Annals of Clinical & Laboratory Science 39:167-175 (2009)
© 2009 Association of Clinical Scientists
Autoimmune Pancreatitis: Case Series and Review of the Literature.
Rada Shakov1,
Joseph R. DePasquale1,
Hossam Elfarra2 and
Robert S. Spira1
1 Division of Gastroenterology, St. Michael’s Medical Center, Newark, New Jersey2 Division of Gastroenterology, St. Joseph’s Regional Medical Center, Paterson, New Jersey
Address correspondence to Rada Shakov, M.D., St. Michael’s Medical Center, 268 Martin Luther King Boulevard, Newark, NJ 07102, USA; tel 718 915 2706; fax 973 877 2984; e-mail radaroze{at}yahoo.com.
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Abstract
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Autoimmune pancreatitis (AuP) is a chronic pancreatic inflammation secondary to an underlying autoimmune mechanism. After early reports of a particular type of pancreatitis associated with hypergammaglobulinemia, others asserted that there is an autoimmune mechanism involved in some patients with chronic pancreatitis. In 1995 AuP was first described as a distinct clinical entity. Since then, there have been many documented cases of AuP in Japan, and now, perhaps due to increased awareness, more cases are being reported in Europe and the United States. Herein we present our experience with 3 cases of AuP and we review the relevant literature. These 3 cases demonstrate the difficulties that exist in making the diagnosis of AuP and the impact that the diagnosis can have on patient management.
Keywords: autoimmune pancreatitis, lymphoplasmacytic pancreatitis, IgG4
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Introduction
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The clinical entity that is now referred to as AuP has been described by a variety of terms over the last 4 decades. These include nonalcoholic duct-destructive chronic pancreatitis, lymphoplasmacytic sclerosing pancreatitis with cholangitis, chronic sclerosing pancreatitis, pseudotumorous pancreatitis, duct-narrowing chronic pancreatitis, idiopathic duct destructive pancreatitis, primary inflammatory pancreatitis, and, recently, idiopathic tumefactive chronic pancreatitis [1–8].
AuP is a chronic pancreatic inflammation secondary to an underlying autoimmune mechanism. The initial recognition that pancreatitis can result from immune dysregulation was a report in 1961 of a case of pancreatitis accompanied by hypergammaglobulinemia [9]. In 1995 the term "autoimmune pancreatitis" was used by Yoshida et al [10], stating that it was a distinct disease. Since then there have been many documented cases of AuP in Japan, and now, due to increased awareness, more cases are being reported [7,11–13].
Herein we describe 3 cases of AuP and we review the pertinent clinical and pathological features of AuP.
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Case Series
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Case 1.
A 50-year-old Hispanic female presented with 5 days of scleral icterus, pruritus, dark urine, clay colored stool, malaise, and fatigue. She denied nausea, vomiting, weight loss, or abdominal pain. Vital signs were stable and physical exam was benign. There was no history of alcohol abuse nor did the patient have any medical conditions such as diabetes, hypertension, or thyroid problems.
Serum analytes revealed an elevated total bilirubin 8.1 mg/dl (reference range 0.2–1.3 mg/dl), direct bilirubin 5.9 mg/dl (reference range 0.1–0.5 mg/dl), alkaline phosphatase (ALP) 562 IU/L (reference range 20–125 IU/L), aspartate aminotransferase (AST) 264 IU/L (reference range 3–35 IU/ L), alanine aminotransferase (ALT) 427 IU/L (reference range 3–40 IU/L), amylase 46 u/L (reference range 0–99 u/L), lipase 18 u/L (reference range 0–59 u/L), and prothrombin time (INR) of 1 (reference range 0.9–1.1). Autoimmune serologic tests, including anti-neutrophil antibody (ANA), perinuclear anti-neutrophil cytoplasmic antibody (pANCA), and anti-smooth muscle antibody (ASMA) were all negative. Ultrasound examination showed an enlarged, heterogeneous pancreas and a common bile duct (CBD) 1 cm in diameter, without evidence of intrahepatic biliary dilatation. Cat scan (CT) of the abdomen demonstrated a "prominent pancreas" (Fig. 1
) and magnetic resonance imaging (MRI) showed a diffusely enlarged pancreas with heterogeneous enhancement. Obstruction of the CBD at the pancreatic head was noted, as well as splenic vein thrombosis. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated a 4 cm distal stricture in the CBD along with proximal dilatation (Fig. 2). Sphincterotomy and placement of a plastic biliary stent into the CBD were performed and antibiotic therapy was initiated.
A pancreatic biopsy was obtained and pathologic examination revealed fragments of fibroadipose tissue with lymphoplasma cells and few eosinophils, without histologic evidence of lymphoma (Fig. 3). The patient was scheduled for a Whipple’s procedure, but antecedent to that a trial of prednisone (40 mg daily po) was started, since the diagnosis of AuP was considered. Within weeks there was remarkable improvement in the patient’s symptoms and normalization of her liver function tests (LFT). On repeat MRI and ERCP, the pancreas and CBD had both returned to normal appearance.
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Fig. 3. Pancreatic biopsy in case 1 shows fragments of fibroadipose tissue with lymphoplasma cells and few eosinophils (H&E stain, 30x).
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Case 2.
A 57-yr-old Asian (South Indian) female presented with weakness, unintentional 20 lb weight loss, dark urine, pruritus, and jaundice of several mo duration. There was no history of alcohol or illicit drug use and the medical history was significant only for hypertension. On physical exam she was a normotensive, afebrile, thin, female with obvious scleral icterus. The abdominal exam was benign without evidence of hepatomegaly or splenomegaly.
Initial serum analytes yielded a total bilirubin of 0.81 mg/dl, ALP 342 IU/L, AST 41 IU/L, ALT 95 IU/L, amylase 63 u/L, and lipase 35 u/L. On CT exam, the gallbladder was moderately distended with wall enhancement, but without gallstones or pericholecystic fluid. The pancreas was without focal or diffuse enlargement. On ultrasound exam, the CBD was dilated to 9 mm without evidence of intrahepatic biliary dilatation. The LFT were repeated and autoimmune serologic tests were obtained. The ALP was IU/L, AST 169 IU/L, and ALT 224 IU/L. The ANA, ASMA, and anti-mitochondrial antibody (AMA) tests were all negative; IgG, however, was elevated, 2,644 mg/dl (reference range 694–1,618 mg/dl). MRI exam showed dilatation of the central intrahepatic and extrahepatic biliary ductal system with dilatation of the gallbladder without calculi, a 1.4 cm CBD, and normal pancreatic duct (PD). The pancreatic head was without signal abnormalities on T1 or T2 weighted sequences. ERCP demonstrated firm bulbous swelling of the major papilla and tissue biopsies were obtained to rule out cholangiocarcinoma or ampullary cancer. There was an area of irregular filling with an apple-core appearance in the distal biliary tree (Fig. 4). Brush cytology samples were obtained with subsequent placement of a 7 cm straight plastic stent across the lesion. The ampullary biopsy revealed acute and chronic inflammation, marked reactive changes, and prominent lymphoid aggregates with extensive crush artifact and focal ill-defined epitheloid cell clusters. No evidence of carcinoma was identified.
Because of the appearance of the distal biliary tree, specifically the apple-core lesion, the patient underwent a successful Whipple’s procedure. After the surgery the patient was noted still to have jaundice, and laboratory analyses were repeated. The total bilirubin and ALP were elevated, 5 mg/dl and 739 u/L, respectively. The cause of these elevations was unknown and an MRI was performed. There was no evidence of intra- or extrahepatic biliary ductal dilatation nor any evidence of a filling defect.
Surgical pathological examinations of biopsies subsequently revealed multiple nodular lymphoplasmacytic infiltrates with acinar destruction in the pancreas, again without evidence of carcinoma. The ampulla, hepatic duct, cystic duct, CBD, and pancreas all had severe diffuse lymphoplasmacytic eosinophilic infiltrates associated with fibrosis and destruction of pancreatic acini, consistent with AuP. The patient was started on daily prednisone therapy with improvement in symptoms and normalization of the serum transaminases and total bilirubin.
Case 3.
A 62-yr-old Caucasian male presented with abdominal and epigastric pain with concomitant 12 lb weight loss. The patient also noticed yellowing of his skin and eyes. There was a history of chronic alcohol abuse, although the extent and quantity were unclear. Medical history was significant for hypercholesterolemia and hypertriglyceridemia. Initial serum analyses showed total bilirubin 2.0 mg/dl, AST 23 IU/L, ALT 32 IU/L, albumin 4 g/dl, amylase 515 u/L, and lipase 648 u/L. CT exam of the abdomen displayed fullness of the pancreatic head without evidence of a discrete mass. A portion of the pancreatic duct near the junction of the neck and body revealed moderate dilatation.
Approximately 1 mo later, the tests were repeated and revealed a total bilirubin of 18.6 mg/dl, AST 354 u/l, ALP 388 u/L, ALT 778 IU/L, direct bilirubin 12.3 mg/dl, positive ANA, and IgG subclass 4 of 113 mg/dl (reference range 1–115 mg/dl). A mass (4.0 x 2.5 x 2 cm) at the pancreatic head was observed on abdominal ultrasound. The CBD was 1.18 cm with some intrahepatic prominence. Subsequent ERCP demonstrated a CBD stricture requiring stent placement. The body of the pancreatic duct displayed beading with distortion of the secondary radicles. Following ERCP the patient under-went endoscopic ultrasound (EUS) with fine needle aspiration (FNA). Although there was no evidence of cancer, there were insufficient cells for sampling and a definitive diagnosis could not be made. A few weeks later the patient was hospitalized with symptoms of cholangitis, which lead to replacement of the original stent. Due to the patient’s history of alcohol abuse and radiologic findings, the differential diagnoses included chronic pancreatitis and pancreatic malignancy. Surgery was recommended based on the inconclusive findings.
The patient underwent a successful Whipple’s procedure and pathological findings were consistent with AuP. Following surgery the patient had complete resolution of his symptoms although he was never treated with corticosteroids.
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Clinical Features of AuP
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Patients with AuP may be completely asymptomatic or have mild abdominal discomfort without attacks of pancreatitis [14]. The most common clinical presentation is painless obstructive jaundice, which is also a common presentation of pancreatic cancer. The biliary obstruction is secondary to autoimmune sclerosing cholangitis involving the bile duct [15]. There appears to be an association with type 2 diabetes, caused by T-cell mediated mechanisms mainly involving islet beta cells and pancreatic duct cells [15]. Unlike most autoimmune processes where there is female preponderance, the most common form of AuP occurs more frequently in males, particularly elderly males, with an overall ratio of approximately 2:1 for all males [16].
AuP patients can be subdivided into clinico-pathologically distinct groups. The first and most common group is seen in older males, mainly in their 60s, and is associated with Sjogren’s syndrome and bile-duct stenosis. Histologically these cases tend to display the lymphoplasmacytic sclerotic pattern of AuP [14]. The second form is seen in younger patients, mainly in their 40s, exhibiting an equal male to female ratio and more frequently found in patients with inflammatory bowel disease. Histologically these cases resemble neutrophilic ductitis [16].
In addition to the sclerotic process and ductal changes, vascular changes can be found. The small veins are more commonly involved. Obliterative arteritis is less common [18]. In some cases (earlier lesions) inflammation is more peri-vascular ("peri-phlebitis"), while in more advanced lesions, venulitis can obscure the involved vessel ("obliterative phlebitis") making the vessel recognizable only by its contours or the remaining lumen that looks like a defect in the center of an inflammatory focus [16].
AuP may in fact be a systemic autoimmune disorder with various extrapancreatic manifestations. Biliary lesions, sialadenitis, retroperitoneal fibrosis, enlarged celiac and hilar lymph nodes, chronic thyroiditis, inter-sititial nephritis, and intersititial pneumonia have been described [19,20].
A new classification system for chronic pancreatitis (TIGAR-O) has been proposed. According to this system, chronic pancreatitis is categorized as idiopathic, genetic, toxic-metabolic, autoimmune, recurrent and severe acute pancreatitis, or obstructive, with AuP classified as an isolated and syndromic type [14,17].
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General Pathological Observations in AuP
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Grossly, the inflammation in AuP is commonly found in the head of the pancreas and can mimic carcinoma [21]. Less frequently, AuP is seen in the body or tail of the pancreas [18,22,23]. A gray to yellow-white induration of the affected tissue occurs with loss of normal lobular shape because of the inflammation. The histologic hallmark in the pancreas is an intense inflammatory cell infiltrate around medium and large sized interlobular ducts [24,25]. In advanced cases involvement of smaller ducts may occur [23,24]. This infiltrate may be mainly subepithelial with rare infiltration of the epithelium with lymphocytes [15]. The lumen may have a star-like appearance because the infiltrates encompass the ducts and narrow their lumens by infolding the epithelium [23]. In later stages periductal fibrosis thickens the duct wall. In contrast to other forms of chronic pancreatitis such as alcoholic, tropical, or hereditary, no distinct ductal dilatations, pseudocysts, or calculi (intra-ductal calcifications) are found in AuP [23].
The biliary tree can also be involved. The common bile duct demonstrates marked thickening of the wall due to a diffuse lymphoplasmacytic infiltrate combined with fibrosis [23]. Intrahepatic biliary involvement can also be present. When this occurs there may be overlapping features with primary sclerosing cholangitis. The gallbladder may also be affected and 25% of resected gallbladder specimens from AuP patients show diffuse acalculous lymphoplasmacytic cholecystitis [27]. This type of cholecystitis associated with AuP is characterized by deep mural inflammation and a significant number of IgG4 positive plasma cells.
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Pathophysiology of AuP
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The pathogenesis of AuP remains a mystery. The occasional coexistence of AuP with other auto-immune diseases suggests that there may be common target antigens in the pancreas and the other exocrine organs, such as the salivary glands, biliary tract, and renal tubules [28]. A number of autoantibodies such as rheumatoid factor (RF), p- ANCA, ANA, ASMA, AMA, antithyroglobulin, and anti-microsomal antibodies have been reported [29]. Other autoantibodies such as antilactoferrin antibody (ALF) and anticarbonic anhydrase II (CA-II) have also been reported. CA-II and ALF are distributed in cells of several exocrine glands and the high prevalence of these antibodies suggests that they might be target antigens in AuP [28].
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Histopathology and Clinical Pathology of AuP
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Microscopic findings in AuP show lymphoplasmacytic sclerosing pancreatitis with diffuse lymphoplasmacytic infiltration and pronounced acinar atrophy [30]. The contiguous soft tissue and the entire pancreas may display fibrosis that is similar to the findings in retroperitoneal fibrosis. Obliterative phlebitis in and around the pancreas can involve the portal vein.
Some AuP patients have abnormally high serum amylase and lipase levels, but these are not specific features. In 94% of patients with AuP, serum levels of IgG4 are elevated [21]. Elevated IgG4 levels in the presence of radiologic findings may warrant initiation of steroid therapy.
Immunohistochemical staining shows mainly CD3 positive T-lymphocytes in the periductal infiltrate, which includes a combination of CD4 and CD8 cells [31]. CD20 positive B-lymphocytes and macrophages that label CD68 are also present [30]. The CD4 and CD8 cells contain HLA-DR. The HLA-DR antigens are expressed on pancreatic duct cells and CD4 positive T cells, which suggests that an autoimmune process is involved in the inflammation [28]. The CD4 cells are divided into Th1 and Th2 type cells based on cytokine production. The Th1 cells predominate over Th2 cells in some cases of AuP. They may be essential in the induction or maintenance of AuP whereas Th2 cytokines may be involved in disease progression, especially local B cell activation [28].
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Imaging Findings in AuP
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The first diagnostic test in AuP patients is often an abdominal ultrasound. A hypoechoic diffuse swelling in the pancreas (sausage-like appearance) or focal swelling of the pancreas mimicking a neoplastic lesion may be observed [32]. Dilatation of the CBD due to inflammation of intrapancreatic portion may be seen as well. The irregular focal or diffuse narrowing of the main PD or the intrapancreatic bile duct, which are often present, may not be seen by ultrasound.
The most common finding on CT is a diffusely enlarged pancreas without peripancreatic fat infiltration, phlegmon, or pseudocysts. A "sausage-like" appearance of the pancreas can be observed. The pancreas appears hypodense as compared to the spleen on arterial enhanced phase whereas in the delayed phase the attenuation increases [33]. A capsule-like low-density rim around the pancreas in early and delayed images can be seen in some patients who show delayed enhancement.
ERCP frequently reveals diffuse segmental irregular narrowing of the main PD [33]. This finding parallels the pathologic findings of the pancreatic duct lumen, which is compressed by lymphoplasmacytic infiltration and fibrosis. The terms "diffuse" and "segmental" are used to describe the narrowing; the former indicates that the entire main PD is narrowed whereas the latter describes strictures involving multiple parts of the pancreas with other parts appearing normally.
MRCP can be used in place of ERCP, but is limited in that AuP is a narrow-duct disease [27]. No exogenous contrast is used in MRCP and the resolution is inferior to that of ERCP, so the pathology of the main PD is not clearly defined.
EUS with core biopsy can be diagnostic for AuP. Immunostaining of tissue for IgG4 is imperative [34]. Unfortunately, core biopsies are done in a limited number of institutions and as of yet the evidence in support of EUS with FNA alone in diagnosing AuP is lacking. [22]. Even when the CT findings are normal, EUS can show diffuse gland enlargement and is a sensitive tool for alterations in echotexture. If one suspects AuP and a diagnosis of pancreatic cancer must be ruled out, then the use of EUS with FNA or EUS with core biopsies should be considered.
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Diagnostic Criteria for AuP
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In 2002 the Japan Pancreas Society published the first diagnostic criteria for AuP [35–37]. These criteria set an initial standard regarding diagnosis. In 2006, the Intractable Pancreatic Diseases research team funded by the Ministry of Health, Labor and Welfare and the Japan Pancreatic Society expanded the diagnostic criteria [19,38]. Response to steroids was added by the Asan Medical Center [35,36]. Kim et al [33,36] and Pearson et al [39] incorporated histology and cytology, an association with other probable autoimmune diseases, and the response to steroids in their proposed criteria. Most recently, new diagnostic criteria were published from the Mayo Clinic [26]. These criteria take into account all aspects of imaging, pathology, laboratory values, and the response to steroids. Table 1 presents a comparison of various formulations of diagnostic criteria for AuP.
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Therapeutic Approaches in AuP
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Steroids are a well-known efficacious treatment in AuP, leading to regression of the inflammatory infiltration and pancreatic fibrosis [5,40,41]. Prednisolone is usually started po at 30–40 mg/day with a taper of 5–10 mg/day to the lowest effective dose at 1–2 week intervals [17,22,35,36,41]. There are second line agents that have also been used, but the outcomes are less clear. These include proton pump inhibitors and histamine 2-receptor antagonists (at their regular doses), atropine sulfate (1.5 mg/day po in divided doses), and scopolamine hydrobromide (1.2–2.4 mg/day) [17,42]. Gabexate mesilate, a protease inhibitor, has also been administered iv at dosages of 100–300 mg/day [17,42]. Morphologic improvement is indicated by normalization of imaging and normalization of IgG4 levels. These are also indices that favor the discontinuation of treatment [43].
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Discussion
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AuP is a major clinical problem because it can be readily mistaken for pancreatic cancer. Our 3 cases illustrate the need for greater awareness of AuP and the difficulties in making a definitive diagnosis.
In case 1, a diagnosis of AuP was not initially entertained. A biopsy of the pancreas was performed to rule out pancreatic cancer or lymphoma. The histology showed evidence of lymphoplasma cells and few eosinophils; there was no histologic evidence of lymphoma. No staining for IgG4 was requested. Fortunately, the treating physicians were aware of AuP as a clinical entity and entertained the diagnosis. In the hope of avoiding unnecessary surgery a trial of steroids was initiated. There was remarkable improvement in the patient’s symptoms and LFT within weeks. The jaundice, malaise, and fatigue resolved and the LFT ultimately normalized. On repeat MRI and ERCP, the pancreas and CBD both returned to normal appearance.
In case 2, an "apple-core" lesion was found on ERCP. The patient was female, presented without abdominal pain, and had an unexplained 20 lb weight loss. The findings appeared most consistent with bile duct or pancreatic malignancy. Parenthetically, the pancreas was normal on imaging studies. Biopsies of the ampulla of Vater and brushings of the bile duct were negative. In short, none of clinical parameters were typical for AuP. As a result the diagnosis was not considered. An IgG4 test was never ordered. No steroids were given. A diagnosis of cholangiocarcinoma was suspected. The patient was sent for surgical evaluation at a university center. At that time surgery was deemed the best option. Only when the pathological finding were reported was AuP diagnosed and the patient was started on steroids.
In case 3, the patient presented with jaundice, unexplained weight loss, and abnormal imaging studies. In addition, he had a history of chronic alcohol abuse. ERCP showed evidence of distortion of the main pancreatic duct. In addition, distortion of secondary radicles, suggestive of chronic alcoholic pancreatitis, was also seen. Serological tests were performed. The ANA was positive but the IgG4 result was normal. Finally, EUS was done but was not diagnostic. Even though a diagnosis of AuP was seriously considered the findings were deemed inconclusive. As a result, the team referred the patient to a university facility that specialized in pancreatic diseases for a second opinion. Surgery was recommended. The patient had a successful Whipple’s procedure performed. His symptoms revolved completely following surgery. Steroids were never started and he remains symptom free.
Physicians in the USA are becoming more aware of AuP as a distinct clinical entity due to the growing number of reported cases in Japan and Europe. AuP should be considered in any patient who presents with pancreatitis, including chronic alcoholics and patients who have only radiologic findings or laboratory results that suggest AuP. In patients with episodes of recurrent pancreatitis or unexplained pancreatitis, AuP is now routinely considered in the differential diagnosis. Based on our experience, we believe that timely diagnosis of AuP requires keen awareness of the disease and an appropriate index of suspicion. This awareness coupled with imaging studies, laboratory tests, and, ultimately, tissue biopsy, will be necessary to make the timely diagnosis.
Our case presentations underscore the varied clinical presentations of AuP. Not all patients are middle-aged men who present with abdominal pain, jaundice, elevated serum IgG4 level, and enlargement of the pancreas. In fact, the clinical presentation, lab results, and imaging studies may not be diagnostic. In case 3 all of the appropriate tests including EUS with FNA were performed and the diagnosis was still uncertain. If a trial of steroids had been included in the diagnostic criteria, surgery might have been avoided. Ultimately, tissue diagnosis with immunohistochemical assays is the gold standard for diagnosis.
New criteria for diagnosing AuP have been developed by various institutions and it is essential for physicians to be cognizant of the updates. Initially, the use of radiology, pathology, and lab values were the key factors in diagnosis. Now the response to steroids has an important role as well. Questions may arise regarding the use of steroids in patients without a definitive diagnosis in an attempt to avoid surgery. A consensus should be established regarding the diagnostic criteria in an effort to aid physicians in evaluating and treating patients appropriately. Although there are a number of criteria available, we believe that the Mayo Clinic criteria [26] are the most comprehensive.
Patients can fit into 1 of 3 groups in which histology, imaging, serum IgG4 values, and response to steroids are taken into account. The inclusion of response to steroids as a diagnostic criterion differentiates the Mayo criteria from the Japanese criteria. This inclusion provides physicians with the broadest scope and best possibility for making the diagnosis of AuP before surgery.
In conclusion, AuP should be considered in any patient presenting with elevated pancreatic enzymes, mild abdominal pain, enlargement of the pancreatic head, and/or hypergammaglobulinemia. A complete evaluation based on established diagnostic criteria should follow. Tissue biopsy with immunohistochemical assays remain the gold standard for diagnosis. A trial of steroids is reasonable if the diagnosis is uncertain after a careful evaluation. This may help avoid unnecessary surgery. Unfortunately, even when AuP is suspected, the diagnosis may not be established until surgical pathology results are available.
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Abstract
Introduction
