- Email: [email protected]
EUS and chronic pancreatitis
IV. THE PANCREAS EUS and chronic pancreatitis Anand V. Sahai, MD, MSc (Epid), FRCPC
EUS provides unique information on pancreatic morphology, but the clinical value of EUS in managing patients with suspected or proven chronic pancreatitis remains controversial. The overriding concern appears to be that widespread application of EUS will result in overdiagnosis of chronic pancreatitis in the general population. Clearly, further work is required to clarify the clinical implications of minor pancreatic changes seen by EUS. However, this does not mean that EUS is of no value or should not be used at all for this indication. There are now several studies documenting good agreement between EUS and other diagnostic modalities that are accepted reference standards for the diagnosis of chronic pancreatitis, particularly endoscopic retrograde pancreatography (ERP). ERP may provide more information than less sensitive tests such as transcutaneous US and CT and may be a safe alternative to ERP and a more practical alternative to functional assays, which require duodenal intubation. However, there are practical issues that may affect its clinical applicability. Before using EUS for this indication, one should be aware of its limitations as well as the remaining unanswered questions regarding the clinical implications of EUS findings. EUS EVALUATION OF THE PANCREAS Diagnostic pancreatic EUS (without EUS-guided fine-needle aspiration) is as safe as conventional gastroscopy.1 However, sedationless EUS would probably be difficult for most patients because of longer procedure times, slightly larger endoscope diameter, and the greater discomfort that may be associated with certain maneuvers (e.g., pushing into the duodenal apex to image the bile ducts).2 In virtually all patients with normal upper GI anatomy (i.e., no history of gastric and/or duodenal surgery such as Billroth II anastomosis), the entire pancreas may be visualized (uncinate process to tail). Current affiliation: Centre Hospitalier de l’Université de Montréal, Hôpital Saint Luc, Montréal, Québec Canada. Funded by a grant from Le Fond de Recherche en Santé du Québec. Reprint requests: Anand V. Sahai, MD, MSc (Epid), FRCPC, Département de Gastroentérologie, CHUM, Hôpital Saint Luc, 1058 Rue Saint Denis, Montréal, Québec, Canada. Copyright © 2002 by the American Society for Gastrointestinal Endoscopy 0016-5107/2002/$35.00 + 0 37/0/127701 doi:10.1067/mge.2002.127701 S76
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Figure 1. The normal pancreas is homogeneous and slightly hyperechoic. The main pancreatic duct is seen as a thin anechoic line.
The uncinate process, ampulla, distal bile duct, and distal pancreatic ducts (Wirsung and Santorini’s ducts) are seen best from the second duodenum, but can also be seen from the duodenal bulb, along with the rest of the pancreatic head and more proximal bile duct. From both these positions, a distinction may be noted between the ventral (more hypoechoic) and dorsal pancreas.3 Pancreas divisum may be suspected if the main pancreatic duct emerging from the papilla of Vater does not appear to traverse from the ventral to the dorsal pancreas or is imperceptible.4 The diagnosis is also supported if there is evidence of a dominant Santorini’s duct and no apparent communication with the ventral duct. On the contrary, pancreas divisum can probably be safely excluded if the main pancreatic duct can be clearly seen traversing from the ventral to the dorsal pancreas and/or can be traced from the major papilla well back and around the genu of the pancreas (unpublished observations). The genu, body, and tail of the pancreas are imaged from the stomach. Care should be taken to ensure complete visualization of the pancreatic parenchyma (particularly of the tail) by ensuring that the main pancreatic duct is followed as far as possible from the genu to the tail. Because retroperitoneal structures may also be confused with pancreatic tissue, it is also important to ensure that the appropriate landmarks (e.g., splenic vein and artery, portal confluence, left kidney, splenic hilum) are seen before concluding that the pancreatic body and tail have been visualized in their entirety. Normal versus abnormal Normally, the pancreatic parenchyma is homogeneous and slightly hyperechoic (Fig. 1). The main VOLUME 56, NO. 4 (SUPPL), 2002
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Figure 2. The normal pancreas often shows a clear distinction (arrows) between the hypoechoic ventral and more hyperechoic dorsal pancreas.
pancreatic duct is seen as a thin anechoic smooth linear structure coursing centrally through the parenchyma. There is also usually a clearly detectable difference in the echo density of the ventral and dorsal pancreas (Fig. 2). This type of appearance is seen typically (75% of the time5) in younger patients undergoing EUS for unrelated indications (i.e., no clinical suspicion of pancreatic disease) and with no history of alcohol consumption. However, in similar older patients, the “classic” normal appearance may be less frequent, despite the absence of suspected or proven pancreatic pathology or alcohol consumption. Age-related changes can be extremely variable. The gland may appear somewhat more inhomogeneous and atrophic, and the main pancreatic duct may be slightly dilated (but generally smooth and not irregular and hyperechoic) (Fig. 3). However, in at least one study, age and body mass index were not independent predictors of pancreatic disease by EUS.6 In more obese patients, the parenchyma may appear more hyperechoic than normal (presumably because of fatty infiltration). Given the potentially wide variation in the EUS appearance of the “normal” pancreas, it is not surprising that distinguishing normal from abnormal may be challenging. However, several authors have addressed this issue objectively and proposed EUS criteria for pancreatic disease. THE EUS CRITERIA FOR PANCREATIC DISEASE It is clear that the US appearance of the normal pancreas (as assessed by either transcutaneous abdominal or endoscopic US) differs from that of a gland with severe calcific chronic pancreatitis (with stones, cysts, ductal dilation, and ductal irregularity). It is logical to assume that the evolution of the US appearance from normal to severely abnormal is gradual and progressive. Studies comparing EUS VOLUME 56, NO. 4 (SUPPL), 2002
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Figure 3. Age-related changes may include dilation of the main pancreatic duct, but the duct walls are smooth and the parenchyma shows no clear evidence of parenchymal criteria for chronic pancreatitis.
with other reference standards for pancreatic disease are based on the hypothesis that EUS can detect these progressive changes and that increases in EUS abnormalities should be proportional to increases in abnormalities (structural and/or functional) seen with other tests. Because EUS provides higher resolution imaging than previously used imaging methods and provides information on both the ducts and parenchyma, it is also logical to assume that it may detect abnormalities not described previously with tests used traditionally to study pancreatic morphology such as transcutaneous US, CT, and ERP. Functional testing is said to become abnormal only after greater than 60% to 70%7 of pancreatic functional reserve is depleted. If this is the case, it may also be reasonable to expect that EUS could detect subtle structural changes that predate functional abnormalities and that mild EUS changes might not correlate with functional abnormalities, whereas severe EUS changes would. Finally, it is clear that even severe chronic pancreatitis (e.g., Cambridge class 4) can be asymptomatic. Therefore, it should not be surprising that EUS may show pancreatic abnormalities in asymptomatic individuals. It has been shown that alcohol consumption is often associated with asymptomatic abnormalities.8,9 A number of EUS criteria for pancreatic disease have been described. Clearly, EUS can demonstrate stones, cysts, and ductal dilation, which can be seen by other methods as well. However, just as EUS can find “CT negative masses,” it may detect smaller stones and cysts and subtler ductal dilation in what might be called CT and/or ERP negative pancreatitis. Lees et al.10,11 first described endosonographic findings in patients with clinical and radiologic evidence of chronic pancreatitis and characterized endosonographic criteria that distinguish normal GASTROINTESTINAL ENDOSCOPY
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Figure 4. The parenchyma is hypoechoic. There are coarse hyperechoic strands that eventually delineate lobules. The main pancreatic duct is of normal caliber, but the duct margins are hyperechoic and irregular.
Figure 5. The parenchyma is hypoechoic and there are scattered hyperechoic foci. The main pancreatic duct is slightly dilated and the duct margins are hyperechoic and irregular.
from abnormal. Wiersema et al.12 refined their definitions and found they occurred frequently in patients with abnormal endoscopic pancreatograms and were absent in healthy volunteers. The criteria for pancreatic disease have been studied primarily at a US frequency of 7.5 MHz. Criteria that are specific to EUS can be divided into two groups: parenchymal and ductal (Figs. 4, 5, and 6) Parenchymal criteria include reduced echogenicity, inhomogeneity, loss of the ventral/dorsal distinction,3 atrophy, hyperechoic foci, hyperechoic strands, and lobularity. They should be sought in the dorsal gland only because the hypoechoic ventral pancreas can show criteria such as hyperechoic foci and strands even in normal individuals. Reduced echogenicity and inhomogeneity are presumably caused by edema and/or reduced fat content. The presence of these changes in the dorsal gland would explain the loss of ventral/dorsal distinction. Hyperechoic foci and strands correspond respectively to small (1-2 mm) hyperechoic dots and thin, hyperechoic lines scatS78
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Figure 6. The parenchyma is atrophic and lobular. However, despite these signs of advanced disease, no hyperechoic foci are visible. The main duct is dilated, hyperechoic, and irregular.
tered in the parenchyma. When there are sufficient strands, they separate the parenchyma into distinct “lobules” that may give the gland a honeycomb appearance. There are sparse data on the histologic correlates of these features, but they suggest that they may represent thickened fibrous deposits or may simply reflect increased visibility of normal connective tissue because of surrounding edema.13-16 One study also found a correlation with the presence of inflammatory cells (i.e., histologic pancreatitis).14 Whatever these changes represent histologically, it is clear that, compared with controls, they are seen more often in patients with clinical pancreatitis (acute or chronic) and in individuals (both symptomatic and asymptomatic) who consume alcohol, which is a proven cause of acute and chronic pancreatitis.6,8,9,12 They are also seen frequently when the pancreatic duct is obstructed by tumors. It is therefore highly likely that these changes reflect some form of pancreatic pathology and are not simply meaningless, nonspecific findings. Ductal criteria specific to EUS include obvious to more subtle ductal dilation (≥3 mm in the head, ≥2 mm in the body, ≥1 mm in the tail), hyperechoic main duct margins, irregular main duct margins, and visible side branches. Normally, the duct walls are invisible; if they become visible, they may be considered hyperechoic. It is unclear whether increased duct wall echogenicity is due to reduced echogenicity of the surrounding parenchyma (e.g., due to edema), to structural changes in the duct wall itself, or to some combination of the two. Presumably, ductal irregularity corresponds to the same irregularity seen by ERP, and visible side branches (seen budding from the main duct) correspond to dilated secondary branches of the main pancreatic duct. Several studies show that the increasing EUS abnormalities correlate with the severity of pancreVOLUME 56, NO. 4 (SUPPL), 2002
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atographic changes6,17-23 and with reductions in secretin-stimulated duodenal bicarbonate.23 A quantitative analysis with 9 possible criteria (hyperechoic foci, hyperechoic strands, lobularity, ductal dilation, ductal irregularity, hyperechoic duct margins, visible side branches, calcifications, and cysts)6 suggests that, in a population at low to moderate risk of chronic pancreatitis (e.g., pretest probability <50%), EUS is most reliable only when it is either clearly normal (≤2 criteria) or clearly abnormal (≥5 criteria). In other words, when EUS is very abnormal, ERP and/or functional tests tend to be abnormal and when EUS is normal or almost normal, other tests tend to be normal. Similarly, when ERP is abnormal, EUS is usually abnormal. Some of the controversy regarding the accuracy of EUS may be due to studies that use 3 or 4 criteria (i.e., mild abnormalities) as threshold values to distinguish normal from abnormal EUS. When EUS is only mildly abnormal, ERP and functional tests are often normal. Whether minimal EUS changes reflect early chronic pancreatic disease is unclear. They do not appear to distinguish patients with and without abdominal pain and/or suspected pancreatic disease8 and may24 or may not20 progress to clinical chronic pancreatitis. By using receiver operating curve (ROC) analysis, a threshold of 3 to 4 criteria often offers the best compromise between sensitivity and specificity (approximately 70% for each), but the more clinically useful predictive values associated with these thresholds (i.e., that answer the question, “What is the chance the patient does or does not have the disease if the test is positive or negative?”) are clearly inadequate (<70%). The positive predictive value is particularly low in populations with a low pretest probability for disease and the negative predictive value is low in populations with a high pretest probability for disease. When the threshold for “normal” is set at ≤2 criteria and the threshold for “abnormal” is set at ≥5 criteria, the predictive values are substantially higher (>85%).6 It should also be noted that, when the threshold number of criteria is set sufficiently high (≥5 criteria), the prevalence of EUS chronic pancreatitis in the general population of patients undergoing EUS for nonpancreatic indications is relatively low (<10%-15%), especially in patients who do not consume alcohol (unpublished observations). PRACTICAL ISSUES AND LIMITATIONS RELATING TO THE USE OF EUS CRITERIA FOR PANCREATIC DISEASE Interpreting pancreatic EUS is therefore easier when the gland is clearly normal or is clearly abnormal. However, in some patients, even experienced endosonographers have difficulty agreeing whether VOLUME 56, NO. 4 (SUPPL), 2002
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disease is present or the results may be equivocal (e.g., 3 or 4 criteria). The endosonographic appearance of the pancreas simply does not have a textbook appearance in many patients. This may be due to variations in patient echogenicity, EUS equipment issues, interobserver variation, operator experience, and the inherent limitations in the EUS criteria themselves (including the distinction between acute and chronic changes). In some patients, it is simply difficult to obtain clear images of the pancreas. The image quality produced by echoendoscopes may also differ. In mechanical radial scanners, one particularly frequent and unrecognized problem may be inadequate maintenance, leading to the presence of air bubbles in the oil contained in the plastic cap used to house the transducer. These air bubbles disperse as the transducer rotates and the result is a low gain grainy image. Air bubbles in the oil must be removed and the oil should also be changed periodically. Curved linear array echoendoscopes are exempt from this problem, but all the published data on EUS and chronic pancreatitis have been obtained with mechanical radial scanning instruments. One study showed moderate ( = 0.56) agreement between mechanical and fixed array instruments,25 but further data are probably required before both types of instruments can be used interchangeably for this indication. It is well known that significant interobserver variation may occur with all types of diagnostic imaging. This may be an issue for EUS and chronic pancreatic disease, but at least one study suggests that it is not greater than with other tests ( = 0.410.46) and that agreement is greatest for more experienced endosonographers.26 Because some of the EUS criteria may be subtle, it is also logical to expect that inexperienced endosonographers or those without appropriate training may produce less reliable and reproducible results. More objective methods of evaluating pancreatic echo architecture (e.g., computer analysis of pancreatic echogenicity) and EUS-guided pancreatic biopsy may overcome the problems of interobserver variability, but these remain experimental at this time. Potential limitations of the EUS criteria themselves should be noted. As stated earlier, with experience, it is generally easy to decide whether the endosonographic appearance of the pancreas in a given patient is normal or abnormal. But in some cases it may be difficult to conclude on the presence of certain criteria, which may be another cause of equivocal results. The only individual criterion that is strongly predictive of chronic pancreatitis is calcification.6 However, because it is the overall appearGASTROINTESTINAL ENDOSCOPY
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ance of the gland that appears to be most predictive of chronic pancreatic disease (i.e., the total number of criteria),6 this is not a problem in itself. But in some cases of fairly advanced disease, the severity of disease may actually make it difficult to appreciate some of the subtler criteria and therefore reduce the total number of observed criteria. For example, in patients with an extremely lobular pancreas, the honeycombed appearance may be so pronounced that distinct hyperechoic foci cannot be appreciated (Fig. 6). In these cases, the pancreatic duct (if not dilated) may also be so difficult to find that subtle ductal abnormalities such as visible side branches may be hidden. Therefore, in these patients, who clearly have advanced pancreatic abnormalities, the total number of criteria may actually be limited to 2 or 3 (e.g. lobulation, hyperechoic ducts, irregular ducts). Similarly, if there is significant atrophy, there may be insufficient parenchyma to appreciate hyperechoic foci, hyperechoic strands, and lobulation. It is also unclear if the criteria can distinguish acute from chronic pancreatitis reliably. Acute edema may produce a lobular appearance. Most studies have tried to exclude patients who have had a documented recent attack of acute pancreatitis. But it is unclear how long the effects of an acute attack continue to affect the endosonographic appearance of the pancreas. Obviously, this issue may come into play when using EUS to diagnose or exclude chronic pancreatitis in patients with acute or recurrent pancreatitis. To reduce this problem, it is probably best to perform EUS as long as possible (several weeks or months) after an acute attack; but further work is required to determine how long endosonographic signs of acute pancreatitis persist. Finally, it is unclear whether the criteria should be interpreted with access to clinical information (especially the patient’s level of alcohol consumption). The impact of clinical information on EUS interpretation has not been assessed formally for this indication, but personal experience suggests that it may be substantial in some cases. Therefore, it is probably best to study the pancreas without access to clinical information (or with as little clinical information as possible), and then to attribute a clinical significance to EUS findings by incorporating clinical variables. SUMMARY AND POTENTIAL CLINICAL UTILITY EUS provides a safe and relatively noninvasive method of obtaining detailed structural information on the pancreatic parenchyma and ducts and related structures (e.g., upper GI mucosa, gall bladder, bile ducts, ampulla). The published data support the ability of EUS to distinguish between patients with S80
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and without pancreatic disease. The EUS criteria for pancreatic disease are a useful tool to quantify pancreatic abnormalities, but they have limitations. EUS abnormalities may be similar in both acute and chronic pancreatitis, but changes found in patients with no clinical evidence of acute pancreatitis are likely to reflect structural alterations of the pancreatic parenchyma and ducts that are found in patients with histologic and/or functional proof of chronic pancreatitis (i.e., true chronic pancreatitis). However, these changes (even when severe) may be asymptomatic and are seen frequently in patients who consume alcohol on a regular basis. EUS is most reliable when the examination is either clearly normal or abnormal. When there is little or no evidence of pancreatic disease by EUS, ERP and functional assays will likely be normal and are therefore unwarranted unless the clinical suspicion of pancreatic disease is very high. In these patients, clinically significant pancreatic disease can most often be excluded. When the examination is clearly abnormal (i.e., ≥5-6 criteria), and there is no evidence of recent acute pancreatitis, there is a strong possibility that the patient has some form of chronic pancreatic disease (this degree of abnormality is extremely unlikely in normal controls who do not consume alcohol). ERP and functional assays have been shown by some groups to also be abnormal in these patients or to become abnormal with time. Therefore, further testing in these patients (at least for diagnostic purposes) may also be unwarranted if the clinical context is compatible with chronic pancreatitis. It should be emphasized that, like all diagnostic imaging, EUS is not infallible and should not replace thoughtful, complete clinical evaluation of the patient. Further work is also required to determine whether EUS findings have any bearing on prognosis or response to therapeutic interventions. In patients in whom the pancreas is not clearly normal or abnormal, the clinical significance of EUS findings is extremely unclear. They do not correlate well with pancreatographic or functional abnormalities, may not progress, and do not distinguish reliably between patients with and without symptoms. At this time, a diagnosis of pancreatic disease should not be made in these patients based on this information alone. Well before establishing their clinical utility, further work is required to determine whether these changes reflect true pancreatic disease or are simply normal variants. CONCLUSIONS Whether we like it or not, EUS will likely be used more and more frequently to diagnose or exclude occult chronic pancreatitis. Given the inherent risks VOLUME 56, NO. 4 (SUPPL), 2002
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and limitations of ERP, the inconvenience of functional testing, the relative safety of EUS, and the range of information it provides, this should not be surprising. EUS has faced (and will likely continue to face) its share of normal and healthy scientific skepticism with regard to its value for this indication. However, the accumulated data suggest that this diagnostic modality can no longer be ignored as a method to look for mild chronic pancreatitis when less sensitive tests such as CT and abdominal US are negative. However, physicians will probably wonder less if, and more how EUS could be useful to them in daily practice only if further work manages to demonstrate that it is actually worth looking for the disease in the first place. REFERENCES 1. Lightdale CJ. Indications, contraindications, and complications of endoscopic ultrasonography. Gastrointest Endosc 1996;43:S15-9. 2. Röesch T, Dennig V. A prospective assessment of complications and patient acceptance of upper GI endoscopic ultrasonography—a multicenter study in 2500 patients [abstract]. Gastrointest Endosc 2000;51:AB177. 3. Savides TJ, Gress FG, Zaidi SA, Ikenberry SO, Hawes RH. Detection of embryological ventral pancreatic parenchyma with endoscopic ultrasound. Gastrointest Endosc 1996;43:14-9. 4. Bhutani MS, Hoffman BJ, Hawes RH. Diagnosis of pancreas divisum by endoscopic ultrasonography. Endoscopy 1999;167-9. 5. Savides TJ, Gress FG, Zaidi SA, Ikenberry SO, Hawes RH. Detection of embryologic ventral pancreatic parenchyma with endoscopic ultrasound. Gastrointest Endosc 1996;43:14-9. 6. Sahai AV, Zimmerman M, Aabakken L, Tarnasky PR, Cunningham JT, van Velse A, et al. Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography. Gastrointest Endosc 1998;48:18-25. 7. Toskes PP. Diagnosis of chronic pancreatitis and exocrine insufficiency. Hosp Prac 1985;20:97-100. 8. Sahai AV, Mishra G, Penman I, Williams D, Wallace MB, Hadzijahic N, et al. EUS to detect evidence of pancreatic disease in patients with persistent or nonspecific dyspepsia. Gastrointest Endosc 2000;52:153-9. 9. Bhutani MS. Endoscopic ultrasonography: changes of chronic pancreatitis in asymptomatic and symptomatic alcoholic patients. J Ultrasound Med 1999;18;455-62. 10. Lees WR. Endoscopic ultrasonography of chronic pancreatitis and pancreatic pseudocysts. Scand J Gastroenterol 1986;123: 123-9. 11. Lees WR, Vallon AG, Denyer ME, Vahl SP, Cotton PB. Prospective study of ultrasonography in chronic pancreatic disease. BMJ 1979;1:162-4.
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12. Wiersema MJ, Hawes RH, Lehman GA, Kochman ML, Sherman S, Kopecky KK. Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin. Endoscopy 1993;25:555-64. 13. Morita Y, Takiguchi M, Yasuda J, Kitamura T, Syakalima M, Hashimoto. Endoscopic and transcutaneous ultrasonographic findings and grey-scale histogram analysis in dogs with caerulein-induced pancreatitis. Veterin Q 1998;20:89-92. 14. Morita Y, Takiguchi M, Yasuda J, Eom K, Hashimoto A. Endoscopic ultrasonographic findings of the pancreas after pancreatic duct ligation in the dog. Vet Radiol Ultrasound 1998;557-62. 15. Lees WR. Endoscopic ultrasonography of chronic pancreatitis and pancreatic pseudocysts. Scand J Gastroenterol Suppl 1986;123:123-9. 16. Zimmerman MJ, Mishra G, Lewin D, Hawes RH, Coyle W, Adams DA, et al. Comparison of EUS findings with histopathology in chronic pancreatitis [abstract]. Gastrointest Endosc 1997;45:AB185. 17. Buscail L, Escourrou J, Moreau J, Delvaux M, Louvel D, Lapeyre F, et al. Endoscopic ultrasonography in chronic pancreatitis: a comparative prospective study with conventional ultrasonography, computed tomography, and ERCP. Pancreas 1995;10:251-7. 18. Dancygier H. Endoscopic ultrasonography in chronic pancreatitis. Gastrointest Endosc Clin N Am 1995;5:795-804. 19. Deviere J, Finet L, Dunham F, Cremer M. Endoscopic ultrasonography in chronic pancreatitis. Endoscopy 1994;26:808-9. 20. Hastier P, Buckley MJ, Francois E, Peten EP, Dumas R, Caroli-Basc FX, et al. A prospective study of pancreatic disease in patients with alcoholic cirrhosis: comparative diagnostic value of ERCP and EUS and long-term significance of isolated parenchymal abnormalities. Gastrointest Endosc 1999;49:705-9. 21. Natterman C, Goldschmidt AJW, Dancygier H. Endosonography in chronic pancreatitis: a comparison between endoscopic retrograde pancreatography and endoscopic ultrasonography. Endoscopy 1993;25:565-70. 22. Zuccaro G, Sivak MV Jr. Endoscopic ultrasonography in the diagnosis of chronic pancreatitis. Endoscopy 1992;24:347-9. 23. Catalano MF, Lahoti S, Geenen JE, Hogan WJ. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc 1998;48:11-7. 24. Kahl S, Glassbrenner B, Leodolter A, Pross M, Schulz H-U, Malfertheiner P. EUS in the diagnosis of early chronic pancreatitis: a prospective follow-up study. Gastrointest Endosc 2002;55:507-11. 25. Lai R, Wiersema MJ, Sahai AV, Chak A, Chang KJ, Kochman ML, et al. Blinded comparison of linear and radial endoscopic ultrasound (EUS) for the evaluation of chronic pancreatitis [abstract]. Gastrointest Endosc 2001;53:AB170. 26. Wallace MB, Hawes RH, Durkalski V, Chak A, Mallery S, Catalano MF, et al. The reliability of EUS for the diagnosis of chronic pancreatitis: interobserver agreement among experienced endosonographers. Gastrointest Endosc 2001;53:294-9.
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EUS provides unique information on pancreatic morphology, but the clinical value of EUS in managing patients with suspected or proven chronic pancreatitis remains controversial. The overriding concern appears to be that widespread application of EUS will result in overdiagnosis of chronic pancreatitis in the general population. Clearly, further work is required to clarify the clinical implications of minor pancreatic changes seen by EUS. However, this does not mean that EUS is of no value or should not be used at all for this indication. There are now several studies documenting good agreement between EUS and other diagnostic modalities that are accepted reference standards for the diagnosis of chronic pancreatitis, particularly endoscopic retrograde pancreatography (ERP). ERP may provide more information than less sensitive tests such as transcutaneous US and CT and may be a safe alternative to ERP and a more practical alternative to functional assays, which require duodenal intubation. However, there are practical issues that may affect its clinical applicability. Before using EUS for this indication, one should be aware of its limitations as well as the remaining unanswered questions regarding the clinical implications of EUS findings. EUS EVALUATION OF THE PANCREAS Diagnostic pancreatic EUS (without EUS-guided fine-needle aspiration) is as safe as conventional gastroscopy.1 However, sedationless EUS would probably be difficult for most patients because of longer procedure times, slightly larger endoscope diameter, and the greater discomfort that may be associated with certain maneuvers (e.g., pushing into the duodenal apex to image the bile ducts).2 In virtually all patients with normal upper GI anatomy (i.e., no history of gastric and/or duodenal surgery such as Billroth II anastomosis), the entire pancreas may be visualized (uncinate process to tail). Current affiliation: Centre Hospitalier de l’Université de Montréal, Hôpital Saint Luc, Montréal, Québec Canada. Funded by a grant from Le Fond de Recherche en Santé du Québec. Reprint requests: Anand V. Sahai, MD, MSc (Epid), FRCPC, Département de Gastroentérologie, CHUM, Hôpital Saint Luc, 1058 Rue Saint Denis, Montréal, Québec, Canada. Copyright © 2002 by the American Society for Gastrointestinal Endoscopy 0016-5107/2002/$35.00 + 0 37/0/127701 doi:10.1067/mge.2002.127701 S76
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Figure 1. The normal pancreas is homogeneous and slightly hyperechoic. The main pancreatic duct is seen as a thin anechoic line.
The uncinate process, ampulla, distal bile duct, and distal pancreatic ducts (Wirsung and Santorini’s ducts) are seen best from the second duodenum, but can also be seen from the duodenal bulb, along with the rest of the pancreatic head and more proximal bile duct. From both these positions, a distinction may be noted between the ventral (more hypoechoic) and dorsal pancreas.3 Pancreas divisum may be suspected if the main pancreatic duct emerging from the papilla of Vater does not appear to traverse from the ventral to the dorsal pancreas or is imperceptible.4 The diagnosis is also supported if there is evidence of a dominant Santorini’s duct and no apparent communication with the ventral duct. On the contrary, pancreas divisum can probably be safely excluded if the main pancreatic duct can be clearly seen traversing from the ventral to the dorsal pancreas and/or can be traced from the major papilla well back and around the genu of the pancreas (unpublished observations). The genu, body, and tail of the pancreas are imaged from the stomach. Care should be taken to ensure complete visualization of the pancreatic parenchyma (particularly of the tail) by ensuring that the main pancreatic duct is followed as far as possible from the genu to the tail. Because retroperitoneal structures may also be confused with pancreatic tissue, it is also important to ensure that the appropriate landmarks (e.g., splenic vein and artery, portal confluence, left kidney, splenic hilum) are seen before concluding that the pancreatic body and tail have been visualized in their entirety. Normal versus abnormal Normally, the pancreatic parenchyma is homogeneous and slightly hyperechoic (Fig. 1). The main VOLUME 56, NO. 4 (SUPPL), 2002
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Figure 2. The normal pancreas often shows a clear distinction (arrows) between the hypoechoic ventral and more hyperechoic dorsal pancreas.
pancreatic duct is seen as a thin anechoic smooth linear structure coursing centrally through the parenchyma. There is also usually a clearly detectable difference in the echo density of the ventral and dorsal pancreas (Fig. 2). This type of appearance is seen typically (75% of the time5) in younger patients undergoing EUS for unrelated indications (i.e., no clinical suspicion of pancreatic disease) and with no history of alcohol consumption. However, in similar older patients, the “classic” normal appearance may be less frequent, despite the absence of suspected or proven pancreatic pathology or alcohol consumption. Age-related changes can be extremely variable. The gland may appear somewhat more inhomogeneous and atrophic, and the main pancreatic duct may be slightly dilated (but generally smooth and not irregular and hyperechoic) (Fig. 3). However, in at least one study, age and body mass index were not independent predictors of pancreatic disease by EUS.6 In more obese patients, the parenchyma may appear more hyperechoic than normal (presumably because of fatty infiltration). Given the potentially wide variation in the EUS appearance of the “normal” pancreas, it is not surprising that distinguishing normal from abnormal may be challenging. However, several authors have addressed this issue objectively and proposed EUS criteria for pancreatic disease. THE EUS CRITERIA FOR PANCREATIC DISEASE It is clear that the US appearance of the normal pancreas (as assessed by either transcutaneous abdominal or endoscopic US) differs from that of a gland with severe calcific chronic pancreatitis (with stones, cysts, ductal dilation, and ductal irregularity). It is logical to assume that the evolution of the US appearance from normal to severely abnormal is gradual and progressive. Studies comparing EUS VOLUME 56, NO. 4 (SUPPL), 2002
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Figure 3. Age-related changes may include dilation of the main pancreatic duct, but the duct walls are smooth and the parenchyma shows no clear evidence of parenchymal criteria for chronic pancreatitis.
with other reference standards for pancreatic disease are based on the hypothesis that EUS can detect these progressive changes and that increases in EUS abnormalities should be proportional to increases in abnormalities (structural and/or functional) seen with other tests. Because EUS provides higher resolution imaging than previously used imaging methods and provides information on both the ducts and parenchyma, it is also logical to assume that it may detect abnormalities not described previously with tests used traditionally to study pancreatic morphology such as transcutaneous US, CT, and ERP. Functional testing is said to become abnormal only after greater than 60% to 70%7 of pancreatic functional reserve is depleted. If this is the case, it may also be reasonable to expect that EUS could detect subtle structural changes that predate functional abnormalities and that mild EUS changes might not correlate with functional abnormalities, whereas severe EUS changes would. Finally, it is clear that even severe chronic pancreatitis (e.g., Cambridge class 4) can be asymptomatic. Therefore, it should not be surprising that EUS may show pancreatic abnormalities in asymptomatic individuals. It has been shown that alcohol consumption is often associated with asymptomatic abnormalities.8,9 A number of EUS criteria for pancreatic disease have been described. Clearly, EUS can demonstrate stones, cysts, and ductal dilation, which can be seen by other methods as well. However, just as EUS can find “CT negative masses,” it may detect smaller stones and cysts and subtler ductal dilation in what might be called CT and/or ERP negative pancreatitis. Lees et al.10,11 first described endosonographic findings in patients with clinical and radiologic evidence of chronic pancreatitis and characterized endosonographic criteria that distinguish normal GASTROINTESTINAL ENDOSCOPY
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Figure 4. The parenchyma is hypoechoic. There are coarse hyperechoic strands that eventually delineate lobules. The main pancreatic duct is of normal caliber, but the duct margins are hyperechoic and irregular.
Figure 5. The parenchyma is hypoechoic and there are scattered hyperechoic foci. The main pancreatic duct is slightly dilated and the duct margins are hyperechoic and irregular.
from abnormal. Wiersema et al.12 refined their definitions and found they occurred frequently in patients with abnormal endoscopic pancreatograms and were absent in healthy volunteers. The criteria for pancreatic disease have been studied primarily at a US frequency of 7.5 MHz. Criteria that are specific to EUS can be divided into two groups: parenchymal and ductal (Figs. 4, 5, and 6) Parenchymal criteria include reduced echogenicity, inhomogeneity, loss of the ventral/dorsal distinction,3 atrophy, hyperechoic foci, hyperechoic strands, and lobularity. They should be sought in the dorsal gland only because the hypoechoic ventral pancreas can show criteria such as hyperechoic foci and strands even in normal individuals. Reduced echogenicity and inhomogeneity are presumably caused by edema and/or reduced fat content. The presence of these changes in the dorsal gland would explain the loss of ventral/dorsal distinction. Hyperechoic foci and strands correspond respectively to small (1-2 mm) hyperechoic dots and thin, hyperechoic lines scatS78
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Figure 6. The parenchyma is atrophic and lobular. However, despite these signs of advanced disease, no hyperechoic foci are visible. The main duct is dilated, hyperechoic, and irregular.
tered in the parenchyma. When there are sufficient strands, they separate the parenchyma into distinct “lobules” that may give the gland a honeycomb appearance. There are sparse data on the histologic correlates of these features, but they suggest that they may represent thickened fibrous deposits or may simply reflect increased visibility of normal connective tissue because of surrounding edema.13-16 One study also found a correlation with the presence of inflammatory cells (i.e., histologic pancreatitis).14 Whatever these changes represent histologically, it is clear that, compared with controls, they are seen more often in patients with clinical pancreatitis (acute or chronic) and in individuals (both symptomatic and asymptomatic) who consume alcohol, which is a proven cause of acute and chronic pancreatitis.6,8,9,12 They are also seen frequently when the pancreatic duct is obstructed by tumors. It is therefore highly likely that these changes reflect some form of pancreatic pathology and are not simply meaningless, nonspecific findings. Ductal criteria specific to EUS include obvious to more subtle ductal dilation (≥3 mm in the head, ≥2 mm in the body, ≥1 mm in the tail), hyperechoic main duct margins, irregular main duct margins, and visible side branches. Normally, the duct walls are invisible; if they become visible, they may be considered hyperechoic. It is unclear whether increased duct wall echogenicity is due to reduced echogenicity of the surrounding parenchyma (e.g., due to edema), to structural changes in the duct wall itself, or to some combination of the two. Presumably, ductal irregularity corresponds to the same irregularity seen by ERP, and visible side branches (seen budding from the main duct) correspond to dilated secondary branches of the main pancreatic duct. Several studies show that the increasing EUS abnormalities correlate with the severity of pancreVOLUME 56, NO. 4 (SUPPL), 2002
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atographic changes6,17-23 and with reductions in secretin-stimulated duodenal bicarbonate.23 A quantitative analysis with 9 possible criteria (hyperechoic foci, hyperechoic strands, lobularity, ductal dilation, ductal irregularity, hyperechoic duct margins, visible side branches, calcifications, and cysts)6 suggests that, in a population at low to moderate risk of chronic pancreatitis (e.g., pretest probability <50%), EUS is most reliable only when it is either clearly normal (≤2 criteria) or clearly abnormal (≥5 criteria). In other words, when EUS is very abnormal, ERP and/or functional tests tend to be abnormal and when EUS is normal or almost normal, other tests tend to be normal. Similarly, when ERP is abnormal, EUS is usually abnormal. Some of the controversy regarding the accuracy of EUS may be due to studies that use 3 or 4 criteria (i.e., mild abnormalities) as threshold values to distinguish normal from abnormal EUS. When EUS is only mildly abnormal, ERP and functional tests are often normal. Whether minimal EUS changes reflect early chronic pancreatic disease is unclear. They do not appear to distinguish patients with and without abdominal pain and/or suspected pancreatic disease8 and may24 or may not20 progress to clinical chronic pancreatitis. By using receiver operating curve (ROC) analysis, a threshold of 3 to 4 criteria often offers the best compromise between sensitivity and specificity (approximately 70% for each), but the more clinically useful predictive values associated with these thresholds (i.e., that answer the question, “What is the chance the patient does or does not have the disease if the test is positive or negative?”) are clearly inadequate (<70%). The positive predictive value is particularly low in populations with a low pretest probability for disease and the negative predictive value is low in populations with a high pretest probability for disease. When the threshold for “normal” is set at ≤2 criteria and the threshold for “abnormal” is set at ≥5 criteria, the predictive values are substantially higher (>85%).6 It should also be noted that, when the threshold number of criteria is set sufficiently high (≥5 criteria), the prevalence of EUS chronic pancreatitis in the general population of patients undergoing EUS for nonpancreatic indications is relatively low (<10%-15%), especially in patients who do not consume alcohol (unpublished observations). PRACTICAL ISSUES AND LIMITATIONS RELATING TO THE USE OF EUS CRITERIA FOR PANCREATIC DISEASE Interpreting pancreatic EUS is therefore easier when the gland is clearly normal or is clearly abnormal. However, in some patients, even experienced endosonographers have difficulty agreeing whether VOLUME 56, NO. 4 (SUPPL), 2002
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disease is present or the results may be equivocal (e.g., 3 or 4 criteria). The endosonographic appearance of the pancreas simply does not have a textbook appearance in many patients. This may be due to variations in patient echogenicity, EUS equipment issues, interobserver variation, operator experience, and the inherent limitations in the EUS criteria themselves (including the distinction between acute and chronic changes). In some patients, it is simply difficult to obtain clear images of the pancreas. The image quality produced by echoendoscopes may also differ. In mechanical radial scanners, one particularly frequent and unrecognized problem may be inadequate maintenance, leading to the presence of air bubbles in the oil contained in the plastic cap used to house the transducer. These air bubbles disperse as the transducer rotates and the result is a low gain grainy image. Air bubbles in the oil must be removed and the oil should also be changed periodically. Curved linear array echoendoscopes are exempt from this problem, but all the published data on EUS and chronic pancreatitis have been obtained with mechanical radial scanning instruments. One study showed moderate ( = 0.56) agreement between mechanical and fixed array instruments,25 but further data are probably required before both types of instruments can be used interchangeably for this indication. It is well known that significant interobserver variation may occur with all types of diagnostic imaging. This may be an issue for EUS and chronic pancreatic disease, but at least one study suggests that it is not greater than with other tests ( = 0.410.46) and that agreement is greatest for more experienced endosonographers.26 Because some of the EUS criteria may be subtle, it is also logical to expect that inexperienced endosonographers or those without appropriate training may produce less reliable and reproducible results. More objective methods of evaluating pancreatic echo architecture (e.g., computer analysis of pancreatic echogenicity) and EUS-guided pancreatic biopsy may overcome the problems of interobserver variability, but these remain experimental at this time. Potential limitations of the EUS criteria themselves should be noted. As stated earlier, with experience, it is generally easy to decide whether the endosonographic appearance of the pancreas in a given patient is normal or abnormal. But in some cases it may be difficult to conclude on the presence of certain criteria, which may be another cause of equivocal results. The only individual criterion that is strongly predictive of chronic pancreatitis is calcification.6 However, because it is the overall appearGASTROINTESTINAL ENDOSCOPY
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ance of the gland that appears to be most predictive of chronic pancreatic disease (i.e., the total number of criteria),6 this is not a problem in itself. But in some cases of fairly advanced disease, the severity of disease may actually make it difficult to appreciate some of the subtler criteria and therefore reduce the total number of observed criteria. For example, in patients with an extremely lobular pancreas, the honeycombed appearance may be so pronounced that distinct hyperechoic foci cannot be appreciated (Fig. 6). In these cases, the pancreatic duct (if not dilated) may also be so difficult to find that subtle ductal abnormalities such as visible side branches may be hidden. Therefore, in these patients, who clearly have advanced pancreatic abnormalities, the total number of criteria may actually be limited to 2 or 3 (e.g. lobulation, hyperechoic ducts, irregular ducts). Similarly, if there is significant atrophy, there may be insufficient parenchyma to appreciate hyperechoic foci, hyperechoic strands, and lobulation. It is also unclear if the criteria can distinguish acute from chronic pancreatitis reliably. Acute edema may produce a lobular appearance. Most studies have tried to exclude patients who have had a documented recent attack of acute pancreatitis. But it is unclear how long the effects of an acute attack continue to affect the endosonographic appearance of the pancreas. Obviously, this issue may come into play when using EUS to diagnose or exclude chronic pancreatitis in patients with acute or recurrent pancreatitis. To reduce this problem, it is probably best to perform EUS as long as possible (several weeks or months) after an acute attack; but further work is required to determine how long endosonographic signs of acute pancreatitis persist. Finally, it is unclear whether the criteria should be interpreted with access to clinical information (especially the patient’s level of alcohol consumption). The impact of clinical information on EUS interpretation has not been assessed formally for this indication, but personal experience suggests that it may be substantial in some cases. Therefore, it is probably best to study the pancreas without access to clinical information (or with as little clinical information as possible), and then to attribute a clinical significance to EUS findings by incorporating clinical variables. SUMMARY AND POTENTIAL CLINICAL UTILITY EUS provides a safe and relatively noninvasive method of obtaining detailed structural information on the pancreatic parenchyma and ducts and related structures (e.g., upper GI mucosa, gall bladder, bile ducts, ampulla). The published data support the ability of EUS to distinguish between patients with S80
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and without pancreatic disease. The EUS criteria for pancreatic disease are a useful tool to quantify pancreatic abnormalities, but they have limitations. EUS abnormalities may be similar in both acute and chronic pancreatitis, but changes found in patients with no clinical evidence of acute pancreatitis are likely to reflect structural alterations of the pancreatic parenchyma and ducts that are found in patients with histologic and/or functional proof of chronic pancreatitis (i.e., true chronic pancreatitis). However, these changes (even when severe) may be asymptomatic and are seen frequently in patients who consume alcohol on a regular basis. EUS is most reliable when the examination is either clearly normal or abnormal. When there is little or no evidence of pancreatic disease by EUS, ERP and functional assays will likely be normal and are therefore unwarranted unless the clinical suspicion of pancreatic disease is very high. In these patients, clinically significant pancreatic disease can most often be excluded. When the examination is clearly abnormal (i.e., ≥5-6 criteria), and there is no evidence of recent acute pancreatitis, there is a strong possibility that the patient has some form of chronic pancreatic disease (this degree of abnormality is extremely unlikely in normal controls who do not consume alcohol). ERP and functional assays have been shown by some groups to also be abnormal in these patients or to become abnormal with time. Therefore, further testing in these patients (at least for diagnostic purposes) may also be unwarranted if the clinical context is compatible with chronic pancreatitis. It should be emphasized that, like all diagnostic imaging, EUS is not infallible and should not replace thoughtful, complete clinical evaluation of the patient. Further work is also required to determine whether EUS findings have any bearing on prognosis or response to therapeutic interventions. In patients in whom the pancreas is not clearly normal or abnormal, the clinical significance of EUS findings is extremely unclear. They do not correlate well with pancreatographic or functional abnormalities, may not progress, and do not distinguish reliably between patients with and without symptoms. At this time, a diagnosis of pancreatic disease should not be made in these patients based on this information alone. Well before establishing their clinical utility, further work is required to determine whether these changes reflect true pancreatic disease or are simply normal variants. CONCLUSIONS Whether we like it or not, EUS will likely be used more and more frequently to diagnose or exclude occult chronic pancreatitis. Given the inherent risks VOLUME 56, NO. 4 (SUPPL), 2002
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and limitations of ERP, the inconvenience of functional testing, the relative safety of EUS, and the range of information it provides, this should not be surprising. EUS has faced (and will likely continue to face) its share of normal and healthy scientific skepticism with regard to its value for this indication. However, the accumulated data suggest that this diagnostic modality can no longer be ignored as a method to look for mild chronic pancreatitis when less sensitive tests such as CT and abdominal US are negative. However, physicians will probably wonder less if, and more how EUS could be useful to them in daily practice only if further work manages to demonstrate that it is actually worth looking for the disease in the first place. REFERENCES 1. Lightdale CJ. Indications, contraindications, and complications of endoscopic ultrasonography. Gastrointest Endosc 1996;43:S15-9. 2. Röesch T, Dennig V. A prospective assessment of complications and patient acceptance of upper GI endoscopic ultrasonography—a multicenter study in 2500 patients [abstract]. Gastrointest Endosc 2000;51:AB177. 3. Savides TJ, Gress FG, Zaidi SA, Ikenberry SO, Hawes RH. Detection of embryological ventral pancreatic parenchyma with endoscopic ultrasound. Gastrointest Endosc 1996;43:14-9. 4. Bhutani MS, Hoffman BJ, Hawes RH. Diagnosis of pancreas divisum by endoscopic ultrasonography. Endoscopy 1999;167-9. 5. Savides TJ, Gress FG, Zaidi SA, Ikenberry SO, Hawes RH. Detection of embryologic ventral pancreatic parenchyma with endoscopic ultrasound. Gastrointest Endosc 1996;43:14-9. 6. Sahai AV, Zimmerman M, Aabakken L, Tarnasky PR, Cunningham JT, van Velse A, et al. Prospective assessment of the ability of endoscopic ultrasound to diagnose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography. Gastrointest Endosc 1998;48:18-25. 7. Toskes PP. Diagnosis of chronic pancreatitis and exocrine insufficiency. Hosp Prac 1985;20:97-100. 8. Sahai AV, Mishra G, Penman I, Williams D, Wallace MB, Hadzijahic N, et al. EUS to detect evidence of pancreatic disease in patients with persistent or nonspecific dyspepsia. Gastrointest Endosc 2000;52:153-9. 9. Bhutani MS. Endoscopic ultrasonography: changes of chronic pancreatitis in asymptomatic and symptomatic alcoholic patients. J Ultrasound Med 1999;18;455-62. 10. Lees WR. Endoscopic ultrasonography of chronic pancreatitis and pancreatic pseudocysts. Scand J Gastroenterol 1986;123: 123-9. 11. Lees WR, Vallon AG, Denyer ME, Vahl SP, Cotton PB. Prospective study of ultrasonography in chronic pancreatic disease. BMJ 1979;1:162-4.
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12. Wiersema MJ, Hawes RH, Lehman GA, Kochman ML, Sherman S, Kopecky KK. Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin. Endoscopy 1993;25:555-64. 13. Morita Y, Takiguchi M, Yasuda J, Kitamura T, Syakalima M, Hashimoto. Endoscopic and transcutaneous ultrasonographic findings and grey-scale histogram analysis in dogs with caerulein-induced pancreatitis. Veterin Q 1998;20:89-92. 14. Morita Y, Takiguchi M, Yasuda J, Eom K, Hashimoto A. Endoscopic ultrasonographic findings of the pancreas after pancreatic duct ligation in the dog. Vet Radiol Ultrasound 1998;557-62. 15. Lees WR. Endoscopic ultrasonography of chronic pancreatitis and pancreatic pseudocysts. Scand J Gastroenterol Suppl 1986;123:123-9. 16. Zimmerman MJ, Mishra G, Lewin D, Hawes RH, Coyle W, Adams DA, et al. Comparison of EUS findings with histopathology in chronic pancreatitis [abstract]. Gastrointest Endosc 1997;45:AB185. 17. Buscail L, Escourrou J, Moreau J, Delvaux M, Louvel D, Lapeyre F, et al. Endoscopic ultrasonography in chronic pancreatitis: a comparative prospective study with conventional ultrasonography, computed tomography, and ERCP. Pancreas 1995;10:251-7. 18. Dancygier H. Endoscopic ultrasonography in chronic pancreatitis. Gastrointest Endosc Clin N Am 1995;5:795-804. 19. Deviere J, Finet L, Dunham F, Cremer M. Endoscopic ultrasonography in chronic pancreatitis. Endoscopy 1994;26:808-9. 20. Hastier P, Buckley MJ, Francois E, Peten EP, Dumas R, Caroli-Basc FX, et al. A prospective study of pancreatic disease in patients with alcoholic cirrhosis: comparative diagnostic value of ERCP and EUS and long-term significance of isolated parenchymal abnormalities. Gastrointest Endosc 1999;49:705-9. 21. Natterman C, Goldschmidt AJW, Dancygier H. Endosonography in chronic pancreatitis: a comparison between endoscopic retrograde pancreatography and endoscopic ultrasonography. Endoscopy 1993;25:565-70. 22. Zuccaro G, Sivak MV Jr. Endoscopic ultrasonography in the diagnosis of chronic pancreatitis. Endoscopy 1992;24:347-9. 23. Catalano MF, Lahoti S, Geenen JE, Hogan WJ. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc 1998;48:11-7. 24. Kahl S, Glassbrenner B, Leodolter A, Pross M, Schulz H-U, Malfertheiner P. EUS in the diagnosis of early chronic pancreatitis: a prospective follow-up study. Gastrointest Endosc 2002;55:507-11. 25. Lai R, Wiersema MJ, Sahai AV, Chak A, Chang KJ, Kochman ML, et al. Blinded comparison of linear and radial endoscopic ultrasound (EUS) for the evaluation of chronic pancreatitis [abstract]. Gastrointest Endosc 2001;53:AB170. 26. Wallace MB, Hawes RH, Durkalski V, Chak A, Mallery S, Catalano MF, et al. The reliability of EUS for the diagnosis of chronic pancreatitis: interobserver agreement among experienced endosonographers. Gastrointest Endosc 2001;53:294-9.
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