Autoimmune pancreatitis is the pancreatic manifestation of a systemic disorder that affects various organs, including the bile duct, retroperitoneum, kidney, and parotid and lacrimal glands. It represents a recently described subset of chronic pancreatitis that is immune mediated and has unique histologic, morphologic, and clinical characteristics. A hallmark of the disease is its rapid response to corticosteroid treatment. Although still a rare disease, autoimmune pancreatitis is increasingly becoming recognized clinically, leading to evolution in the understanding of its prognosis, clinical characteristics, and treatment.
Autoimmune pancreatitis (AIP) represents a unique subset of chronic inflammatory pancreatic disease with distinct clinical, morphologic, and histopathologic features that typically responds dramatically to steroid treatment . Named in 1995 by Yoshida and colleagues , the clinical characteristics of the disease had been described as early as 1961. It took several decades for it to be accepted as a distinctive entity; in fact, as recently as 2003, the American Pancreatic Association still debated its existence . In the last 5 years, however, AIP has generated significant interest from clinicians and researchers, resulting in a better understanding of its pathophysiology and clinical manifestations. Although still a rare disease, it is increasingly being recognized and its existence is no longer in doubt.
This article details the full spectrum of AIP. It focuses on the history, definition, and pathophysiology of this disease. Clinical, radiographic, and histologic features are discussed as are the current diagnostic classification recommendations. Finally, this article outlines current therapeutic approaches and suggests future areas of study.
Historical Milestones
AIP is a relatively newly characterized disease entity, with much of our knowledge gained in only the last decade. Sarles and colleagues in 1961 were the first to describe an autoimmune phenomenon in relation to “sclerosis of the pancreas”. Although treatment with immune-modulating therapy was not suggested at that time, this spurred interest in this entity over the next several decades. Several terms were then used to subsequently describe the disease, including “chronic sclerosing pancreatitis,” “lymphoplasmacytic sclerosing pancreatitis,” “nonalcoholic duct-destructive pancreatitis,” “sclerosing pancreatitis,” “sclerosing pancreaticocholangitis,” and “autoimmune chronic pancreatitis” .
In 1991, Kawaguchi and colleagues described a variant of cholangitis extensively involving the pancreas. This description was quickly followed by several other reports describing other organ involvement in patients who had AIP . Ito and colleagues subsequently described the first three cases of AIP that were successfully treated with corticosteroids. In a seminal study published in 2001, Hamano and colleagues reported that elevated serum IgG4 levels were associated with sclerosing pancreatitis and that treatment with corticosteroid therapy successfully decreased these levels. The first diagnostic criteria were proposed by the Japanese Pancreas Society in 2001 and subsequently modified in 2006 . Chari and colleagues in 2006 proposed new diagnostic criteria, which included histologic, imaging, and serologic characteristics and other organ involvement and response to corticosteroids.
Definition
AIP has been defined as “the pancreatic manifestation of a systemic fibroinflammatory disease which affects not only the pancreas but also various other organs including bile duct, salivary glands, the retroperitoneum and lymph nodes. Organs affected by AIP have a lymphoplasmacytic infiltrate rich in IgG4 positive cells and the inflammatory process responds to steroid therapy” . The systemic disease of which AIP is a manifestation has been called IgG4-related systemic disease (ISD) in recognition that all organs afflicted show a dense lymphoplasmacytic infiltrate rich in IgG4-positive cells . The detection of elevated serum IgG4 levels in 5% to 10% of subjects who do not have AIP and tissue infiltration with IgG4-positive cells in more than 20% of pancreatic cancer patients questions the pathogenic role of IgG4 in this systemic disorder, however .
Definition
AIP has been defined as “the pancreatic manifestation of a systemic fibroinflammatory disease which affects not only the pancreas but also various other organs including bile duct, salivary glands, the retroperitoneum and lymph nodes. Organs affected by AIP have a lymphoplasmacytic infiltrate rich in IgG4 positive cells and the inflammatory process responds to steroid therapy” . The systemic disease of which AIP is a manifestation has been called IgG4-related systemic disease (ISD) in recognition that all organs afflicted show a dense lymphoplasmacytic infiltrate rich in IgG4-positive cells . The detection of elevated serum IgG4 levels in 5% to 10% of subjects who do not have AIP and tissue infiltration with IgG4-positive cells in more than 20% of pancreatic cancer patients questions the pathogenic role of IgG4 in this systemic disorder, however .
Epidemiology
Almost all data describing the epidemiology of AIP come from Japan. In 2002, Nishimori and colleagues randomly surveyed Japanese hospitals on how many patients they had who had pancreatitis in 2002 who fulfilled the diagnostic criteria for AIP as proposed by the Japan Pancreas Society. Based on this survey, the prevalence of patients who had AIP in Japan was estimated to be 0.82 per 100,000. AIP was predominantly seen in men past middle age (older than 45 years). Other Japanese series have described the prevalence of disease between 5% and 6% of all patients who have chronic pancreatitis .
The prevalence of AIP in the United States is unknown, because no extensive population-based studies have been performed. Because AIP often mimics pancreatic cancer in its initial presentation, the best estimates of prevalence of AIP are in patients undergoing resection for presumed pancreatic cancer because of obstructive jaundice or a pancreatic mass. In three recent studies, 43 of 1808 (2.4%) pancreatic resections were reported to have lymphoplasmacytic sclerosing pancreatitis (LPSP) on histologic examination of the resected specimen . Another retrospective evaluation of 245 pathology specimens at the Mayo Clinic from patients who underwent resection for benign pancreatic disease revealed that 27 (11%) represented AIP with a “tumefactive” presentation .
Males are nearly twice as likely as females to develop AIP and the average age of onset is in the fifth decade . In fact, 85% of patients are older than 50 years of age. One study that has evaluated the clinical characteristics of younger (less than 40 years old) patients who had AIP found that compared with older patients, the young are more likely to present with features of abdominal pain and elevated amylase .
Pathogenesis
Currently, the pathogenesis of AIP is unknown, although it almost certainly reflects an immune-mediated process. Genetic susceptibility to AIP has been linked to both the HLA-DRB1 ∗ 0405-DQB1 ∗ 0401 in the class II and the ABCF1 proximal to C3-2-11 telomeric of HLA-E in the class I regions . In addition, a recent report described the genetic association of Fc receptor-like 3 polymorphisms with AIP in Japanese patients .
The trigger for AIP remains elusive. It is hypothesized that HLA-DR antigens on the pancreatic ductal and acinar cells may serve as antigens recognized by CD4 + producing interferon-γ and CD8 + T lymphocytes, leading to subsequent inflammation. Polymorphisms of the cytotoxic T lymphocyte-associated antigen 4, a key negative regulator of the T-cell immune response, have been demonstrated in patients who have AIP . An etiologic role for antigenic Helicobacter pylori infection by way of molecular mimicry has also been proposed .
Like many immune-mediated diseases, AIP has been linked to many other autoimmune conditions, such as Sjögren syndrome, retroperitoneal fibrosis, and primary sclerosing cholangitis (PSC) . The work by Kamisawa and colleagues, however , has shown that these associated conditions are in fact manifestations of a new clinicopathological entity, IgG4-related systemic disease (ISD) that is characterized by tissue infiltration with abundant IgG4-positive plasma cells. These associated conditions often mimic other well-known diseases. For example, unlike Sjögren syndrome, the salivary and lacrimal gland pathology associated with AIP, called chronic sclerosing sialadenitis, is not associated with rheumatoid arthritis, is not usually associated with SSA and SSB antibodies, and responds to corticosteroids. In the past this condition has also been called Mikulicz disease or Kuttner tumor . Similarly, the biliary involvement in ISD has recently been termed IgG4-associated cholangitis (IAC) and may resemble cholangiocarcinoma or PSC . Other possible manifestations of ISD include Reidel thyroiditis and IgG4-associated nephritis . Whether AIP is truly associated with any other distinct autoimmune disorder needs confirmation in case-control studies.
Clinical Features
Most patients who have AIP are male and older than 50 years . The male/female predominance is approximately 2:1 . Female patients are more prevalent in the subset of AIP associated with parotid gland involvement, however . Although the age of onset is typically in the sixth decade, AIP has been described in patients in their 30s . Patients affected by AIP have been described in Eastern and Western first-world countries and in developing countries. The authors have seen histologically proven AIP in many patients from India and in Indian immigrants to the United States . AIP has also been described as an incidental finding at autopsy .
AIP has diverse clinical presentations, which may be classified in relation to onset of disease as acute or late and by the organs affected as predominantly pancreatic or extrapancreatic presentations. The most common acute presentation is with painless obstructive jaundice . Very uncommonly patients may present with typical acute pancreatitis. In the postacute phase AIP may present or be incidentally discovered because of a persistent pancreatic mass, atrophic pancreas with or without calcification, or pancreatic steatorrhea. Although patients who have AIP may have radiologic evidence of pancreatic calcification or atrophy, unlike in usual chronic pancreatitis it is painless. The pancreatic manifestations of AIP thus can mimic pancreatic cancer, acute pancreatitis, painless chronic pancreatitis, or unexplained pancreatic functional insufficiency.
The extrapancreatic manifestations are equally diverse and may be seen simultaneously with its pancreatic manifestations, may precede them, or may occur many years later when the pancreatic disease may or may not be symptomatic. The most common extrapancreatic organ involved is the biliary tree, wherein distal biliary involvement mimics pancreatic cancer–related stricture. More proximal involvement may trigger suspicion of cholangiocarcinoma or PSC. Other well-described manifestations include salivary gland involvement resembling Sjögren syndrome, mediastinal adenopathy resembling sarcoidosis, retroperitoneal fibrosis, and tubulointerstitial nephritis .
The acute presentation of AIP is with obstructive jaundice and it has received the most attention because it closely mimics the presentation of pancreatic cancer. The inflamed gland can often have the appearance of a pancreatic head mass, suggesting pancreatic adenocarcinoma. In fact, before recognition of AIP as a clinical entity, patients frequently underwent pancreatic resection for suspicion of pancreatic adenocarcinoma . Current diagnostic criteria have significantly enhanced our ability to recognize AIP and the Japanese and Korean diagnostic criteria are designed exclusively to diagnose AIP in this setting and distinguish it from pancreatic cancer.
Jaundice is usually secondary to entrapment of the intrapancreatic bile duct in an inflamed gland ; however, a true IgG4-associated distal cholangitis is also seen on histology in some patients . Although jaundice is the most common clinical symptom at presentation occurring in up to 80% of patients, multiple other symptoms have been described, such as abdominal pain, back pain, recurrent vomiting, and weight loss . Although described, acute or recurrent acute pancreatitis is a rare presenting complaint in AIP, and may be more common in younger patients . Diabetes mellitus has been reported at presentation in AIP and up to 50% of patients may present with glucose intolerance . About half of patients treated with corticosteroids have subsequent improvement in their glucose intolerance, and complete resolution of diabetes mellitus following treatment has been reported . Virtually all patients who have AIP have narrowing of dorsal or ventral pancreatic ducts on pancreatography . Idiopathic pancreatic steatorrhea should also prompt concern for AIP, especially in elderly males. Table 1 summarizes the common, atypical, and rare clinical features encountered in AIP.
| Feature | Typical (>50%) | Less common (10%–50%) | Rare (<10%) |
|---|---|---|---|
| Presenting complaint | Obstructive jaundice | Abdominal pain, weight loss, diabetes, steatorrhea | Clinical acute pancreatitis, asymptomatic |
| Histology | LPSP | IDCP | Extensive fibrosis, minimal inflammation |
| Pancreatic imaging | Diffusely enlarged gland with delayed and rim enhancement, irregular narrowed pancreatic duct | Parenchymal atrophy, intraductal calcification | Pseudocyst |
| Serology | Elevated serum IgG4 levels | Normal serum IgG4 levels | |
| Other organ involvement | Bile duct, kidneys, lymphadenopathy | Retroperitoneum, salivary gland | Mesenteritis, inflammatory bowel disease |
| Response to steroids | Complete | Incomplete | Refractory to steroids |
Histopathology
On gross examination, the pancreas in AIP is often noted to be indurated and firm . Classically, the predominant histologic feature of AIP has been dense infiltration of the periductal space with plasma cells and T lymphocytes. Associated with this infiltrate is acinar destruction, obliterative phlebitis involving the major and minor veins, and storiform or “whirling” fibrosis of the pancreatic parenchyma, which can extend to contiguous peripancreatic soft tissue . This constellation of histopathologic findings defines LPSP ( Fig. 1 ) . A less common histopathologic variant termed idiopathic duct-centric chronic pancreatitis is characterized by a neutrophilic infiltrate with occasional microabscesses and rare obliterative phlebitis . Nearly a third of patients who have AIP develop pancreatic calcification and atrophy and the appearance can resemble usual chronic calcific pancreatitis.
It is well accepted that AIP has a diagnostic pancreatic histology that distinguishes it from usual chronic pancreatitis and pancreatic cancer. Additionally, the pancreas and other organs involved in AIP show abundant infiltration with IgG4-positive cells. Immunostaining pancreatic tissue for IgG4 positivity has been shown to be a helpful adjunct in diagnosing AIP . Pancreatic resection specimens show diagnostic histology in almost all patients who have AIP in whom they are available. Histologic diagnosis of AIP requires preservation of tissue architecture, however, and hence fine-needle aspirates used to diagnose pancreatic cancer are not suitable for diagnosing AIP. The use of endoscopic ultrasound (EUS)–guided Trucut biopsy has emerged as an effective and safe tool for obtaining pancreatic biopsies in AIP . When core biopsies are obtained, the diagnostic sensitivity of pancreatic histology for AIP depends on the size of the tissue sample. For example, in a report from Mayo Clinic, only 7 of 16 (44%) subjects who underwent pancreatic core biopsy showed the full spectrum of diagnostic changes of LPSP, and 15 of 16 (94%) patients had diagnostic IgG4 immunostaining . The pancreas is often not uniformly involved by classic AIP features, however, and thus sampling error can occur , especially if visibly uninvolved areas are biopsied. In addition, staining of involved extrapancreatic tissues, such as the biliary tree, retroperitoneum, and colon, has revealed IgG4 positivity in affected patients . At this time, it is unclear whether pancreatic histology predicts disease severity or progression to endocrine or exocrine insufficiency.
Imaging Features
Characteristic cross-sectional and ultrasound imaging features have been well described in AIP. Classically, the pancreatic parenchyma is diffusely enlarged, forming a sausage-shaped gland with featureless borders ( Fig. 2 ) . Other classic features that may be present include delayed and prolonged contrast enhancement, a rimlike capsule surrounding the gland on delayed enhancement sequences (the hypoattenuation halo), a nondilated, ectatic pancreatic duct, and the absence of peripancreatic fat hypoenhancement . In a recent study, dual-phase CT scans of 74 patients (25 AIP, 33 pancreatic adenocarcinoma, and 16 normal pancreas) were independently evaluated by three radiologists blinded to clinical diagnosis . Readers correctly identified 17 to 19 of 25 AIPs (sensitivity 68%–76%) and overall accuracy was 81% to 85%. The authors concluded that dual-phase CT of the pancreas was moderately accurate in the diagnosis of AIP and in differentiating it from pancreatic carcinoma. Findings that were relatively specific for AIP included a diffusely enlarged pancreas, diffusely decreased pancreatic enhancement, and presence of a capsule-like rim, bile duct wall enhancement, and solid renal lesions.
MRI characteristically reveals enlargement of the pancreas with decreased signal intensity on T1-weighted MR images, increased signal intensity on T2-weighted MR images, and, occasionally, a hypointense capsule-like rim . Magnetic resonance cholangiopancreatography (MRCP) is often helpful in characterizing the pancreatic and bile ducts, although the narrowed segment of the pancreatic duct is not well visualized. Narrowing of the anterior superior pancreaticoduodenal artery, posterior superior pancreaticoduodenal artery, and transpancreatic artery on angiographic evaluation has also been described in AIP patients .
Increasingly, endoscopic ultrasound has been used to evaluate patients for AIP . Not only can the parenchyma and biliary and pancreatic ducts be visualized, EUS also provides an opportunity to obtain Trucut biopsy samples. Intraductal ultrasound can also be used to evaluate indeterminate biliary strictures. Levy and colleagues have reported on the diagnostic usefulness of Trucut biopsy in three patients who had suspected pancreatic adenocarcinoma with planned surgical resection following indeterminate fine-needle aspiration. In two of the patients, AIP was diagnosed using Trucut biopsy; in the other chronic pancreatitis was diagnosed. In all patients, unnecessary surgery was avoided.
Cholangiography has been shown to be an accurate method to differentiate AIP from primary sclerosing cholongitis (PSC). Nakazawa and colleagues reported that bandlike stricture, beaded or pruned-tree appearance, and diverticulum-like formation were significantly more frequent in patients who had PSC. In contrast, segmental stricture, long stricture with prestenotic dilatation, and stricture of the distal common bile duct were significantly more common in sclerosing cholangitis with AIP. Increased uptake with whole-body (18)F-fluorodeoxyglucose positron emission tomography is seen in the pancreas and extrapancreatic lesions of patients who have AIP .
A characteristic feature of the acute presentation of AIP is that the pancreatic changes improve, if not completely resolve, with corticosteroid treatment . In our experience, failure of the pancreatic imaging to significantly improve after a 2- to 4-week course of corticosteroids should cast doubt on the diagnosis of AIP ( Fig. 3 ).
Serology
Increased numbers of circulating immunoglobulins, specifically immunoglobulin subclass 4, are a hallmark of the disease . In a landmark study, Hamano and colleagues reported that serum IgG4 levels were highly (95%) sensitive and highly (97%) specific for AIP. In a recent study of 510 patients from the United States including 45 who had AIP, 135 who had pancreatic cancer, 62 who had no pancreatic disease, and 268 who had other pancreatic diseases, the sensitivity, specificity, and positive predictive values for elevated serum IgG4 (>140 mg/dL) for diagnosis of AIP were 76%, 93%, and 36%, respectively. When using a cutoff of twice the upper limit of normal for serum IgG4 (>280 mg/dL), the corresponding values were 53%, 99%, and 75%, respectively . In this study, 5% to 10% of non-AIP patient groups, including 10% of patients who had ductal adenocarcinoma, had elevated IgG4 levels . In addition, serum IgG4 levels, even in the presence of classic histologic findings of AIP, can be normal ( Table 2 ) .
| AIP | Normal pancreas | Pancreatic cancer | Benign pancreatic tumor | Chronic pancreatitis | |
|---|---|---|---|---|---|
| Number a | 45 | 62 | 135 | 64 | 79 |
| Mean IgG4 ± SM | 550 ± 99 | 49 ± 6 | 68 ± 9 | 47 ± 5 | 46 ± 5 |
| Range | 16–2890 | 3–263 | 3–1140 | 3–195 | 3–231 |
| Proportion elevated >140 mg/dL | 76% | 4.8% | 9.6% | 4.7% | 6.3% |
Elevated titers of many autoantibodies have been described in AIP. Autoantibodies against carbonic anhydrase II and IV and lactoferrin are detected in most patients who have AIP . Involvement of antinuclear and anti–smooth muscle antibodies has also been described . Autoantibodies to the pancreatic secretory trypsin inhibitor have been shown to be elevated in nearly 50% of AIP patients compared with controls . None of these autoantibodies have prediction characteristics that equal that of IgG4. Levels of total IgG and gamma globulins are also increased in AIP. In our experience, however, it is unusual to have elevated serum levels of IgG or gamma globulins without elevation of serum IgG4 levels. Although a combination of serum IgG4 levels and autoantibody titers of antinuclear antibodies and rheumatoid factor modestly increases sensitivity, it also significantly reduces specificity. The authors do not routinely use autoantibody titers to diagnose AIP.
Other Organ Involvement
Other organs are often involved in AIP; their involvement may be diagnosed before, simultaneous with, or after the diagnosis of AIP. Biliary tract is involved in 60% to 100% of all patients presenting with AIP and has recently been termed IAC . IAC affects both intra- and extrahepatic bile ducts, with the distal common bile duct being the most common site of involvement . Biliary imaging may not necessarily reveal involvement, even when present microscopically . Histologically, a lymphoplasmacytic infiltrate surrounds the bile ducts in a pattern similar to that seen in the pancreas and IgG4-positive staining is often present .
AIP coexisting with PSC has been described , although this is likely not primary sclerosing cholangitis but IgG4-associated cholangitis. It has also been shown that in a small proportion of patients who have aggressive PSC, serum IgG4 levels are elevated suggesting a possible role for corticosteroid therapy . One should be cautious in diagnosing IAC simply based on elevated serum IgG4 levels, however, because false-positive elevations may occur in true PSC. IAC differs from PSC in that there is generally less intrahepatic involvement, the strictures can be transient under observation, the strictures are usually segmental, and patients are typically pANCA negative . Inflammatory bowel disease, which is present in 70% of PSC, is less common (6%) in IAC . Analogous to the response seen in the inflammatory component of pancreatic involvement, inflammation of the biliary tree typically responds to corticosteroid treatment, although the specific response of each duct segment is still being evaluated .
In addition to the biliary system, multiple other organs may be involved in ISD . Hamano and colleagues reviewed the frequency, distribution, clinical characteristics, and pathology of five extrapancreatic lesions in 64 patients who had AIP and found the most frequent extrapancreatic lesion was hilar lymphadenopathy (80.4%), followed by extrapancreatic bile duct lesions (73.9%), lacrimal and salivary gland lesions (39.1%), hypothyroidism (22.2%), and retroperitoneal fibrosis (12.5%). No patients had all five types of lesions. Patients who had hilar lymphadenopathy or lacrimal and salivary gland lesions were found to have significantly higher IgG4 levels than those who did not. Both intrinsic (tubulointestinal fibrosis) and extrinsic (hydronephrosis secondary to retroperitoneal fibrosis) renal disease have been associated with AIP, as has inflammatory pneumonitis and inflammatory pseudotumor of the liver . Fig. 4 demonstrates some of the more common extrapancreatic manifestations associated with AIP.
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