endocrine neoplasia, pancreatic adenocarcinoma) or followup (IPMNs) is required, but it is still unknown if milder changes in the images represent disease. In the present study12, EUS was able to detect signs of chronic pancreatitis, according to the Rosemont classification13, more frequently in the CAPH group (32.4%) than in the control group (4.4%). However, subjects with EUS findings “consistent with chronic pancreatitis” using the Rosemont criteria was observed at a similar percentage in the two groups (5.9% vs. 2.9%). Moderate–severe pancreatic fibrosis has been observed in 15% of autopsy of patients without any evidence of pancreatic diseases and without excessive alcohol intake, at a mean age of 66.1 ± 15.9 years.14 Additionally, the mean age of subjects in the CAPH group with pancreatic alterations was significantly higher than that in the CAPH group with normal EUS, and it has been shown that pancreatic fibrosis increases with age15-17. The impact of mild pancreatic changes on clinical outcomes are not known, but they are likely not clinically relevant and, therefore, do not require followup. However, only prospective studies on long-term outcomes in patients with CAPH and early (mild) chronic pancreatic features at EUS or s-MRCP can explain the true role of these alterations and their clinical impact.
A second key point is how to evaluate the pancreas in patients with CAPH. Di Leo et al.12 proposed EUS as the preferred instrumental investigation in CAPH. EUS seems to better diagnose IPMNs by evaluating the communication between cyst and pancreatic ductal system, and early chronic pancreatitis, with the limitations previously reported. However, negative issues related to EUS compared to MRCP include its higher costs and invasiveness, and it is operator-dependent. Additionally, it is still unknown if the diagnostic gain by EUS compared to s-MRCP is clinically relevant. Finally, some subjects require follow-up and EUS cannot be used as an imaging modality in this setting. Thus, MRI and MRCP remain the current imaging modalities of choice for subjects with CAPH. The uncertainty about the significance of mild pancreatic alterations observed using EUS also allows us to make some considerations on the use of secretin with MRI in patients with CAPH. The use of secretin improves diagnostic accuracy for pancreas divisum and early chronic pancreatitis. Because pancreas divisum in absence of symptoms can be considered only an anatomic abnormality, and the meaning of early (mild) chronic pancreatitis in CAPH is still unknown, MRI with MRCP sequences without secretin stimulation probably represent the first appropriate imaging modality approach (index evaluation), and can be proposed in the follow up of CAPH subjects with pancreatic alterations, to evaluate possible progression of the potential disease. Careful evaluation of patients with CAPH using the most accurate imaging technique seems to confirm that “the more we see, the less we know”.
Conflict of interest: none
References 1.
Frulloni L, Patrizi F, Bernardoni L, et al. Pancreatic hyperenzymemia: clinical significance and diagnostic approach. Jop 2005;6:536-51.
2.
Warshaw AL, Lee KH. Macroamylasemia and other chronic nonspecific hyperamylasemias: chemical oddities or clinical entities? Am J Surg 1978;135:48893.
3.
Gullo
L.
Chronic
nonpathological
hyperamylasemia
of
pancreatic
origin.
Gastroenterology 1996;110:1905-8. 4.
Gullo L. Familial pancreatic hyperenzymemia. Pancreas 2000;20:158-60.
5.
Gullo L. Day-to-day variations of serum pancreatic enzymes in benign pancreatic hyperenzymemia. Clin Gastroenterol Hepatol 2007;5:70-4.
6.
Gullo L. Benign pancreatic hyperenzymemia or Gullo's syndrome. Jop 2006;7:2412; author reply 243-4.
7.
Amodio A, Manfredi R, Katsotourchi AM, et al. Prospective evaluation of subjects with chronic asymptomatic pancreatic hyperenzymemia. Am J Gastroenterol 2012;107:1089-95.
8.
Donati F, Boraschi P, Gigoni R, et al. Secretin-stimulated MR cholangiopancreatography in the evaluation of asymptomatic patients with non-specific pancreatic hyperenzymemia. Eur J Radiol 2010;75:e38-44.
9.
Testoni PA, Mariani A, Curioni S, et al. Pancreatic ductal abnormalities documented by secretin-enhanced MRCP in asymptomatic subjects with chronic pancreatic hyperenzymemia. Am J Gastroenterol 2009;104:1780-6.
10.
Pezzilli R, Morselli-Labate AM, Casadei R, et al. Chronic asymptomatic pancreatic hyperenzymemia is a benign condition in only half of the cases: a prospective study. Scand J Gastroenterol 2009;44:888-93.
11.
Mortele KJ, Wiesner W, Zou KH, et al. Asymptomatic nonspecific serum hyperamylasemia and hyperlipasemia: spectrum of MRCP findings and clinical implications. Abdom Imaging 2004;29:109-14.
12.
Di Leo M, Petrone MC, Zuppardo RA, et al. Pancreatic morpho-functional imaging as a diagnostic approach forchronic asymptomatic pancreatic hyperenzymemia. Dig Liv Dis 2016.
13.
Catalano MF, Sahai A, Levy M, et al. EUS-based criteria for the diagnosis of chronic
pancreatitis:
the
Rosemont
classification.
Gastrointest
Endosc
2009;69:1251-61. 14.
van Geenen EJ, Smits MM, Schreuder TC, et al. Smoking is related to pancreatic fibrosis in humans. Am J Gastroenterol 2011;106:1161-6; quiz 1167.
15.
Detlefsen S, Sipos B, Feyerabend B, et al. Pancreatic fibrosis associated with age and ductal papillary hyperplasia. Virchows Arch 2005;447:800-5.
16.
Stamm BH. Incidence and diagnostic significance of minor pathologic changes in the adult pancreas at autopsy: a systematic study of 112 autopsies in patients without known pancreatic disease. Hum Pathol 1984;15:677-83.
17.
Shimizu M, Hayashi T, Saitoh Y, et al. Interstitial fibrosis in the pancreas. Am J Clin Pathol 1989;91:531-4.