A Study of Chronic Pancreatitis by Serial Endoscopic Pancreatography

GASTROENTEROLOGY 1981;81:884-91 A Study of Chronic Pancreatitis by Serial Endoscopic Pancreatography ATSUO NAGATA, TATSUJI HOMMA, KOZO TAMAI, KAZUYA UENO, KATSUHIDE SHIMAKURA, HISAO OGUCHI, SEIICHI FURUTA, and MASAYUKI ODA The Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan The pancreatic duct system was studied with repeated endoscopic retrograde pancreatography in 31 patients with chronic pancreatitis, 32 patients with suspected chronic pancreatitis, and 16 controls without pancreatic disease. In chronic alcoholic pancreatitis the pancreatograms showed marked changes during the initial examination with progression even after abstinence or reduction of drinking. In the alcoholics with suspected chronic pancreatitis, progressive lesions in branch ducts with almost intact main ducts were recognized. In contrast, no remarkable alterations on serial pancreatograms were observed in nonalcoholic cases with definite or suspected chronic pancreatitis. These results suggest that pancreatic duct lesions play an important role in the development and progression of chronic alcoholic pancreatitis in contrast to chronic nonalcoholic pancreatitis. The human, pancreas is not accessible to serial biopsy, and characteristic lesions similar to human chronic pancreatitis have not been reproduced in animals. Therefore, it is difficult to clarify the sequence of chronic pancreatitis from the initial morphologic lesions to the late stages. Endoscopic retrograde pancreatography (ERP) has recently become an important means for diagnosing chronic pancreatitis by demonstrating the radiologic morphology of the pancreatic duct (1-7). The pancreatograms in chronic pancreatitis have been correlated with histologic changes and the severity of the disease (1,2,8). In this paper we attempt to elucidate the evolution Received January 14, 1981. Accepted June 8, 1981. Address requests for reprints to: Atsuo Nagata, M.D., The Second Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahimachi, Matsumoto 390, Japan. This work was supported in part by a grant for "Chronic Pancreatitis" from the Japanese Ministry of Health and Welfare. 1981 by the American Gastroenterological Association 0016-5085/81/110884-08$02.50 of chronic pancreatitis in the pancreatic duct system from early to late stages by examining serial pancreatograms from cases with definite or suspected chronic pancreatitis and from cases of nonpancreatic disease. Patients and Methods From December 1970 to April 1979 a total of 1684 patients with suspected pancreatic or hepatobiliary disease successfully underwent endoscopic retrograde cholangiopancreatography (ERCP) at the Shinshu University Hospital and affiliated hospitals. Seventy-one patients-34 with definite and 37 with suspected chronic pancreatitiswere examined prospectively by ERP more than two times at intervals of 1 yr or more. Patients gave informed consent. As the controls, 22 patients with nonpancreatic disease who had undergone serial pancreatography with the above intervals were selected retrospectively. Patients with carcinoma of the pancreas were excluded in this study. Of these 93 patients, 14 were excluded because of unsatisfactory serial visualization of duct system or because of alcoholism, plus other etiologic factors. The remaining 79 patients were divided into three groups (Table 1). The first group was composed of 16 nonalcoholic control patients with hepatobiliary disease without clinical signs of pancreatitis. The second group was composed of 31 patients, 15 with chronic alcoholic pancreatitis (CAP) and 16 with chronic nonalcoholic pancreatitis (CNAP). The diagnosis of chronic pancreatitis was confirmed by fulfilling at least one of the following criteria; (a) histologic confirmation at laparotomy, (b) radiologic calcification of the pancreas or (c) significant impairment of exocrine pancreatic function as shown by pancreozymin-secretin test (PST) with associated symptoms. The main clinical symptoms and diagnostic criteria of individual patients in this group were summarized in Table 2. The third group was composed of 32 patients in whom chronic pancreatitis was suggested by presenting symptoms (pain, steatorrhea, diabetes, pancreatic mass) and ab-

November 1981 SERIAL ERP IN CHRONIC PANCREATITIS 885 Table 1. Profiles of the Patients in the Study No. of cases Age Group Etiology Male Female Years Average Controls Nonpancreatic disease 16 8 25-74 53.3 Cholelithiasis 3 Cholecystitis 2 Congenital cystic dilatation of the CBDo 1 Carcinoma of the CBD 1 Chronic hepatitis 2 Liver cirrhosis 3 Chronic intraphepatic cholestasis 3 Thorotrast liver 1 Chronic pancreatitis Alcoholic 15 1 28-68 49.1 Nonalcoholic 16 14 19-78 50.9 Biliary 2 Idiopathic 14 Suspected chronic pancreatitis Alcoholic 5 0 37-57 47.4 Nonalcoholic 27 11 25-66 50.8 Biliary 6 Idiopathic 15 Others 6 o Common bile duct. normal amylase levels in serum and urine, but whose symptoms failed to fulfill the criteria for definite diagnosis of chronic pancreatitis as indicated before. There were several causes of confirmed and suspected chronic pancreatitis including alcoholism, and biliary, idiopathic, and other factors (peptic ulcer, periampullary diverticulum, and hepatic disease). Alcoholism was the assumed cause if the daily alcohol consumption was over 80 g of ethanol for more than 7 yr. A detailed questionnaire about alcohol intake and changing aspects of drinking habits was given to both patients and their families. All cases were diagnosed at the initial ERP. Endoscopic retrograde pancreatography was conducted with fiberduodenoscope type JF B, JF B 2, or JF B 3 (Olympus Corporation of Japan. Chiyoda, Tokyo. Japan. Pancreatograms were taken routinely with patients in the prone position and, when necessary, in the right and left oblique positions. The main duct and its branches in the initial and subsequent ERP were compared with regard to the following findings: (a) main pancreatic duct: dilatation and/or stenosis, irregular wall, obstruction, cystic formation, intraductal calculi. and shortened length of main duct; (b) branch duct: rigidity, stenosis and/or dilatation. and simple or cystic dilatation. The degree of abnormality on pathologic ERP findings was graded as slight, moderate, and marked. The moderate and marked gradings were in accordance with Kasugai's criteria for ERCP diagnosis of moderate and advanced chronic pancreatitis (2). The slight category included mild rigidity, tortuosity, irregular wall of the main du ct and simple dilatation of the main duct with ordinary branches. and changes resembling Kasugai's minimal pancreatitis. Results Control Patients The follow-up period in this group varied from 1.0 to 4.4 yr with a mean of 2.3 yr. The majority of patients had normal ERP findings, except for 3 who showed slight changes (simple dilatation of the main duct in 2 patients, mild irregular wall of the main duct at the tail of the pancreas in 1 patient) during the initial examination. Fourteen of 16 patients had unaltered duct system on serial ERPs. In 2 patients a simple dilatation of the main duct developed in the course of the disease. One patient with chronic hepatitis had a normal cholangiopancreatogram on the first examination. Four years and 3 mo later the second ERCP revealed a simple dilatation of the main pancreatic duct with stones in the common bile duct. In the other patient the initial ERP showed a normal pancreatic duct with gallbladder stones, but a simple dilatation of the main duct associated with carcinoma at the distal portion of the common bile duct was observed on the second ERP after 2.7 yr. Chronic Alcoholic Pancreatitis Schematic illustrations of serial ERPs of 15 patients with CAP are shown in Figure 1. The follow-up period in this group varied from 1.6 to 5.3 yr with a mean of 2.4 yr.

886 NAGATA ET AL. GASTROENTEROLOGY Vol. 81, No.5 Table 2. The Main Clinical Features and Diagnostic Bases of Individual Patients with Chronic Alcoholic or Nonalcoholic Pancreatitis Clinical features Patient No. Pain Diabetes Histology Alcoholic pancreatitis 1 2 NT 3 4 NT 5 NT 6 NT 7 8 NT 9 NT 10 NT 11 NT NT 12 13 NT 14 NT 15 NT Diagnostic bases Calcification PST Nonalcoholic Pancreatitis 16 NT 17 NT 18 NT 19 NT 20 NT NT 21 NT 22 NT 23 NT 24 25 NT 26 NT NT 27 NT NT 28 NT 29 NT 30 31 NT Pain: severe, moderate, dull, - painless. Diabetes: overt, glucose intolerance by oral glucose tolerance test, - normal glucose tolerance. Histology: histological confirmation. Calcification: radiological calcification, - negative. PST pancreozymin-secretin test: three factors decreased (volume, maximum bicarbonate concentration, amylase output), two factors decreased, one factor decreased. NT: not tested. NT Eleven of the 12 patients showing marked change (5 of them with calcification) and 1 of the 2 patients showing moderate change on the initial ERPs exhibited a variety of abnormalities either in the main pancreatic duct or in its branches that further progressed during the course of the disease. Of these 12 cases, 11 had progressive changes in the main duct, including side branches in many cases, and the remaining one (case 7) had changes only in its branches. Three patients (cases 2,14, and 15) remained unchanged. Details of new or intensified changes in the main pancreatic duct were as follows: dilatation or stenosis separately or concurrently in 7 patients (cases 3-5,9,11-13); obstruction in 1 patient (case 6); irregular wall in 5 patients (cases 1,8,10,11, and 13); cystic formation in 1 patient (case 12); intraductal calculi in 2 patients (cases 5 and 13); and shortening of the length of the main duct in 2 patients (cases 4 and 8). Segmental abnormalities of the main duct at the body and tail of the pancreas were extended to the head of the pancreas in 3 patients (cases 5,11, and 13). In 5 patients with stenosis in the head of the pancreas accompanying dilatation in its distal portion, such lesions as narrowed wall, obstruction, stenosis, and dilatation developed in the portion where dilatation had existed on the initial ERPs (cases 4,6,8-10). As regards the pancreatographic changes in ductal branches, dilatation in 3 patients (cases 4,6, and 7), stenosis and dilatation in 2 patients (cases 7 and 8), and cystic dilatation in 5 patients (cases 4,7,8,12, and probably 5) developed on subsequent ERPs. Besides these pancreatic duct changes, new or ex-

November 1981 SERIAL ERP IN CHRONIC PANCREATITIS 887 Case No name age. se)( Schema of serial ERCP findings I T.T 47 M 2 3 4 HN 44 M. EY 58 M. MK 29 F. : y. :: Y ", 18.. 5 K.K. 68 M. 6 7 8 9 10 I 1 K.M. 55. M. MY 45 M. HT 40. M. K.T 53. M. BY 53. M. KS. 61 M. Ix (".- 'J.Ji: J s J "' (pa... 2.0 -------c>-... 2.5 2.0,... Figure 1. Schema of serial ERCP findings in cases with chronic alcoholic pancreatitis. Drinking habits: "abstinence, ""reduced, """continued. # Calcification of the pancreas. 12 13 14 S.K 49 M. M.M. 47. M. KA 41 M. r l.,/,jl: 14, = 0.8 V 2.5 15 T.T. 46. M. acerbated stenosis of the distal portion in the common bile duct was found in 5 patients (cases 1,4,5,8, and 13) during the course of the disease. Representative serial pancreatograms illustrating progressive ductal alterations are shown in Figure 2. Unexpectedly, ERP pictures in 3 of 4 patients who abstained from alcohol and 7 of 8 patients who reduced their drinking revealed progressive ductal changes. Two patients underwent surgery during their observation period: One with transgastric cystogastrostomy (case 12) showed progressive changes in the main duct, although stenosis at the body due to compression by a large cyst was managed through an operation. In the other patient, with pancreaticojejunostomy (case 7), the main duct remained unchanged, but the patient's branch lesions were progressive. Chronic Nonalcoholic Pancreatitis The serial ERPs of the 16 patients with chronic nonalcoholic pancreatitis (CNAP) are schematically illustrated in Figure 3. As to causes, biliary tract disease existed in 2 patients (case 24 and 30) and noncontributory idiopathic disease existed in the remaining 14 patients. Follow-up period of this group was from 1.6 to 6.8 yr with a mean of 3.6 yr. On the initial ERP the majority of patients in this group showed normal or slight changes (cases 20 31), except for 4 patients (3 with calcification of the pancreas) who presented with marked changes. Progressive alterations on serial pancreatograms were found only in the main duct of 3 patients (cases 17, 29, and 30). Two of these patients showed only slight changes such as tortuosity and rigidity of the main

888 NAGATA ET AL. GASTROENTEROLOGY Vol. 81, No.5 Figure 2. Serial pancreatograms in a case with chronic alcoholic pancreatitis (case 9). A. The initial pancreatogram. Irregular stenosis in the main duct at the head of the pancreas is seen and irregular dilatation of the main duct and its side branches distal to this region are noted. B. ERP pictures after 2 yr. Stenosis in the head spread widely and irregular stenosis developed in the dilated main duct at the body of the pancreas. The changes of branch ducts are progressive. duct (case 29) and irregular wall at the tail of the pancreas (case 30). The remaining 1 patient with calcified pancreatitis presented increased stenosis of the main duct at the head of the pancreas (case 17). By and large, no progressive changes in ductal branches were found in patients of this group. Suspected Chronic Pancreatitis Seven of the 32 patients in this group revealed progressive changes on serial ERPs during the course of the disease. Schema of pancreatographic changes in these 7 cases are shown in Figure 4. Progressive ductal alterations were found in 5 alcoholic patients during an average observation period of 4.7 yr (3.0-5.8 yr). Four of 5 patients (cases 32-35) demonstrated progressive changes of ductal branches including stenosis and simple or cystic dilatation, although their main ducts remained unchanged. The remaining 1 patient exhibited progressive changes of the main duct as well as of its branches. Definite chronic pancreatitis developed in 2 of these 5 alcoholic cases (cases 34 and 36). Five years and 10 mo after the initial ERP, case 34 showed increased cystic dilatation in branches, accompanied by marked impairment in pancreatic exocrine function as shown by PST. Patient 36 who had recurrent attacks of abdominal pain with hyperamylasemia initially exhibited normal findings in the main duct, and normal PST, except for acinar filling and slight dilatation in side branches. Four years and 4 mo after the initial ERP his pancreatogram illustrated remarkably exacerbated stenosis, irregular wall, and large cystic formation in the main duct. Pancreozymin-secretin test at this stage also demonstrated marked impairments. On the other hand, sequential pancreatograms in

November 1981 SERIAL ERP IN CHRONIC PANCREATITIS 889 Case name No age. sex BK" 17 78. M Schema of serial ERCP findings 16 s.o.>- 49 F. lw s -1-.4 <-t 'r 1'f.r4 t' IR... 18 M.Y.--,-..:..' 58 F. 1.6 19 C.O." ----------' 64 F rp 3.4 tr< 20 fr N.A.-- II 46. F. 5.0 U S.N." 21 49 F. 2204 <, C" (, T.H.",q: -..; 22 64. F /' -, T.Y.-- 23 67. F. r6cj"" 24 H.O. - ----------' 25 26 27 49. F. 2.0. 1.6 S.K." 37. F. 5.4 S.F." - 19. F. I.T." d..- 46. F. " /..-. CX." 28-49. F. 32 F.G." 29 42. F r-- <r 1.8-.. I.I- V 30 H.T. - Y --- 53. M. 28 C.K." 31 ----"- - 44. F. 68 Figure 3. Schema of serial ERCP pictures in cases with chronic nonalcoholic pancreatitis. Etiology: "biliary, ""idiopathic. the majority of nonalcoholic patients in this group remained unchanged at the average follow-up period of 3.3 yr (1.0-7.2). Only 2 of 27 patients presented slight progressive changes including irregular wall in the main duct in the course of 3.4 or 6.0 yr, respectively (cases 37 and 38). Discussion The natural history of chronic pancreatitis appears to progress histologically and functionally (9). There have been some follow-up studies on chronic pancreatitis from the viewpoint of exocrine and endocrine pancreatic function. However, studies with respect to the sequential pancreatographic examinations on confirmed or suspected chronic pancreatitis patients have rarely been carried out. We believe the serial pancreatograms shown here reflect the sequential morphologic changes in the pancreas. However, limitations in the evaluation of ERP findings, particularly duct branch changes, can be related to either a filling pressure or a volume/ time effect of the contrast material. We paid attention to these points in evaluating the results. In our control group, serial pancreatograms in 14 of 16 patients (87.5%) remained entirely unchanged while the remaining 2 cases showed only dilatation in the main duct related to obvious biliary disease. Chronic alcoholic pancreatitis appears to be clinically distinct from other forms of chronic pancreatitis (18-14). Remarkable differences not only in the degree of abnormalities but also in the progression of pancreatic abnormality were observed between alcoholic and nonalcoholic patients with either suspected or confirmed chronic pancreatitis. As stated earlier, detailed questionnaires con-

890 NAGATA ET AL. GASTROENTEROLOGY Vol. 81. No.5 Figure 4. Schema of serial ERP findings in cases with suspected chronic pancreatitis which presented progressive ductal changes. "Alcoholic patient. ""nonalcoholic patient. Case name. No. age. sex. Schema of serial ERCP findings 32 A.T. J?4e/ 53. M 33 H.F. 48. M. t3? "e-<" 34 1Is T.Y. 57. M. 35 M.I. L.L r 42. M. (, \!( r- qzd( 36-7lr.. A.F.,--. Jr 1 37. M..... - - - 4.3.. <, rr": j) ( 37 M.K. G7;; 42. M.. 38 S.N. :1(*'< C:(, 59. M. cerning drinking habits were given to patients and their families, despite the common knowledge that an exact assessment of drinking habits is very difficult in patients with alcohol overindulgence. In a large portion of the patients with CAP, pancreatographic alterations were already marked at the initial study and, despite reduction or abstinence of drinking, and even, in some cases, surgical intervention, showed further progression on the subsequent ERP. These results imply that the duct system may be injured by alcohol and that the ducts, once altered, participate in the development of chronic pancreatitis even after the aggravating factors are eliminated. There are some reports to support these possible mechanisms (11,15,16). We assume that the increase of ethanol concentration in pancreatic fluid after alcohol-drinking, which has been confirmed experimentally, may alter the physico-chemical character of pancreatic juice and directly injure pancreatic ductal cells (16). Even with total abstention from alcohol, once the patient has advanced pancreatic disease there is a relentless progression and the lesions become self-perpetuating (17,18). The progression of the main pancreatic duct abnormality in the alcoholic group was interesting. When abnormalities on the initial ERP were limited to the body and tail of the pancreas. with the head of the pancreas almost normal, the head and entire main duct were subsequently involved in 3 patients. More typical progression was seen in 5 patients where a variety of changes (irregularity, obstruction, stenosis, and dilatation) took place in a dilated segment proximal to stenosis in the head of the pancreas. This may, in part, be due to outflow obstruction. Changes in branch ducts were also interesting. In the suspected CAP group, 4 of 5 patients showed progressive changes exclusively in branches without progressive changes of the main duct. This suggests that alterations of branch ducts may evolve initially and then extend to the main duct in CAP. This is in accordance with the results of Kasugai et al, (1,2) who showed by ERP that the main duct appeared normal early in chronic pancreatitis, with only localized areas of variation in caliber and dilatation of the branches, and Salres et a1. (11) who showed histologically that the initial lesion in CAP was probably obstruction of the finer pancreatic ducts with proximal dilatation and normal duct. Dreiling and Bordalo (15) also recognized ductular changes at the initial stage of the disease. Oda (16) reported that the derangement of pancreatic branch ducts could be observed by three-dimensional reconstruction of the pancreatic ducts in alcoholics who had no histologic findings of chronic pancreatitis. In addition to these various findings of serial ERP, shortening length of the pancreatic main duct was also found in some patients with CAP during followup study, seeming to relate shrunken pancreas, due to marked parenchymal destruction, to fibrosis in advanced pancreatitis. In nonalcoholic patients with suspected or proven chronic pancreatitis, initial pancreatographic changes were nearly normal or slight, and not progressive during the course of the disease. These cases may have a different mode of progression with relative sparing of the pancreatic duct system, although a further long-term study is necessary to confirm this hypothesis. The simple dilatation of the duct associated with aging has been pointed out (19). However, it seems

November 1981 SERIAL ERP IN CHRONIC PANCREATITIS 891 to be negligible in our study, as the age distribution and period of observation were matched fairly well in each group. References 1. Kasugai T, Kuno N, Kobayashi S, et al. Endoscopic pancreatocholangiography. II. The pathological endoscopic pancreatocholangiography. Gastroenterology 1972;63:227-34. 2. Kasugai T, Kuno N, Kizu M. Manometric endoscopic retrograde pancreatocholangiography. Technique, significance, and evaluation. Am J Dig Dis 1974;19:489-502. 3. Cotton PB. Cannulation of the papilla of Vater by endoscopy and cholangiopancreatography (ERCP). Gut 1972;13:1014-25. 4. Wiesner W, Weiss HD, Anacker H. Erste Erfahrungen mit der duodenoskopischen retrograden Pankreatographie in der Diagnostik der chronischen Pankreatitis. Dtsch Med Wochenschr 1972;97:991-3. 5. Ogoshi K, Niwa M, Hara Y, et al. Endoscopic pancreatocholangiography in the evaluation of pancreatic and biliary disease. Gastroenterology 1973;64:210-6. 6. Zimmon DS, Falkenstein DB, Abram RM, et al. Endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis of pancreatic inflammatory disease. Radiology 1974;113: 287-97. 7. Rohman CA, Silvis SE, Vennes JA. Evaluation of the endoscopic pancreatogram. Radiology 1974;113:297-304. 8. Howard JM, Nedwich A. Correlation of the histologic observations and operative findings in patients with chronic pancreatitis. Surg Gynecol Obstet 1971;132:387-95. 9. Sarles H. Proposal adopted unanimously by the participants of the symposium on pancreatitis'at Marseilles, 1963. Bibl Gastroenterol 1965;7:7-8. 10. Marks IN, Banks S. The etiology, clinical features and diagnosis of pancreatitis in the South Western Cape. S Afr Med J 1963;37:1039-53. 11. Sarles H, Sarles JC, Camatte R, et al. Observations on 205 confirmed cases of acute pancreatitis, recurring pancreatitis and chronic pancreatitis. Gut 1965;6:545-9. 12. Howard JM, Ehrlich EW. The etiology of pancreatitis. A review of clinical experience. Ann Surg 1960;152:135-46. 13. Hatayama K. A clinical investigation of chronic pancreatitis. Comparative study between alcoholic pancreatitis and nonalcoholic pancreatitis. Gastroenterol Jpn 1978;13:127-39. 14. Homma T, Nagata A, Yoshizawa S, et al. Studies on pancreatic duct system. II. Comparative study of histological features, and three-dimensional reconstructions of pancreatic ducts. Gastroenterol Jpn 1979;14:475-82. 15. Dreiling DA, Bordalo O. Secretory pattern in minimal pancreatic inflammatory pathology. Am J Gastroenterol 1973;60:60 9. 16. Oda M. The onset and natural course of chronic alcoholic pancreatitis. Gastroenterol Jpn 1979;14:628-30. 17. Strum WS, Spiro HM. Chronic pancreatitis. Ann Intern Med 1971;74:264-77. 18. Banks PA. Pathology of chronic pancreatitis. In: Banks PA, ed. Pancreatitis. New York & London: Plenum Medical Book Co., 1979:181-7. 19. Kreel L, Sandin B. Changes in pancreatic morphology associated with aging. Gut 1973;14:962-70.