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75-Year-Old Man With Abdominal Pain and Weight Loss
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75-Year-Old Man With Abdominal Pain and Weight Loss MICHAEL D. LEISE, MD*; KURT M. JACOBSON, MD*; AND SURESH T. CHARI, MD†
A
75-year-old man presented to the outpatient clinic with a 9-kg weight loss during the preceding several months and mild midepigastric pain radiating to the back. His medical history was unremarkable. He was a former smoker and lifelong nondrinker. Review of systems was notable only for a slightly decreased appetite, but no nausea, vomiting, or diarrhea was reported. On physical examination, the patient was afebrile and had normal vital signs. However, cachexia and jaundice with scleral icterus were evident. Abdominal examination revealed mild midepigastric tenderness without rebound, guarding, or hepatosplenomegaly and a negative Murphy sign. Findings on the rest of the physical examination were unremarkable. Results of a complete blood cell count and electrolyte studies were within normal limits. Additional test results included the following (reference ranges provided parenthetically): alanine aminotransferase, 425 U/L (7-55 U/L); aspartate aminotransferase, 127 U/L (8-48 U/L); alkaline phosphatase, 582 U/L (45-115 U/L); total bilirubin, 8.9 mg/dL (0.1-1.10 mg/dL); direct bilirubin, 7.1 mg/dL (0.00.3 mg/dL); and lipase, less than 10 U/L (10-73 U/L). The erythrocyte sedimentation rate was elevated at 71 mm/1 h (0-22 mm/1 h). Hepatitis testing that included hepatitis B surface antigen, IgM antibodies to hepatitis B core antigen, and hepatitis C virus (enzyme immunoassay) yielded normal results. 1. In this patient, which one of the following is the most likely diagnosis? a. Acute pancreatitis b. Cholecystitis c. Acute hepatitis d. Pancreatic carcinoma e. Cholangitis Acute pancreatitis is an acute inflammatory process usually associated with severe abdominal pain and elevated serum levels of pancreatic enzymes. The lipase level below 10 U/L in this patient does not support this diagnosis. Bilirubin and alkaline phosphatase elevations as high as those in this patient are not common in uncomplicated cholecystitis because biliary obstruction is usually limited to the cystic duct and gallbladder. Although elevated liver transaminase levels could suggest hepatitis, the degree of alkaline phosphatase elevation (>5 times the upper limit of normal), weight loss, and patient age suggest an obstructive process. Therefore, acute hepatitis is not the most likely diagnosis. The constellation of epigastric pain radiating to the back, cachexia, and jaundice makes pancreatic carciMayo Clin Proc.
•
noma the most likely diagnosis. Cholangitis would be concerning in this patient with evidence of biliary obstruction and abdominal pain; however, the normal leukocyte count, lack of fever, and insidious course make this diagnosis less likely. After the initial evaluation of the patient, further imaging studies were required to confirm the presumptive diagnosis. 2. Which one of the following imaging studies would be most appropriate in this patient? a. Ultrasonography (US) of the abdomen b. Computed tomography (CT) of the abdomen c. Magnetic resonance imaging of the abdomen d. Endoscopic retrograde cholangiopancreatography (ERCP) e. Esophagogastroduodenoscopy Abdominal US would be appropriate if acute cholecystitis or cholangitis were suspected. The visualization of gallstones in conjunction with either a positive sonographic Murphy sign or gallbladder wall thickening provides a positive predictive value greater than 90% for the diagnosis of cholecystitis. Abdominal US is also more sensitive than CT for detecting biliary dilatation from common bile duct stones. However, this patient’s clinical findings suggest a malignant process involving the biliary tree or pancreas. Therefore, CT is the most appropriate initial imaging modality because it is more sensitive and specific than US for pancreatic cancer.1 Although CT and magnetic resonance imaging have similar sensitivity and specificity for the diagnosis of extrahepatic malignancies, CT is easier and less expensive to perform.2 Endoscopic retrograde cholangiopancreatography is preferably used when therapy is likely to be needed after a pancreatobiliary process amenable to ERCP has been identified on less invasive imaging. Because of the substantially greater potential for serious complications associated with ERCP, it is not ideal for initial evaluation. Esophagogastroduodenoscopy would be inappropriate for this patient who has evidence of biliary obstruction. *Resident in Internal Medicine, Mayo School of Graduate Medical Education, Mayo Clinic, Rochester, MN. †Adviser to residents and Consultant in Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. See end of article for correct answers to questions. Individual reprints of this article are not available. Address correspondence to Suresh T. Chari, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]). © 2008 Mayo Foundation for Medical Education and Research
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FIGURE. Computed tomographic images showing dilated intrahepatic and extrahepatic bile ducts (arrow) (left), diffusely enlarged pancreas and thickened and enhanced bile duct walls (arrow) (middle), and soft-tissue prominence surrounding abdominal aorta (arrow) (right).
Computed tomography of the abdomen and pelvis (Figure) revealed marked intrahepatic and extrahepatic bile duct dilatation with enhancement of the walls of the bile ducts and diffuse sausage-shaped enlargement of the pancreas. No discrete pancreatic or biliary mass was visualized. A marked soft-tissue prominence surrounded the abdominal aorta, suggestive of retroperitoneal fibrosis. Computed tomography showed no obvious malignant process as the cause of our patient’s symptoms. Therefore, further imaging with ERCP or magnetic resonance cholangiopancreatography (MRCP) was indicated to investigate the possibility of a retained stone in the common bile duct. Because the patient refused more invasive ERCP, MRCP was performed. The modality revealed multiple dilated intrahepatic and extrahepatic bile ducts, thickened and enhanced walls of the extrahepatic bile ducts, and a mildly dilated and segmentally thickened main pancreatic duct extending to the level of the pancreatic head. The pancreas was diffusely enlarged. No definitive pancreatic mass, bile duct stone, or other obstructing ductal lesion was identified. 3. Considering the MRCP findings in this patient, which one of the following is the most likely diagnosis? a. Pancreatic cancer b. Cholangiocarcinoma c. Primary biliary cirrhosis (PBC) d. Primary sclerosing cholangitis (PSC) e. Autoimmune pancreatitis (AIP) The patient had no evidence of pancreatic cancer or cholangiocarcinoma, but these diagnoses are still possible given that many early carcinomas are difficult to visualize on imaging. However, the absence of frank hepatobiliary or pancreatic cancer should lead to consideration of other causes of obstructive jaundice. Although PBC can manifest as jaundice, this entity, which classically involves the small bile ducts rather than the larger intrahepatic and extrahe1162
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patic duct involvement seen in this patient, usually occurs in women. Thus, PBC was not probable in this patient. The characteristic radiologic manifestations of PSC on MRCP or ERCP are multifocal stricturing and dilatation of intrahepatic and/or extrahepatic ducts, referred to as the string of beads sign, which was absent in this case. The combination of a diffusely enlarged pancreas, intrahepatic and extrahepatic duct dilatation, diffuse irregular thickening of the main pancreatic duct and intrapancreatic duct, and retroperitoneal fibrosis make AIP the most likely diagnosis.3 Further studies were needed to help confirm the diagnosis of AIP. 4. In light of the constellation of radiologic findings in this patient, which one of the following would be the most appropriate next step? a. Referral for pancreaticoduodenectomy b. Antinuclear antibody testing c. Serum IgG4 determinations d. Computed tomography–guided pancreatic biopsy e. Endoscopic ultrasonography (EUS) with fine-needle aspiration (FNA) biopsy Diagnostic modalities are still warranted at this time, and referral for pancreaticoduodenectomy would be inappropriate. Autoimmune pancreatitis is associated with other serologic abnormalities, including elevated titers of γ-globulins, IgG, and a variety of antibodies including antinuclear antibody, rheumatoid factor, anti–carbonic anhydrase antibody, and antilactoferrin antibody. However, elevations of many of these antibodies, including antinuclear antibody, are nonspecific, especially in elderly patients, and would not be the most helpful tests. Elevated levels of the IgG4 subset of IgG have been found to be a sensitive and specific marker for AIP; therefore, IgG4 determination would be the next test of choice. Both CTguided pancreatic biopsy and EUS with FNA biopsy have an important role in the diagnosis of AIP and would charac-
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teristically reveal a lymphoplasmacytic infiltrate but would not be the most appropriate next step because of invasiveness and the cost of the procedures. Serum IgG levels were obtained and revealed the following: total IgG, 2620 mg/dL (600-1500 mg/dL); IgG1, 1710 mg/dL (490-1140 mg/dL); IgG2, 857 mg/dL (150640 mg/dL); IgG3, 124 mg/dL (20-110 mg/dL); and IgG4, 548 mg/dL (8-140 mg/dL). The markedly elevated IgG4 level was strongly suggestive of AIP. Other notable laboratory test results included a random blood glucose level of 650 mg/dL (70-100 mg/dL). The clinical history of mild epigastric pain, jaundice, and weight loss in conjunction with the finding of an enlarged sausage-shaped pancreas with a peripheral halo on CT and a positive IgG4 test strongly supported the diagnosis of AIP with associated cholangitis. Thereafter, treatment recommendations were given to the patient. 5. Which one of the following would be the most appropriate treatment for this patient? a. Oral corticosteroids b. Intravenous corticosteroids c. Azathioprine d. Pancreaticoduodenectomy e. Pancreatic duct stent During the initial presentation of AIP, oral corticosteroids can relieve symptoms such as dyspepsia and cholestasis, resolve pancreatic swelling and biliary strictures, and ameliorate new-onset diabetes. Although such improvement has been noted to occur spontaneously in conservatively treated patients, corticosteroids appear to bring about these improvements in structure and function consistently and rapidly and therefore represent the best treatment option. No data are available on the use of intravenous corticosteroids for this condition. Azathioprine may have a role as a corticosteroid-sparing agent in patients who experience relapse after withdrawal of corticosteroids but would not be the initial drug of choice. Neither pancreaticoduodenectomy nor pancreatic duct stent would provide clear benefit. These procedures are invasive and can be associated with substantial morbidity. Our patient’s initial symptoms resolved spontaneously. At 3, 6, and 12 months of follow-up, he had regained islet cell function and was managing his diabetes with diet and exercise. DISCUSSION This case emphasizes the need for careful clinical and radiologic evaluation of patients presenting with symptoms that are suggestive of pancreatic carcinoma to avoid unnecessary surgical intervention. Autoimmune pancreatitis is an Mayo Clin Proc.
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uncommon cause of benign fibroinflammatory pancreatic disease that can mimic pancreatic adenocarcinoma clinically and radiologically.3 Autoimmune pancreatitis has been called lymphoplasmacytic sclerosing pancreatitis, primary inflammatory pancreatitis, and sclerosing pancreaticocholangitis. Retrospective studies have shown that, in more than 2.5% of pancreaticoduodenectomies performed for suspected adenocarcinoma of the pancreas, the patient actually had AIP.4,5 Identifying AIP is important because corticosteroid therapy usually resolves most or all symptoms that may prompt unnecessary Whipple procedures.6 Autoimmune pancreatitis is diagnosed most commonly in male patients, with a 2:1 male-female ratio. Age at presentation is variable, with ranges reported from 30 to 80 years, but the disorder occurs most commonly in the sixth decade of life. Patients with AIP often present with symptoms suggestive of mild pancreatitis, including mild abdominal pain, weight loss, jaundice, and an obstructive pattern on liver tests, but the disease is associated with less pain than chronic pancreatitis. In the past, it has been “associated” with other autoimmune diseases, including PSC and Sjögren syndrome.7 However, recent studies suggest that these “associations” are in fact extrapancreatic manifestations of AIP that mimic other disease states.8 Radiologic studies are often performed during the workup of patients with abdominal pain. Although some symptoms that occur in AIP can mimic those of other disease processes being considered, certain findings are more characteristic of AIP. Radiologic features suggestive of AIP include focal or diffuse pancreatic enlargement with minimal peripancreatic inflammation and the absence of vascular encasement on CT or EUS.3 Diffuse irregular narrowing of the main pancreatic duct with associated multiple strictures can be seen on ERCP.3 The 2002 Japan Pancreas Society criteria9 for the diagnosis of AIP relied heavily on radiologic characteristics and mandated that imaging studies display diffuse enlargement of the pancreas along with diffuse (>33%) main pancreatic duct narrowing with an irregular wall. Recently, these criteria were revised to include patients with focal enlargement and/or focal pancreatic duct strictures.10 A recent report of the experience with AIP at Mayo Clinic supported multiple radiologic presentations, including a minority of patients with classic diffuse pancreatic enlargement, a majority with focal enlargement, and other presentations, including a distinct mass, typical acute pancreatitis changes, and a normal gland.8 Retroperitoneal fibrosis and biliary strictures have also been reported.8 Characteristic histologic findings are dense periductal and stromal lymphoplasmacytic infiltrates with stromal fibroplastic proliferation.11 Tissue biopsy is often attempted to assist with the diagnosis of AIP. However, one series found needle or wedge biopsies of the pancreas to be
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diagnostic only 50% of the time.12 Adding an IgG4 immunostain to histologic studies can greatly enhance sensitivity, as demonstrated in a recent publication.8 Hamano et al6 investigated the sensitivity and specificity of serum IgG4 for the diagnosis of AIP. Patients with AIP were found to have markedly elevated levels of IgG4, a rare immunoglobulin that can bind the C1q complement and activate the classic complement pathway. These investigators described significantly higher IgG4 serum levels in patients with AIP in contrast to those in patients with adenocarcinoma of the pancreas, chronic pancreatitis, PSC, PBC, or Sjögren syndrome. The trigger for the IgG4 elevation and its pathogenetic role in AIP are unknown. Currently, the proposed diagnostic criteria for AIP include those from the Japan Pancreas Society9,10 and the Mayo Clinic HISORt criteria proposed by Chari et al.8 The HISORt criteria suggest that to identify the full spectrum of changes associated with AIP, one must recognize its 5 cardinal features involving findings on histology, imaging, and serology; other organ involvement; and response to corticosteroid therapy. The diagnosis of AIP can be established in patients with 1 or more of the following: (1) diagnostic histologic results, (2) characteristic features on pancreatic imaging and abnormal serologic findings, or (3) pancreatic disease with abnormal serologic results and/ or other organ involvement that responds to corticosteroid therapy. The HISORt criteria consider a wide range of disease manifestations, deemphasize radiologic findings as the sine qua non for diagnosis, and emphasize both histologic findings and IgG4 immunostaining of pancreatic core biopsy specimens as a possible criterion standard for diagnosis. In cases in which AIP is strongly suspected but histologic findings are unavailable and the results of imaging studies are not classic, response to corticosteroid therapy can be used as a diagnostic test. Autoimmune pancreatitis has been found to be extremely responsive to corticosteroid therapy in multiple reports and studies,6,13-15 although symptoms may recur. Improvement in the characteristic radiologic findings, including diffuse pancreatic enlargement, and reduction in serum IgG4 levels have been shown with corticosteroid therapy.3,6,15 Secondary improvement in insulin secretion and glycemic control in patients with newly acquired or preexisting diabetes has also been reported after administration of corticosteroids.13,14,16 The typical dosage of prednisone was 40 mg/d for 4 weeks and then 5 mg each week thereafter before discontinuation.
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Clinicians need to be aware of AIP and its close mimicry of pancreatic cancer. At the very least, AIP should be included in the differential diagnosis of patients whose clinical presentation resembles pancreatic cancer. Careful review of clinical, radiologic, and serologic findings can be suggestive of AIP, with the cornerstone of diagnosis being histologic findings and immunostaining for IgG4.
REFERENCES 1. Bipat S, Phoa SS, van Delden OM, et al. Ultrasonography, computed tomography and magnetic resonance imaging for diagnosis and determining resectability of pancreatic adenocarcinoma: a meta-analysis. J Comput Assist Tomogr. 2005;29(4):438-445. 2. Delbeke D, Pinson CW. Pancreatic tumors: role of imaging in the diagnosis, staging, and treatment. J Hepatobiliary Pancreat Surg. 2004;11(1):4-10. 3. Sahani DV, Kalva SP, Farrell J, et al. Autoimmune pancreatitis: imaging features. Radiology. 2004 Nov;233(2):345-352. Epub 2004 Sep 30. 4. Abraham SC, Wilentz RE, Yeo CJ, et al. Pancreaticoduodenectomy (Whipple resections) in patients without malignancy: are they all ‘chronic pancreatitis’? Am J Surg Pathol. 2003;27(1):110-120. 5. Hardacre JM, Iacobuzio-Donahue CA, Sohn TA, et al. Results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing pancreatitis. Ann Surg. 2003;237(6):853-859. 6. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344(10):732-738. 7. Montefusco PP, Geiss AC, Bronzo RL, Randall S, Kahn E, McKinley MJ. Sclerosing cholangitis, chronic pancreatitis, and Sjogren’s syndrome: a syndrome complex. Am J Surg. 1984;147(6):822-826. 8. Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol. 2006 Aug; 4(8):1010-1016. Epub 2006 Jul 14. 9. Pearson RK, Longnecker DS, Chari ST, et al. Autoimmune pancreatitis: does it exist? Pancreas. 2003;27(1):1-13. 10. Okazaki K, Kawa S, Kamisawa T, et al. Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal. J Gastroenterol. 2006;41(7):626631. 11. Deshpande V, Mino-Kenudson MM, Brugge WR, et al. Endoscopic ultrasound guided fine needle aspiration biopsy of autoimmune pancreatitis: diagnostic criteria and pitfalls. Am J Surg Pathol. 2005;29(11):1464-1471. 12. Zamboni G, Luttges J, Capelli P, et al. Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study on 53 resection specimens and 9 biopsy specimens. Virchows Arch. 2004 Dec;445(6): 552-563. Epub 2004 Oct 27. 13. Tanaka S, Kobayashi T, Nakanishi K, et al. Corticosteroid-responsive diabetes mellitus associated with autoimmune pancreatitis [letter]. Lancet. 2000;356(9233):910-911. 14. Kamisawa T, Egawa N, Inokuma S, et al. Pancreatic endocrine and exocrine function and salivary gland function in autoimmune pancreatitis before and after steroid therapy. Pancreas. 2003;27(3):235-238. 15. Kamisawa T, Egawa N, Nakajima H, et al. Morphological changes after steroid therapy in autoimmune pancreatitis. Scand J Gastroenterol. 2004; 39(11):1155-1158. 16. Tanaka S, Kobayashi T, Nakanishi K, et al. Evidence of primary β-cell destruction by T-cells and β-cell differentiation from pancreatic ductal cells in diabetes associated with active autoimmune chronic pancreatitis. Diabetes Care. 2001;24(9):1661-1667.
Correct answers: 1. d, 2. b, 3. e, 4. c, 5. a
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75-Year-Old Man With Abdominal Pain and Weight Loss MICHAEL D. LEISE, MD*; KURT M. JACOBSON, MD*; AND SURESH T. CHARI, MD†
A
75-year-old man presented to the outpatient clinic with a 9-kg weight loss during the preceding several months and mild midepigastric pain radiating to the back. His medical history was unremarkable. He was a former smoker and lifelong nondrinker. Review of systems was notable only for a slightly decreased appetite, but no nausea, vomiting, or diarrhea was reported. On physical examination, the patient was afebrile and had normal vital signs. However, cachexia and jaundice with scleral icterus were evident. Abdominal examination revealed mild midepigastric tenderness without rebound, guarding, or hepatosplenomegaly and a negative Murphy sign. Findings on the rest of the physical examination were unremarkable. Results of a complete blood cell count and electrolyte studies were within normal limits. Additional test results included the following (reference ranges provided parenthetically): alanine aminotransferase, 425 U/L (7-55 U/L); aspartate aminotransferase, 127 U/L (8-48 U/L); alkaline phosphatase, 582 U/L (45-115 U/L); total bilirubin, 8.9 mg/dL (0.1-1.10 mg/dL); direct bilirubin, 7.1 mg/dL (0.00.3 mg/dL); and lipase, less than 10 U/L (10-73 U/L). The erythrocyte sedimentation rate was elevated at 71 mm/1 h (0-22 mm/1 h). Hepatitis testing that included hepatitis B surface antigen, IgM antibodies to hepatitis B core antigen, and hepatitis C virus (enzyme immunoassay) yielded normal results. 1. In this patient, which one of the following is the most likely diagnosis? a. Acute pancreatitis b. Cholecystitis c. Acute hepatitis d. Pancreatic carcinoma e. Cholangitis Acute pancreatitis is an acute inflammatory process usually associated with severe abdominal pain and elevated serum levels of pancreatic enzymes. The lipase level below 10 U/L in this patient does not support this diagnosis. Bilirubin and alkaline phosphatase elevations as high as those in this patient are not common in uncomplicated cholecystitis because biliary obstruction is usually limited to the cystic duct and gallbladder. Although elevated liver transaminase levels could suggest hepatitis, the degree of alkaline phosphatase elevation (>5 times the upper limit of normal), weight loss, and patient age suggest an obstructive process. Therefore, acute hepatitis is not the most likely diagnosis. The constellation of epigastric pain radiating to the back, cachexia, and jaundice makes pancreatic carciMayo Clin Proc.
•
noma the most likely diagnosis. Cholangitis would be concerning in this patient with evidence of biliary obstruction and abdominal pain; however, the normal leukocyte count, lack of fever, and insidious course make this diagnosis less likely. After the initial evaluation of the patient, further imaging studies were required to confirm the presumptive diagnosis. 2. Which one of the following imaging studies would be most appropriate in this patient? a. Ultrasonography (US) of the abdomen b. Computed tomography (CT) of the abdomen c. Magnetic resonance imaging of the abdomen d. Endoscopic retrograde cholangiopancreatography (ERCP) e. Esophagogastroduodenoscopy Abdominal US would be appropriate if acute cholecystitis or cholangitis were suspected. The visualization of gallstones in conjunction with either a positive sonographic Murphy sign or gallbladder wall thickening provides a positive predictive value greater than 90% for the diagnosis of cholecystitis. Abdominal US is also more sensitive than CT for detecting biliary dilatation from common bile duct stones. However, this patient’s clinical findings suggest a malignant process involving the biliary tree or pancreas. Therefore, CT is the most appropriate initial imaging modality because it is more sensitive and specific than US for pancreatic cancer.1 Although CT and magnetic resonance imaging have similar sensitivity and specificity for the diagnosis of extrahepatic malignancies, CT is easier and less expensive to perform.2 Endoscopic retrograde cholangiopancreatography is preferably used when therapy is likely to be needed after a pancreatobiliary process amenable to ERCP has been identified on less invasive imaging. Because of the substantially greater potential for serious complications associated with ERCP, it is not ideal for initial evaluation. Esophagogastroduodenoscopy would be inappropriate for this patient who has evidence of biliary obstruction. *Resident in Internal Medicine, Mayo School of Graduate Medical Education, Mayo Clinic, Rochester, MN. †Adviser to residents and Consultant in Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. See end of article for correct answers to questions. Individual reprints of this article are not available. Address correspondence to Suresh T. Chari, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]). © 2008 Mayo Foundation for Medical Education and Research
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FIGURE. Computed tomographic images showing dilated intrahepatic and extrahepatic bile ducts (arrow) (left), diffusely enlarged pancreas and thickened and enhanced bile duct walls (arrow) (middle), and soft-tissue prominence surrounding abdominal aorta (arrow) (right).
Computed tomography of the abdomen and pelvis (Figure) revealed marked intrahepatic and extrahepatic bile duct dilatation with enhancement of the walls of the bile ducts and diffuse sausage-shaped enlargement of the pancreas. No discrete pancreatic or biliary mass was visualized. A marked soft-tissue prominence surrounded the abdominal aorta, suggestive of retroperitoneal fibrosis. Computed tomography showed no obvious malignant process as the cause of our patient’s symptoms. Therefore, further imaging with ERCP or magnetic resonance cholangiopancreatography (MRCP) was indicated to investigate the possibility of a retained stone in the common bile duct. Because the patient refused more invasive ERCP, MRCP was performed. The modality revealed multiple dilated intrahepatic and extrahepatic bile ducts, thickened and enhanced walls of the extrahepatic bile ducts, and a mildly dilated and segmentally thickened main pancreatic duct extending to the level of the pancreatic head. The pancreas was diffusely enlarged. No definitive pancreatic mass, bile duct stone, or other obstructing ductal lesion was identified. 3. Considering the MRCP findings in this patient, which one of the following is the most likely diagnosis? a. Pancreatic cancer b. Cholangiocarcinoma c. Primary biliary cirrhosis (PBC) d. Primary sclerosing cholangitis (PSC) e. Autoimmune pancreatitis (AIP) The patient had no evidence of pancreatic cancer or cholangiocarcinoma, but these diagnoses are still possible given that many early carcinomas are difficult to visualize on imaging. However, the absence of frank hepatobiliary or pancreatic cancer should lead to consideration of other causes of obstructive jaundice. Although PBC can manifest as jaundice, this entity, which classically involves the small bile ducts rather than the larger intrahepatic and extrahe1162
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patic duct involvement seen in this patient, usually occurs in women. Thus, PBC was not probable in this patient. The characteristic radiologic manifestations of PSC on MRCP or ERCP are multifocal stricturing and dilatation of intrahepatic and/or extrahepatic ducts, referred to as the string of beads sign, which was absent in this case. The combination of a diffusely enlarged pancreas, intrahepatic and extrahepatic duct dilatation, diffuse irregular thickening of the main pancreatic duct and intrapancreatic duct, and retroperitoneal fibrosis make AIP the most likely diagnosis.3 Further studies were needed to help confirm the diagnosis of AIP. 4. In light of the constellation of radiologic findings in this patient, which one of the following would be the most appropriate next step? a. Referral for pancreaticoduodenectomy b. Antinuclear antibody testing c. Serum IgG4 determinations d. Computed tomography–guided pancreatic biopsy e. Endoscopic ultrasonography (EUS) with fine-needle aspiration (FNA) biopsy Diagnostic modalities are still warranted at this time, and referral for pancreaticoduodenectomy would be inappropriate. Autoimmune pancreatitis is associated with other serologic abnormalities, including elevated titers of γ-globulins, IgG, and a variety of antibodies including antinuclear antibody, rheumatoid factor, anti–carbonic anhydrase antibody, and antilactoferrin antibody. However, elevations of many of these antibodies, including antinuclear antibody, are nonspecific, especially in elderly patients, and would not be the most helpful tests. Elevated levels of the IgG4 subset of IgG have been found to be a sensitive and specific marker for AIP; therefore, IgG4 determination would be the next test of choice. Both CTguided pancreatic biopsy and EUS with FNA biopsy have an important role in the diagnosis of AIP and would charac-
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teristically reveal a lymphoplasmacytic infiltrate but would not be the most appropriate next step because of invasiveness and the cost of the procedures. Serum IgG levels were obtained and revealed the following: total IgG, 2620 mg/dL (600-1500 mg/dL); IgG1, 1710 mg/dL (490-1140 mg/dL); IgG2, 857 mg/dL (150640 mg/dL); IgG3, 124 mg/dL (20-110 mg/dL); and IgG4, 548 mg/dL (8-140 mg/dL). The markedly elevated IgG4 level was strongly suggestive of AIP. Other notable laboratory test results included a random blood glucose level of 650 mg/dL (70-100 mg/dL). The clinical history of mild epigastric pain, jaundice, and weight loss in conjunction with the finding of an enlarged sausage-shaped pancreas with a peripheral halo on CT and a positive IgG4 test strongly supported the diagnosis of AIP with associated cholangitis. Thereafter, treatment recommendations were given to the patient. 5. Which one of the following would be the most appropriate treatment for this patient? a. Oral corticosteroids b. Intravenous corticosteroids c. Azathioprine d. Pancreaticoduodenectomy e. Pancreatic duct stent During the initial presentation of AIP, oral corticosteroids can relieve symptoms such as dyspepsia and cholestasis, resolve pancreatic swelling and biliary strictures, and ameliorate new-onset diabetes. Although such improvement has been noted to occur spontaneously in conservatively treated patients, corticosteroids appear to bring about these improvements in structure and function consistently and rapidly and therefore represent the best treatment option. No data are available on the use of intravenous corticosteroids for this condition. Azathioprine may have a role as a corticosteroid-sparing agent in patients who experience relapse after withdrawal of corticosteroids but would not be the initial drug of choice. Neither pancreaticoduodenectomy nor pancreatic duct stent would provide clear benefit. These procedures are invasive and can be associated with substantial morbidity. Our patient’s initial symptoms resolved spontaneously. At 3, 6, and 12 months of follow-up, he had regained islet cell function and was managing his diabetes with diet and exercise. DISCUSSION This case emphasizes the need for careful clinical and radiologic evaluation of patients presenting with symptoms that are suggestive of pancreatic carcinoma to avoid unnecessary surgical intervention. Autoimmune pancreatitis is an Mayo Clin Proc.
•
uncommon cause of benign fibroinflammatory pancreatic disease that can mimic pancreatic adenocarcinoma clinically and radiologically.3 Autoimmune pancreatitis has been called lymphoplasmacytic sclerosing pancreatitis, primary inflammatory pancreatitis, and sclerosing pancreaticocholangitis. Retrospective studies have shown that, in more than 2.5% of pancreaticoduodenectomies performed for suspected adenocarcinoma of the pancreas, the patient actually had AIP.4,5 Identifying AIP is important because corticosteroid therapy usually resolves most or all symptoms that may prompt unnecessary Whipple procedures.6 Autoimmune pancreatitis is diagnosed most commonly in male patients, with a 2:1 male-female ratio. Age at presentation is variable, with ranges reported from 30 to 80 years, but the disorder occurs most commonly in the sixth decade of life. Patients with AIP often present with symptoms suggestive of mild pancreatitis, including mild abdominal pain, weight loss, jaundice, and an obstructive pattern on liver tests, but the disease is associated with less pain than chronic pancreatitis. In the past, it has been “associated” with other autoimmune diseases, including PSC and Sjögren syndrome.7 However, recent studies suggest that these “associations” are in fact extrapancreatic manifestations of AIP that mimic other disease states.8 Radiologic studies are often performed during the workup of patients with abdominal pain. Although some symptoms that occur in AIP can mimic those of other disease processes being considered, certain findings are more characteristic of AIP. Radiologic features suggestive of AIP include focal or diffuse pancreatic enlargement with minimal peripancreatic inflammation and the absence of vascular encasement on CT or EUS.3 Diffuse irregular narrowing of the main pancreatic duct with associated multiple strictures can be seen on ERCP.3 The 2002 Japan Pancreas Society criteria9 for the diagnosis of AIP relied heavily on radiologic characteristics and mandated that imaging studies display diffuse enlargement of the pancreas along with diffuse (>33%) main pancreatic duct narrowing with an irregular wall. Recently, these criteria were revised to include patients with focal enlargement and/or focal pancreatic duct strictures.10 A recent report of the experience with AIP at Mayo Clinic supported multiple radiologic presentations, including a minority of patients with classic diffuse pancreatic enlargement, a majority with focal enlargement, and other presentations, including a distinct mass, typical acute pancreatitis changes, and a normal gland.8 Retroperitoneal fibrosis and biliary strictures have also been reported.8 Characteristic histologic findings are dense periductal and stromal lymphoplasmacytic infiltrates with stromal fibroplastic proliferation.11 Tissue biopsy is often attempted to assist with the diagnosis of AIP. However, one series found needle or wedge biopsies of the pancreas to be
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diagnostic only 50% of the time.12 Adding an IgG4 immunostain to histologic studies can greatly enhance sensitivity, as demonstrated in a recent publication.8 Hamano et al6 investigated the sensitivity and specificity of serum IgG4 for the diagnosis of AIP. Patients with AIP were found to have markedly elevated levels of IgG4, a rare immunoglobulin that can bind the C1q complement and activate the classic complement pathway. These investigators described significantly higher IgG4 serum levels in patients with AIP in contrast to those in patients with adenocarcinoma of the pancreas, chronic pancreatitis, PSC, PBC, or Sjögren syndrome. The trigger for the IgG4 elevation and its pathogenetic role in AIP are unknown. Currently, the proposed diagnostic criteria for AIP include those from the Japan Pancreas Society9,10 and the Mayo Clinic HISORt criteria proposed by Chari et al.8 The HISORt criteria suggest that to identify the full spectrum of changes associated with AIP, one must recognize its 5 cardinal features involving findings on histology, imaging, and serology; other organ involvement; and response to corticosteroid therapy. The diagnosis of AIP can be established in patients with 1 or more of the following: (1) diagnostic histologic results, (2) characteristic features on pancreatic imaging and abnormal serologic findings, or (3) pancreatic disease with abnormal serologic results and/ or other organ involvement that responds to corticosteroid therapy. The HISORt criteria consider a wide range of disease manifestations, deemphasize radiologic findings as the sine qua non for diagnosis, and emphasize both histologic findings and IgG4 immunostaining of pancreatic core biopsy specimens as a possible criterion standard for diagnosis. In cases in which AIP is strongly suspected but histologic findings are unavailable and the results of imaging studies are not classic, response to corticosteroid therapy can be used as a diagnostic test. Autoimmune pancreatitis has been found to be extremely responsive to corticosteroid therapy in multiple reports and studies,6,13-15 although symptoms may recur. Improvement in the characteristic radiologic findings, including diffuse pancreatic enlargement, and reduction in serum IgG4 levels have been shown with corticosteroid therapy.3,6,15 Secondary improvement in insulin secretion and glycemic control in patients with newly acquired or preexisting diabetes has also been reported after administration of corticosteroids.13,14,16 The typical dosage of prednisone was 40 mg/d for 4 weeks and then 5 mg each week thereafter before discontinuation.
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Clinicians need to be aware of AIP and its close mimicry of pancreatic cancer. At the very least, AIP should be included in the differential diagnosis of patients whose clinical presentation resembles pancreatic cancer. Careful review of clinical, radiologic, and serologic findings can be suggestive of AIP, with the cornerstone of diagnosis being histologic findings and immunostaining for IgG4.
REFERENCES 1. Bipat S, Phoa SS, van Delden OM, et al. Ultrasonography, computed tomography and magnetic resonance imaging for diagnosis and determining resectability of pancreatic adenocarcinoma: a meta-analysis. J Comput Assist Tomogr. 2005;29(4):438-445. 2. Delbeke D, Pinson CW. Pancreatic tumors: role of imaging in the diagnosis, staging, and treatment. J Hepatobiliary Pancreat Surg. 2004;11(1):4-10. 3. Sahani DV, Kalva SP, Farrell J, et al. Autoimmune pancreatitis: imaging features. Radiology. 2004 Nov;233(2):345-352. Epub 2004 Sep 30. 4. Abraham SC, Wilentz RE, Yeo CJ, et al. Pancreaticoduodenectomy (Whipple resections) in patients without malignancy: are they all ‘chronic pancreatitis’? Am J Surg Pathol. 2003;27(1):110-120. 5. Hardacre JM, Iacobuzio-Donahue CA, Sohn TA, et al. Results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing pancreatitis. Ann Surg. 2003;237(6):853-859. 6. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344(10):732-738. 7. Montefusco PP, Geiss AC, Bronzo RL, Randall S, Kahn E, McKinley MJ. Sclerosing cholangitis, chronic pancreatitis, and Sjogren’s syndrome: a syndrome complex. Am J Surg. 1984;147(6):822-826. 8. Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol. 2006 Aug; 4(8):1010-1016. Epub 2006 Jul 14. 9. Pearson RK, Longnecker DS, Chari ST, et al. Autoimmune pancreatitis: does it exist? Pancreas. 2003;27(1):1-13. 10. Okazaki K, Kawa S, Kamisawa T, et al. Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal. J Gastroenterol. 2006;41(7):626631. 11. Deshpande V, Mino-Kenudson MM, Brugge WR, et al. Endoscopic ultrasound guided fine needle aspiration biopsy of autoimmune pancreatitis: diagnostic criteria and pitfalls. Am J Surg Pathol. 2005;29(11):1464-1471. 12. Zamboni G, Luttges J, Capelli P, et al. Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study on 53 resection specimens and 9 biopsy specimens. Virchows Arch. 2004 Dec;445(6): 552-563. Epub 2004 Oct 27. 13. Tanaka S, Kobayashi T, Nakanishi K, et al. Corticosteroid-responsive diabetes mellitus associated with autoimmune pancreatitis [letter]. Lancet. 2000;356(9233):910-911. 14. Kamisawa T, Egawa N, Inokuma S, et al. Pancreatic endocrine and exocrine function and salivary gland function in autoimmune pancreatitis before and after steroid therapy. Pancreas. 2003;27(3):235-238. 15. Kamisawa T, Egawa N, Nakajima H, et al. Morphological changes after steroid therapy in autoimmune pancreatitis. Scand J Gastroenterol. 2004; 39(11):1155-1158. 16. Tanaka S, Kobayashi T, Nakanishi K, et al. Evidence of primary β-cell destruction by T-cells and β-cell differentiation from pancreatic ductal cells in diabetes associated with active autoimmune chronic pancreatitis. Diabetes Care. 2001;24(9):1661-1667.
Correct answers: 1. d, 2. b, 3. e, 4. c, 5. a
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