Involvement of the Biliary System in Autoimmune Pancreatitis: A Follow-up Study

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2003;1: Involvement of the Biliary System in Autoimmune Pancreatitis: A Follow-up Study KENJI HIRANO,* YASUSHI SHIRATORI,* YUTAKA KOMATSU,* NATSUYO YAMAMOTO,* NAOKI SASAHIRA,* NOBUO TODA,* HIROYUKI ISAYAMA,* MINORU TADA,* TAKESHI TSUJINO, RYO NAKATA, TATEO KAWASE, TETSUO KATAMOTO, TAKAO KAWABE,* and MASAO OMATA* *Department of Gastroenterology, University of Tokyo, Tokyo; Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo; Department of Gastroenterology, Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Tokyo; and Department of Gastroenterology, JR Tokyo General Hospital, Tokyo, Japan Background & Aims: The aim of this study was to define the bile duct changes associated with autoimmune pancreatitis. Methods: Eight patients with autoimmune pancreatitis were followed for a mean of 4 years.the clinical features of these patients, including extrapancreatic bile duct changes, were examined by using biochemical parameters and several imaging modalities.pathologic features of the pancreas and liver were examined by using the biopsy specimens of 7 patients. Results: Diffuse or focal narrowing of the main pancreatic duct was observed in all patients.histologic examination of the pancreas showed lymphoplasmacyte infiltration with severe fibrosis and acinar cell depletion.in 6 patients extrapancreatic bile duct changes such as stricture of the bile duct at hilus or intrahepatic area were observed. In 2 patients abnormalities in the bile duct and pancreas were detected simultaneously at diagnosis, and changes in the bile duct were observed later in 4 patients.lymphoplasmacyte infiltration and fibrosis were observed in the portal area of all 7 liver biopsy samples. Five of the patients with bile duct changes received steroid therapy, and the pathological changes improved. Conclusions: Extrapancreatic bile duct changes are frequently associated with autoimmune pancreatitis.similar pathogenic mechanism might produce the biliary tract and pancreatic abnormalities in autoimmune pancreatitis resulting in a similar histopathology in the liver and pancreas and response to steroid therapy. The initial report by Sarles et al. 1,2 of cases of pancreatitis associated with hypergammaglobulinemia has been followed by numerous articles indicating the occasional coexistence of pancreatitis with autoimmune diseases such as Sjögren s syndrome, 3 primary biliary cirrhosis (PBC), 4 primary sclerosing cholangitis (PSC), 4 7 Crohn s disease, and ulcerative colitis. 3,8 These findings suggest the involvement of an autoimmune mechanism in the pathogenesis of pancreatitis in some patients and the recent recognition of autoimmune pancreatitis. 9 Although the diagnostic criteria of autoimmune pancreatitis have not been definitely established, the following characteristics are currently used 10 : (1) diffuse swelling of the pancreas, (2) diffuse irregular narrowing of the main pancreatic duct on endoscopic retrograde cholangiopancreatography (ERCP) images, (3) fibrotic changes with lymphoplasmacyte infiltration, (4) increased levels of serum gammaglobulinemia or IgG, (5) the presence of autoantibodies such as antinuclear antibodies (ANAs), rheumatoid factor (RF), and anticarbonic anhydrase-ii (ACA-II), (6) occasional association with another autoimmune disease, (7) effectiveness of steroid therapy, (8) mild symptoms usually without acute attacks of pancreatitis, (9) stenosis of the common bile duct in the intrapancreatic area as a result of pancreatitis, (10) the absence of pancreatic cysts, and (11) the absence of pancreatic calcification. In addition, there are also cases of autoimmune pancreatitis exhibiting eosinophilia 11 or increased levels of serum IgE. 9,12,13 Stenosis of the common bile duct in the intrapancreatic area usually occurs with autoimmune pancreatitis caused by pancreas inflammation. However, although Abbreviations used in this paper: ACA-II, anticarbonic anhydrase-ii; ALP, alkaline phosphatase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CRP, C-reactive protein; CT, computed tomography; D.Bil, direct bilirubin; EBD, endoscopic biliary drainage; ERCP, endoscopic retrograde cholangiopancreatography; FBS, fasting blood sugar; GAD, glutamic acid decarboxylase; -GTP, -glutamyl transpeptidase; HbA1c, hemoglobin A1c; IDUS, intraductal ultrasonography; MPO-ANCA, myeloperoxidase antineutrophil cytoplasmic antibody; MRI, magnetic resonance imaging; PBC, primary biliary cirrhosis; PFD, pancreatic function diagnostic test; PNPD, pancreatitis with narrowing pancreatic duct; PSC, primary sclerosing cholangitis; PTBD, percutaneous transhepatic biliary drainage; PTC, percutaneous transhepatic cholangiography; RF, rheumatoid factor; RNP, ribonucleoprotein; SSA, sicca syndrome A; SSB, sicca syndrome B; T.Bil, total bilirubin; US, ultrasonography by the American Gastroenterological Association /03/$30.00 PII: /S (03)

2 454 HIRANO ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol.1, No.6 there are several reports of autoimmune pancreatitis with biliary system changes, 6,10 extrapancreatic bile duct changes have not been reported extensively. In this follow-up study some bile duct changes occurred during long-term observation. Because the late occurrence of bile duct changes and histologic findings of the liver have not been clearly reported, we analyzed the clinical and histologic characteristics of 8 patients with autoimmune pancreatitis, 6 of whom exhibited extrapancreatic bile duct changes either at the time of diagnosis or during follow-up. Patients and Methods We evaluated 8 patients diagnosed with autoimmune pancreatitis from our own institution and affiliated hospitals during The 6 men and 2 women were years old (mean, 65.6 years). During this period, 202 patients were diagnosed with chronic pancreatitis. Blood chemistry tests included amylase, lipase, AST, ALT, alkaline phosphatase (ALP), -glutamyl transpeptidase ( - GTP), total bilirubin (T.Bil), direct bilirubin (D.Bil), C-reactive protein (CRP), fasting blood sugar (FBS), and hemoglobin A1c (HbA1c). We also measured the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). Immunologic blood parameters included IgG, the IgG4 subclass, and autoimmune antibodies such as ANA, RF, ACA- II, anti sicca syndrome A (anti-ssa), anti sicca syndrome B (anti-ssb), anti-dna, anti-ribonucleoprotein (anti-rnp), anti glutamic acid decarboxylase (anti-gad), myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA), and antimitochondrial antibody (AMA). The IgG4 subclass and ACA-II were measured by nephelometry and Western blot analysis, respectively, by using serum samples stored at 30 C. Imaging Modalities Ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) were performed in all patients. For the spiral CT studies, 100 ml of low-osmolar iodinated contrast material (Omnipaque 300R; Daiichi Pharmaceutical Co., Tokyo, Japan) was injected at a rate of 3 ml/s with a power injector. CT scanning (Light Speed QX/I; GE Medical Systems, Milwaukee, WI) commenced 40 seconds after the start of injection. The examination was performed during one 20-second breath-hold with a 7.5 mm/s table feed. Images were reconstructed in 2.5-mm increments. Delayed images were obtained 90 seconds after the start of contrast injection at 10-mm intervals. MRI was performed with a 1.5 T super-conducting unit (Magnectom Vision; Siemens, Erlangen, Germany). Slices were 5 mm thick, and the interslice gap was 0 mm. T1-weighted gradient-echo images (180/6 TR/TE) and T2-weighted (3000/ 120) fast spin echo images, both without fat suppression, were acquired. ERCP was performed in all patients, and percutaneous transhepatic cholangiography (PTC) was performed in 2 patients. Intraductal ultrasonography (IDUS) was performed in 1 patient by using a 2.0-mm diameter ultrasonic probe at a frequency of 20 MHz (UM-G20-29R; Olympus Optical Co., Tokyo, Japan) to evaluate the thickening of the bile duct wall. Biopsy of the Pancreas and Liver A pancreatic biopsy was performed in 7 of the 8 patients. US-guided biopsy of the pancreas was performed in 6 patients by using a 20-gauge biopsy needle, and biopsy by laparotomy was performed in 1. Liver biopsy was performed in 7 patients. Immunohistochemical studies were performed on all biopsy specimens by the streptavidin-biotin method, and UCHL-1, L26 (Dako Japan Co., Kyoto, Japan), CD4, and CD8 (Nichirei Co., Tokyo, Japan) antigens were used. The antibody for UCHL-1 and L26 was used at a dilution of 1:100, and the antibody for CD4 and CD8 was at a dilution of 1:1. Stained cells in the pancreas and the portal area of the liver were counted under a high-power field ( 400) at more than 3 fields. Diagnosis A diagnosis of autoimmune pancreatitis was based on the following criteria 9,11,13 : (1) clinical symptoms associated with pancreatitis, (2) increased serum IgG or the presence of antibodies, (3) diffuse or focal swelling of the pancreas on US and CT, (4) an abnormally narrow pancreatic duct on ERCP, (5) histologic confirmation of fibrotic changes with lymphoplasmacyte infiltration present in the biopsy specimen of the pancreas, and (6) clinical improvement with steroid therapy (which is useful to differentiate autoimmune pancreatitis from other pancreatic diseases including pancreatic cancer). 10 Treatment Initially, percutaneous transhepatic biliary drainage (PTBD) or endoscopic biliary drainage (EBD) was performed in patients with jaundice. Prednisolone at an initial dose of mg/day was administered for 4 weeks. Thereafter, follow-up imaging tests were performed. Blood chemistry tests were performed once a week. Prednisolone was reduced by 5 mg biweekly until a final dose of 5 mg/day was reached. Prednisolone at a dose of 5 mg/day was used as maintenance therapy. Results Patient Profile The clinical profiles of 8 patients with autoimmune pancreatitis are summarized in Table 1. During the course

3 November 2003 THE BILIARY SYSTEM IN AUTOIMMUNE PANCREATITIS 455 Table 1. Clinical Profiles of Patients Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Age (yr) Gender Male Male Male Male Male Female Female Male Chief complaint Jaundice Jaundice Jaundice Jaundice Jaundice Back pain Jaundice Jaundice Combined diseases Other autoimmune diseases Diabetes mellitus FBS ( mg/dl) HbA1c ( %) Biochemical parameters Pancreas Amylase ( IU/L) Lipase (10 48 IU/L) PFD ( 70%) Liver AST (4 44 IU/L) ALT (4 44 IU/L) ALP ( IU/L) GTP ( 50 IU/L) T.Bil ( 1.1 mg/dl) D.Bil ( 0.5 mg/dl) TP ( g/dl) Alb ( 3.6 g/dl) Inflammation Leukocyte count ( / L) Platelet count ( / L) Eosinophilia ( 1000/ L) CRP ( 0.4 mg/dl) ESR (mm/h) Immunologic parameters -globulin ( %) IgG ( mg/dl) a b IgG4 ( 135 mg/dl) c 1420 IgE ( 250 U/mL) ANA ( 80) RF ACA-II Anti-DNA Anti-RNP Anti-GAD Tumor markers CEA ( 5 ng/ml) CA19-9 ( 37 U/L) NOTE. Anti-SSA, anti-ssb, MPO-ANCA, and AMA were negative in all cases. ACA-II measured by Western blot analysis. MPO-ANCA was measured by enzyme-linked immunosorbent assay. IgG subclass was analyzed by nephelometry. TP, total protein; Alb, albumin; ESR, erythrocyte sedimentation rate (units or normal values). a IgG rose to 2124 mg/dl 4 years later. b IgG rose to 1835 mg/dl 1 year later. c IgG4 rose to 218 mg/dl 1 year later. of a mean follow-up of 4 years (range, months), 7 patients exhibited jaundice and 3 patients experienced mild abdominal pain. Elevated AST, ALT, ALP, and -GTP levels were observed in all 8 patients, an elevated amylase level was observed in 2 patients, and slight elevation of CRP was observed in 5 patients. Increased levels of IgG and IgG4 were observed in 5 and 7 patients, respectively. ANA and ACA-II were positive in 2 and 3 patients, respectively, whereas RF and anti-rnp were positive in only 1 patient. The other autoimmune antibodies tested for were negative, and anti-gad antibody was negative in all 4 patients with diabetes mellitus. Concerning tumor markers, an increased level of CEA was observed in 1 patient characterized as a heavy smoker (Brinkman index, 40 20). Elevated CA19-9 levels were found in 5 patients. An association with other autoimmune diseases such as Sjögren s syndrome and ulcerative colitis was not observed; however, 4 patients had type II diabetes mellitus, which was found at the time that autoimmune pancreatitis was diagnosed.

4 456 HIRANO ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol.1, No.6 Figure 1. Images of the main pancreatic duct and biliary tract system in patients with autoimmune pancreatitis (case 4). (A) Irregular narrowing of main pancreatic duct was observed on ERCP. (B) At the time of autoimmune pancreatitis diagnosis, abnormalities of extrapancreatic bile duct were not detected. The narrowing of intrapancreatic common bile duct was observed. Although the middle segment of the common bile duct appears normal under cholangiography, IDUS showed wall thickening of the bile duct. (C) Four months later, multiple stricture of the intrahepatic bile duct were identified.

5 November 2003 THE BILIARY SYSTEM IN AUTOIMMUNE PANCREATITIS 457 Pancreatic function diagnostic test (PFD) was performed in 3 patients, and 2 showed mildly disturbed pancreatic exocrine function. Imaging Features of the Pancreas and Biliary Tract Pancreas. Narrowing of the main pancreatic duct was confirmed on ERCP in all 8 patients (Figure 1A). Diffuse swelling of the pancreas was recognized in 7 of the 8 patients. In the remaining patient (case 1), swelling was observed only in the pancreas head (Figure 2A). In case 7, pancreas size did not appear to be abnormally large before prednisolone treatment, but its size was noticeably smaller after treatment, suggesting a swelling of the pancreas beforehand. A capsule-like rim was noticed in all patients (Figure 2A) except case 7, and delayed enhancement of the pancreas was recognized in all 8 patients. Biliary tract. Imaging findings of the biliary tract (Table 2) showed abnormalities in all parts of the biliary tract. Narrowing of the intrapancreatic common bile duct and the dilation of the intrahepatic bile duct were observed in 7 patients. Irregularity of extrapancreatic bile duct changes such as stricture of the bile duct at hilus or intrahepatic area was observed on ERCP or PTC in 6 patients (Figure 1B, Figure 2B); in 2 patients (cases 1 and 6), extrapancreatic bile duct changes were noted at the diagnosis of autoimmune pancreatitis. In the remaining 4 patients (cases 2 5), extrapancreatic bile duct changes were detected 4 44 months after diagnosis but before steroid therapy began (Figure 1C, Figure 3). IDUS showed wall thickening of the common bile duct even in the segment in which abnormalities were not clearly observed with cholangiography (Figure 1B). A low density area in the bile duct was observed on CT scan in 2 patients (cases 1 and 2; Figure 2C). Others. A soft tissue density mass around the abdominal aorta suggestive of retroperitoneal fibrosis was recognized on CT scan in 3 cases (cases 1, 6, and 8) (Figure 2A). 14 In all, the soft tissue mass was localized only to the area around the abdominal aorta, and hydronephrosis was not observed. Slight ascites was detected on US in 1 patient (case 1). Histologic Findings of the Pancreas and Liver Pancreas. Pancreatic tissue was obtained in 7 patients by US-guided needle biopsy of the pancreas in 6 and pancreatic biopsy by laparotomy in 1 (case 8). In all 7 patients, there was lymphoplasmacyte infiltration with severe fibrosis and acinar cell depletion (Figure 2A) (Table 3). Immunohistochemical study showed that the lymphocytes consisted mainly of UCHL-1 T cells predominantly of CD8-positivity as opposed to CD4-positivity (Figure 4). L-26 B cells were few in number. In case 5, immunohistochemistry could not be done because the pancreatic biopsy specimen was too small. Liver. Needle liver biopsy was performed in 7 patients; 6 patients (cases 1 6) had extrapancreatic bile duct changes on ERCP. The patient with normal extrapancreatic ducts (case 7) had elevated AST, ALT, ALP, and -GTP levels. Histologic findings (Table 3) mainly consisted of lymphoplasmacyte infiltration with fibrosis in the portal area (Figure 2C). In 2 patients (cases 4 and 6) marked fibrosis was prominent, but lymphoplasmacyte infiltration was scanty. Disappearance of the intralobular bile duct was observed in 2 patients (cases 1 and 2). Furthermore, the needle biopsy specimen from the low echoic tumor-like lesion around the bile duct in case 1 showed fibrotic tissue with mild inflammatory cell infiltration (Figure 2C). This histologic finding was similar to that of the pancreas specimen. Immunohistochemical examination showed that most of the lymphocytes in the portal area consisted mainly of UCHL-1 T cells predominantly of CD8-positivity rather than CD4-positivity (Figure 5). L-26 B cells were observed rarely. Treatment The types and results of treatment are summarized in Table 4. Initially, in the 7 patients with jaundice, PTBD was performed in 2 patients and EBD with an 8.5F Tannenbaum stent in 5 patients. Prednisolone therapy was performed in 7 patients. Of these 7 patients, extrapancreatic bile duct changes on ERCP occurred during follow-up in the 5 patients who were not treated with steroids initially (cases 1, 2, 4, 5, and 6). In case 2, prednisolone was administered 28 months after extrapancreatic bile duct changes were confirmed on ERCP because these changes had progressed. In cases 1, 4, 5, and 6, prednisolone was administered within 3 weeks after the bile duct changes had been confirmed in the extrapancreatic region. Prednisolone was discontinued after 29 months in 1 patient (case 8). In all 7 cases, after prednisolone therapy there was a decrease in AST, ALT, ALP, and -GTP values with the improvement of pancreatic swelling, narrowing of the main pancreatic duct, bile duct strictures, and retroperitoneal fibrosis (Figure 6A and B). In addition, the low density area around the bile duct on CT scan disappeared after prednisolone therapy in cases 1 and 2 (Figure 6C). IDUS was performed in 1 patient (case 1) both before and after prednisolone therapy, demonstrating a remarkable decrease in the thickening of the bile duct wall (Figure 6B).

6 458 HIRANO ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol.1, No.6 Figure 2. Imaging and histology of the patients presenting low-density area in the hepatic duct on CT (case 1). (A) CT scan showed swelling of the pancreatic head, a capsule-like rim (arrowheads), and a concentrated soft tissue mass around the abdominal aorta suggestive of retroperitoneal fibrosis. (Inset) Histologic examination of the pancreas showed lymphoplasmacyte infiltration with severe fibrosis and acinar cell depletion. H&E, original magnification 100. (B) PTC showed multiple strictures of the hilar and intrahepatic bile ducts. IDUS performed during PTC showed marked thickening of the hilar duct wall (arrowheads). (C) CT scan showed a low-density area in the right hepatic duct (arrowheads). (Inset) Histologic examination of the liver showed lymphoplasmacytes infiltration with mild fibrosis in the portal area. H&E, original magnification 100. Histologic examination of the tumor-like lesion around the bile duct on US, which coincided with the low-density area on CT, showed fibrotic tissue with mild inflammatory cell infiltration. H&E, original magnification 100.

7 November 2003 THE BILIARY SYSTEM IN AUTOIMMUNE PANCREATITIS 459 Table 2. Biliary Tract Imaging Findings Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 CBD changes Narrowing of intrapancreatic CBD Irregularity of extrapancreatic CBD 3 a Stricture of bile duct at hilus 3 a 3 b 3 a Multiple strictures of IHBD 3 a 3 b 3 c Dilation of IHBD CBD, common bile duct; IHBD, intrahepatic bile duct. a Found after 12 months. b Found after 44 months. c Found after 4 months. Aggravation or amelioration of diabetes mellitus was assessed by measuring HbA1c level. Aggravation of diabetes mellitus as a result of prednisolone treatment occurred in 2 patients (cases 1 and 8). In case 8, pancreatitis recurred 6 months after discontinuation of prednisolone. In 2 patients (cases 6 and 7), diabetes mellitus improved after prednisolone treatment, and in 1 patient (case 4), there was no change in diabetes. PFD testing, an indirect test of pancreatic function that is insensitive for detection of mild pancreatic insufficiency, was performed before and after prednisolone treatment in 2 patients (cases 5 and 6). Both patients had a slight improvement in pancreatic exocrine function after treatment (case 5, 52.0% 56.1%; case 6, 54.3% 61.3%); however, it is unclear whether this improvement is significant. Discussion In 1982 Epstein et al. 4 reported 3 cases of chronic pancreatitis associated with PSC. These patients had Figure 3. Kaplan-Meier graph showing incidence rate of extrapancreatic bile duct changes. diffuse irregularity of the main pancreatic duct on ERCP. However, it is difficult for us to ascertain whether they had autoimmune pancreatitis 9,10 because of the lack of other imaging tests, tests of autoimmunity and response to steroid therapy. Because the concept of autoimmune pancreatitis 9,10 is recent, many of the changes that occur with this disease have not been identified. Autoimmune pancreatitis is thought to be a type of chronic pancreatitis. Therefore, test results commonly abnormal in acute pancreatitis, such as leukocyte count, CRP, and amylase, are not necessarily abnormal in autoimmune pancreatitis. The diagnosis of autoimmune pancreatitis is currently based on imaging procedures that can detect abnormalities such as pancreatic swelling and irregular narrowing of the main pancreatic duct, by the presence of autoimmune-related abnormalities (increased IgG level and positive autoimmune antibodies such as ANA, RF, and ACA-II), and histopathology of the pancreas (lymphoplasmacyte infiltration with fibrosis). Specifically, diffuse swelling of the pancreas and a capsule-like rim 10,15 17 might be present on CT, US, and MRI. Some patients also have focal swelling or multiple focal masses that simulate pancreatic cancer. 6,13,18 20 In this study, diffuse swelling of the pancreas was observed in 7 of the 8 patients (88%), and focal swelling of the pancreas was found in the remaining patient. Diffuse irregular narrowing of the main pancreatic duct on ERCP images occurred in all cases. Delayed enhancement on CT study showed a capsule-like rim in all cases. In addition, consistent with previous reports, a soft tissue mass suggestive of retroperitoneal fibrosis was observed in 3 patients (38%). Previously, autoimmune pancreatitis without the presence of autoantibodies such as ANA or RF was described as sclerosing pancreatitis 6 or pancreatitis with a narrowing pancreatic duct (PNPD). 24 In our 8 patients only 3 had biochemical signs of autoantibodies in peripheral blood (3 patients were positive for ACA-II and 1 patient was also positive for anti-rnp). Thus, from the

8 460 HIRANO ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol.1, No.6 Table 3. Pancreatic and Hepatic Histologic Findings Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Pancreas Lymphoplasmacyte infiltration Fibrosis Liver Lymphoplasmacyte infiltration (portal area) Fibrosis (portal area) biopsy specimen and on the basis of the absence of autoantibodies, 5 patients could be characterized as having sclerosing chronic pancreatitis with lymphoplasmatic cell inflammation. However, a previous report pointed out the overlap of sclerosing pancreatitis or PNPD with autoimmune pancreatitis. 10 For example, 3 patients (cases 3 5) in our study did not have increased levels of IgG initially, but IgG level increased subsequently in 2 patients (cases 3 and 5). Therefore, autoimmune pancreatitis does not always present definite biochemical and immunologic abnormalities such as increased levels of IgG ( 1700 mg/dl) and ANA at the time of initial diagnosis. 13 The major histopathologic finding of the pancreas in this study was lymphoplasmacyte infiltration with marked fibrosis. However, the lymphoplasmacyte infiltration was not prominent in all patients. This difference in prominence might be due to the small sample size of biopsy specimens in which fibrosis was abundant. Even in patients without prominent lymphoplasmacyte infiltration, we had an impression that there was more lymphoplasmacyte infiltration than that seen in typical chronic pancreatitis with severe fibrosis (Figure 2A); however, it is necessary to confirm this point by using a large number of specimens of patients with autoimmune pancreatitis as well as those with typical chronic pancreatitis. The amount of infiltration in this pattern seems more than that described by Lankisch and Banks, 25 who stated that only slight lymphocytic infiltrates occur in typical chronic pancreatitis with pronounced scarring. Extrapancreatic bile duct changes associated with autoimmune pancreatitis have not been firmly established. In this study, 6 patients had extrapancreatic bile duct changes that often appeared after the pancreatic changes such as pancreatic swelling and narrowing of main pancreatic duct. Two patients did not have extrapancreatic bile duct changes on ERCP; however, the 1 patient who underwent a liver biopsy because of elevated AST, ALT, ALP, and -GTP values had similar pathologic findings such as lymphoplasmacyte infiltration with mild fibrosis in the portal area. Although a late occurrence of extrapancreatic bile duct changes was observed in 4 patients when steroid therapy was not initiated, the bile duct changes associated with autoimmune pancreatitis might be present and observed with IDUS even if the changes are not observed on ERCP (case 4, Figure 1B). Furthermore, biopsy findings of the low echoic tumorlike lesion in the bile duct on US resembled those of the Figure 4. (Case 2) (original magnification 400 ). Immunohistochemical study showed that the lymphocytes consisted mainly of UCHL-1 T cells predominantly of CD8-positivity as opposed to CD4-positivity. L-26 B cells were few in number. Figure 5. (Case 5) (original magnification 400 ). Immunohistochemical study showed most of the lymphocytes in the portal area consisted mainly of UCHL-1 T cells predominantly of CD8-positivity as opposed to CD4-positivity. L-26 B cells were few in number.

9 November 2003 THE BILIARY SYSTEM IN AUTOIMMUNE PANCREATITIS 461 Table 4. Treatment for the Patients T.Bil IgG IgG4 ANA CA19-9 HbA1c PFD (%) Swelling of pancreas Stricture of intrapancreatic CBD Stricture of extrapancreatic bile duct Case 1: PTBD followed 3 wk later by PSL 30 mg Before PTBD After PTBD/before PSL mo after PSL yr after PSL Case 2: EBD followed 28 mo later by PSL 30 mg Before EBD After EBD/before PSL a 1 mo after PSL Case 3: EBD Before EBD yr after EBD b Case 4: EBD followed 6 mo later by PSL 30 mg Before EBD After EBD/before PSL c 1 mo after PSL yr after PSL Case 5: EBD followed 12 mo later by PSL 30 mg Before EBD After EBD/before PSL a 1 mo after PSL yr after PSL Case 6: PSL 40 mg Before PSL mo after PSL yr after PSL Case 7: EBD soon followed by PSL 40 mg Before EBD PSL , mo after EBD PSL yr after PSL Case 8: PTBD soon followed by PSL 25 mg Before PTBD PSL mo after PTBD PSL yr after PSL withdrawal PSL, prednisolone; PFD, pancreatic function diagnostic test 70% normal. a Present after 12 mo. b Present after 44 mo. c Present after 4 mo. pancreas, indicating the possibility that the same pathogenic mechanism underlies the pancreatic and bile duct changes. On the basis of this study, CD8 T cells might be the predominant infiltration of the pancreas and the portal area of the liver. Nishino et al. 26 previously reported that CD8 T cells were the predominant infiltration in the pancreas of patients with autoimmune pancreatitis; however, Okazaki et al. 27 reported that the infiltration consisted mainly of CD4 T cells. Tanaka et al. 28 reported CD8 T-cell infiltration of the islets, but they did not clarify which CD4 or CD8 T cells were around the ductal cells. Because we recovered only very

10 462 HIRANO ET AL. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol.1, No.6 small specimens, mainly by needle biopsy, there is the possibility that we encountered sampling errors resulting from insufficient specimens. At present, we cannot conclude that CD8 T cells play a major role in the development of pancreatitis. The extrapancreatic bile duct changes associated with autoimmune pancreatitis in this study might be consistent with an entity previously described as lymphoplasmacytic sclerosing pancreatitis with cholangitis, 6 sclerosing pancreatocholangitis, 29 inflammatory pseudotumor from sclerosing cholangitis, 30 or atypical primary sclerosing cholangitis associated with unusual pancreatitis. 31 Previous studies reported that perinuclear ANCA is often positive (65% 72%) in classic PSC. 32,33 The target molecules of perinuclear ANCA positive sera might include lactoferrin, MPO, cathepsin G, laminarase, and 1 -antitrypsin. 33 In this study, MPO-ANCA was negative in all patients. In addition, all 8 cases were negative for AMA. Thus, the bile duct changes associated with autoimmune pancreatitis might differ from PSC and PBC. In this study IgG level was elevated in 5 patients and IgG4 in 7 patients. Even if total IgG level was not elevated, there was a recognizable increase in the level of serum IgG4. None of our patients had other diseases such as atopic dermatitis, asthma, or parasitic diseases, in which elevated IgG4 levels have been observed. 34,35 Our data coincide with the data of Hamano et al., 12 which showed an increased level of serum IgG4 concentration in patients with sclerosing pancreatitis (seemingly autoimmune pancreatitis). Hamano et al. also reported that the level of serum IgG4 concentration was normal in 8 patients with classic PSC. We measured the level of serum IgG4 in 8 patients with classic PSC and in 7 patients with bile duct carcinoma, and all had normal IgG4 levels with the exception of 1 patient with classic PSC. Therefore, IgG4 might be useful in differentiating classic PSC, bile duct carcinoma, and the bile duct changes associated with autoimmune pancreatitis. The use of IgG4 level for differentiating diagnoses between PSC and bile duct changes associated with autoimmune pancreatitis, however, has not been corroborated. Steroid Š Figure 6. Improvement of the pancreatic swelling and bile duct stricture after prednisolone treatment (case 1). (A) Compared with Figure 2A, swelling of the pancreatic head and fibrosis around the abdominal aorta improved after prednisolone treatment. Compared with Figure 2B, PTC showed an improvement of bile duct changes after prednisolone treatment. IDUS performed during PTC showed an improvement after prednisolone treatment. The thickness of the low echoic layer changed from 5 to 3 mm (arrowheads). (C) Compared with Figure 2C, the low-density area in the right hepatic duct disappeared after prednisolone treatment.

11 November 2003 THE BILIARY SYSTEM IN AUTOIMMUNE PANCREATITIS 463 therapy reduced pancreatic swelling and bile duct strictures in this study, as confirmed on ERCP after 4-week prednisolone administration. Furthermore, the tumorlike lesion in the hepatic bile duct consisting of fibrous tissue and inflammatory cell infiltration disappeared after steroid therapy. The bile duct changes associated with autoimmune pancreatitis also responded to steroid therapy. Long-term observation, however, will be necessary to confirm this observation. Rapid improvement of bile duct changes by steroid therapy was important to differentiate the bile duct changes associated with autoimmune pancreatitis from classic PSC, because this rapid improvement does not occur in classic PSC. 36 In this study, 8 of a total 202 patients from 4 different gastroenterology institutions screened out from the group of patients with chronic pancreatitis had autoimmune pancreatitis. Although the medical diagnostic standards among the 4 institutions were similar, some differences existed in testing and treatment, which is a weakness in this study. For example, the incidence of autoimmune pancreatitis was slightly higher (3.96%, 8 of 202) than reported by Ito et al. 11 (1.86%, 3 of 161), possibly because the 4 institutions were tertiary hospitals in the Tokyo metropolitan area in which patients with slight or mild alcoholic pancreatitis were not admitted. The increased incidence might also be because awareness of this disease entity has gradually increased, particularly after the report by Hamano et al. 12 about elevated IgG4 in autoimmune pancreatitis. After this manuscript was finished at the end of 2001, 9 patients were diagnosed with autoimmune pancreatitis in our institution and affiliated hospitals during 2002, and 3 had extrapancreatic bile duct changes visualized by ERCP at diagnosis of autoimmune pancreatitis. Although we observed a high frequency (75%) of extrapancreatic bile duct changes during follow-up, this high frequency of late occurrence of extrapancreatic bile duct changes might not be observed in the remaining 6 patients because these patients received steroid therapy at an early stage. Awareness of the extrapancreatic bile duct changes associated with autoimmune pancreatitis might be a more definite way to differentiate this entity from pancreatic and biliary malignancy, thereby preventing unnecessary surgery. Therefore, detailed evaluation of the entire biliary tract is indispensable in autoimmune pancreatitis. References 1. Sarles H, Sarles JC, Muratore R, Guien C. Chronic inflammatory sclerosis of the pancreas: an autonomous pancreatic disease? Am J Dig Dis 1961;6: Sarles H, Sarles JC, Camatte R, Muratore R, Gaiani M, Guien C, Pastor J, LeRoy F. Observation on 205 confirmed cases of acute pancreatitis, recurring pancreatitis, and chronic pancreatitis. 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