Autoimmune pancreatitis (AIP) is a unique form of corticosteroid responsive chronic pancreatitis. In recent years, a distinct clinical presentation, histology, serology, and subtypes of AIP have been identified. This rare form of chronic pancreatitis was probably first described by Henry Sarles in the 1960s. He described a type of sclerosing pancreatitis associated with hypergammaglobulinemia, which is very similar to the present-day description of AIP. The term autoimmune pancreatitis was not used until 1995, when it was coined by Yoshida and colleagues to describe a type of chronic pancreatitis associated with Sjögren-like syndrome. Early descriptions of the disease were mostly in the form of case reports. Major milestones in the description of AIP include Hamano and colleagues’ description of the association between serum IgG4 and AIP, Kamisawa and coworkers’ explanation that AIP was a systemic disease affecting multiple organs, and Chari and colleagues’ publication of the Histology, Imaging, Serology, Other organ involvement and Response to therapy (HISORt) criteria for the diagnosis of AIP.
As with any new entity, a plethora of terms and synonyms were used to describe the same disease. A major reason for this varied use of terms is that AIP is a heterogeneous disease. We now know that previously described entities such as lymphoplasmacytic sclerosing pancreatitis, idiopathic duct centric pancreatitis, IgG4-associated pancreatitis, and steroid-sensitive sclerosing pancreatitis are descriptions of the subtypes of AIP and not different diseases. The use of these alternate terms hindered progress; therefore, it was recently agreed that AIP should be divided into type 1 and type 2 to facilitate international uniformity in description.
Subtypes of AIP
AIP is a heterogeneous disease with two distinct subtypes: type 1 and type 2, which are classified according to histology. However, the clinical presentation can suggest a strong basis for suspecting one subtype from the other, as there are numerous differences between the two subtypes, along with a few similarities ( Table 1 ). Most of the current literature on AIP is based on what we know about type 1 AIP. We are still in the early stages of understanding and describing type 2 AIP. In this article, unless explicitly stated, the generic term AIP pertains to type 1 AIP.
| Type 1 AIP | Type 2 AIP | |
|---|---|---|
| Gender distribution | M > F | M = F |
| Histology | ||
| • Lymphoplasmacytic infiltrate | Yes | Yes |
| • Storiform fibrosis | Present | Infrequent |
| • Obliterative phlebitis | Present | Infrequent |
| • IgG4 + cell infiltrate | Present | Scant|none |
| • Pancreatic duct destruction | Absent | Present |
| • GEL lesions | Absent | Present |
| Histologic confirmation need for diagnosis | Not in all cases | Yes |
| Serum IgG4 elevated | Mostly | No |
| Other organ involvement | Yes | No |
| Responds to steroids | Yes | Yes |
| Disease relapse | Present | Absent |
| Association with IBD | Some | Strong |
Type 1 AIP is best described as the pancreatic manifestation of a systemic fibroinflammatory disease, which at its core has a unique histology and tissue infiltration of immunoglobulin G4 (IgG4)-positive inflammatory cells. This systemic disease can affect many different organs in such a manner that the umbrella term “immunoglobulin G4–associated systemic diseases” is used to underscore the unique role played by IgG4. All the organs afflicted by immunoglobulin G4–associated systemic diseases, including the pancreas, share a common, distinct, and discernible histology. Almost all of the early descriptions of type 1 AIP came from Asia, Japan in particular, and type 1 continues to be the predominant subtype seen there. In addition to the established diagnostic criteria that exist for type 1 AIP, the clinical presentation is so distinctive that histologic confirmation is needed in a small proportion of patients. Conversely, type 2 AIP, with its discernible histology, appears to exclusively affect the pancreas. Most of the literature describing this subtype comes from Europe and the United States. As of now, although type 2 AIP can be clinically suspected, histologic confirmation is need in all cases to make a certain diagnosis. The differences between the two subtypes are illustrated in Table 1 . It is important to note that the two subtypes are virtually indistinguishable on cross-sectional imaging, and both types are exquisitely sensitive to steroid therapy.
Pathophysiology
Because AIP is so responsive to steroid therapy, an autoimmune cause has been inferred. The precise pathogenesis of AIP has not been elucidated; however, there are interesting genetic and immunologic associations, in addition to the possibility of molecular mimicry, surrounding AIP. The most striking observation is the association between serum IgG4 and AIP. IgG4 constitutes the smallest fraction of total IgG in humans. IgG4 is involved in the activation of the classic pathway of complement. Marked elevation in serum IgG4 is seen in only a limited number of autoimmune and parasitic diseases. It is still unclear if IgG4 plays a direct pathogenic role in developing AIP or if it is an epiphenomenon. Preliminary genetic studies from Japan have suggested that a specific human leukocyte antigen (HLA) type (DRB1*0405-DQB1*0401) is associated with AIP. Molecular mimicry by microbial pathogen, which leads to a cross reaction with endogenous antigens, has been postulated as a cause of many autoimmune conditions including AIP. There is limited evidence pointing toward Helicobacter pylori as the punitive organism. The theory suggests that exposure to Helicobacter pylori could lead to AIP in predisposed individuals.
Pathophysiology
Because AIP is so responsive to steroid therapy, an autoimmune cause has been inferred. The precise pathogenesis of AIP has not been elucidated; however, there are interesting genetic and immunologic associations, in addition to the possibility of molecular mimicry, surrounding AIP. The most striking observation is the association between serum IgG4 and AIP. IgG4 constitutes the smallest fraction of total IgG in humans. IgG4 is involved in the activation of the classic pathway of complement. Marked elevation in serum IgG4 is seen in only a limited number of autoimmune and parasitic diseases. It is still unclear if IgG4 plays a direct pathogenic role in developing AIP or if it is an epiphenomenon. Preliminary genetic studies from Japan have suggested that a specific human leukocyte antigen (HLA) type (DRB1*0405-DQB1*0401) is associated with AIP. Molecular mimicry by microbial pathogen, which leads to a cross reaction with endogenous antigens, has been postulated as a cause of many autoimmune conditions including AIP. There is limited evidence pointing toward Helicobacter pylori as the punitive organism. The theory suggests that exposure to Helicobacter pylori could lead to AIP in predisposed individuals.
Histology
Both subtypes of autoimmune pancreatitis have common histologic features (periductal lymphoplasmacytic infiltrate and an inflammatory cellular stroma), which positively differentiate it from other types of chronic pancreatitis. In addition, histology serves as the basis for distinguishing the two clinical phenotypes of AIP. The histologic hallmark of type 1 AIP is a set of four features, which together are called lymphoplasmacytic sclerosing pancreatitis (LPSP). LPSP consists of a dense periductal lymphoplasmacytic infiltrate, storiform pancreatic fibrosis, presence of IgG4-positive cells (>10/high-power field), and obliterative phlebitis. In addition, the pancreatic ductal architecture is often preserved and there are prominent lymphoid follicles. When most, if not all, of these features are present, they substantiate the diagnosis of type 1 AIP. In this context, it is important to point out that the presence of IgG4-positive cells is just one of the features of LPSP and that the histologic diagnosis of type 1 AIP should not be made or excluded solely on the presence or absence of this one feature alone. Features of LPSP are also seen in the histologic specimens of the other organs involved in type 1 AIP: salivary glands and lymph nodes.
On histology, type 2 AIP also consists of a predominantly lymphoplasmacytic infiltrate but with a few key differences from type 1 AIP. There is a dense periductal inflammation with neutrophils leading to duct destruction in most cases. This characteristic lesion is called a granulocyte epithelial lesion. These lesions are pathognomonic of type 2 AIP. There is no inflammation around the intrapancreatic artery or vein and there are scant groups of IgG4-positive cells. In both forms of AIP, there is a striking absence of intraductal protein plugs, stones, and pseudocysts, which are seen in other types of chronic pancreatitis.
Clinical Context
The true incidence of AIP is unknown. The best estimates so far come from studies of patients who were presumed to have pancreatic cancer and underwent resection, but the resection specimen showed AIP. AIP was the diagnosis in approximately 3% to 5% of such patients. In Japan, the incidence of AIP was reported to be 0.82 per 100,000 people. The clinical presentation of AIP can be best divided into the acute and the postacute phase. In the acute phase, the classic presentation of AIP is that of obstructive jaundice with abdominal imaging consistent with pancreatic enlargement. Thus, in clinical practice it is imperative to differentiate AIP from pancreatic cancer. Less commonly, AIP presents with mild abdominal pain; elevated pancreatic enzymes, which may also signal acute pancreatitis; or jaundice with proximal bile duct involvement, which must be differentiated from cholangiocarcinoma. In the postacute phase, AIP can present with pancreatic atrophy and steatorrhea resembling chronic pancreatitis. A recent study from the Mayo Clinic concluded that fewer than 33% of patients with AIP have features of acute or chronic pancreatitis at presentation. More importantly, only 7 of 178 (3.9%) patients evaluated for etiology of suspected pancreatitis had AIP. Although mild abdominal pain can be seen occasionally in patients with AIP, a feature conspicuous by its absence in AIP is severe unremitting abdominal pain requiring narcotic pain medications. The presence of such severe pain should prompt a reevaluation of the diagnosis. Diabetes mellitus (DM) is seen in up to 50% of patients with AIP. Interestingly, this DM resolves in a proportion of patients with corticosteroid therapy. After initial treatment with corticosteroids, the pancreas can undergo atrophy on cross-sectional imaging, which can be accompanied by significant steatorrhea (postacute phase presentation). Untreated AIP can also lead to pancreatic atrophy and fibrosis, which in its late stages can be indistinguishable from other forms of chronic pancreatitis.
Imaging
Pancreatic imaging is the cornerstone to the diagnosis of AIP. Pancreatic imaging can be subdivided into pancreatic parenchyma imaging and pancreatic ductal imaging. Pancreatic parenchymal imaging in the form of computed tomography (CT) or magnetic resonance imaging (MRI) is often performed as part of the initial testing for obstructive jaundice. A pancreas protocol abdominal CT is rapidly becoming the imaging modality of choice to diagnose AIP. Such a CT scan serves not only to diagnose AIP, but also to help rule in or rule out pancreatic cancer. There are three classic features of AIP on a pancreas protocol abdominal CT: a diffusely enlarged, sausage-shaped pancreas with featureless borders; a low-density rim surrounding the pancreas; and delayed enhancement of the pancreas in the late arterial phase. ( Figs. 1 and 2 ). The presence of a low-density mass, along with an abrupt cutoff of a dilated pancreatic duct and atrophy of the pancreas distal to the obstruction, are all signs of pancreatic cancer, which can be detected on CT/MRI ( Fig. 3 ) . AIP can also present as a focal enlargement of the pancreas, in which case it can be very challenging to differentiate it from pancreatic cancer by imaging alone. Although MRI of the abdomen is comparable to a CT scan, higher cost and decreased availably limit its use. On MRI, T1-weighted images of the pancreas are often less intense than T2-weighted images when compared to the liver. Endoscopic ultrasound (EUS) plays a very important adjunctive role in the workup of AIP. Although classic EUS features of AIP have been described (such as a diffusely hypoechoic gland), the greatest benefit of EUS is the access it provides to obtain pancreatic tissue by fine-needle aspiration (FNA) or a core biopsy. Although an FNA is sufficient for diagnosing pancreatic cancer, it is not adequate for diagnosing AIP. For histologic confirmation of AIP a core biopsy of the pancreas is needed, and it can also help to establish the basis for the subtypes of AIP. EUS-FNA is paramount in ruling out pancreatic cancer in patients with nonclassic CT imaging features. EUS elastography and positron emission tomography (PET) are exciting newer additions to the imaging armamentarium and hold much promise, but at present are not incorporated into the existing diagnostic criteria.
Pancreatic duct imaging with endoscopic retrograde pancreatography (ERP) can be a useful adjunct in the diagnosis of AIP, especially in patients with nonclassic CT abdominal features for AIP, as well as for pancreatic cancer. A recently concluded study found that ERP features of AIP include the presence of a long narrow stricture (more than one third of the main pancreas duct), the lack of upstream dilation from the stricture, side branches arising from the strictured portion of the duct, and multiple noncontiguous strictures ( Figs. 4 and 5 ) . The presence of all these features is more suggestive of AIP than the presence of any one of them. Although magnetic resonance cholangiopancreatography (MRCP) is an attractive minimally invasive way of visualizing the pancreatic duct, ERP and MRCP have not been compared to each other.
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