Autoimmune setting of acute pancreatitis associated with inflammatory

Autoimmune pancreatitis (AIP) has been described as a chronic fibroinflammatory pancreatic disease that is corticosteroid-responsive when used as a management strategy. There are two well-described subtypes of AIP within the literature. Lymphoplasmacytic sclerosing pancreatitis (LPSP) belongs to the spectrum of immunoglobulin G-subclass-4 related disease with obstructive jaundice being the most common manifestation of the disease. LPSP also has several extrapancreatic pathologies associated with it, including lacrimal and salivary gland lesions, hilar lymphadenopathy and pulmonary lesions, sclerosing cholangitis, retroperitoneal fibrosis, and tubulointerstitial nephritis. Idiopathic duct-entric pancreatitis (IDCP) is a similar but distinct manifestation of AIP that mimics LPSP radiologically but presents usually with abdominal pain in the setting of acute pancreatitis associated with inflammatory bowel disease (IBD). IgG4 elevations in LPSP are typical while IDCP rarely occurs with IgG4 elevations. Histologically, there are some similarities while there are also some distinct differences between LPSP and IDCP. LPSP presents with lobular lymphoplasmacytic infiltrate obliterative phlebitis and storiform fibrosis while IDCP presents with granulocyte epithelial lesion (GEL), described as intraepithelial and intraluminal neutrophils that infiltrate the small and medium-sized ducts. Management of AIP typically consists of corticosteroid administration for 2-4 weeks followed by a steroid taper, which studies have shown reduces the relapse rate in patients being treated for AIP. If relapse occurs or steroids are not tolerated by the patient, Rituximab (RTX) has shown good efficacy when managing AIP patients who failed steroid therapy or cannot tolerate steroids. The long-term outcomes of AIP has been recently studied and some clinical manifestations after prolonged follow up found that some patients would go on to develop exocrine and endocrine dysfunction, particularly after stopping corticosteroid therapy. There has been much debate on whether AIP increases the risk of developing pancreatic malignancy or extrapancreatic malignancy. Most studies have come to the conclusion that the risk of developing a malignancy in patients with AIP is similar to the risk in the general population. However, one must be mindful that pancreatic malignancy can happen concurrently with AIP and should be ruled out prior to starting therapy.


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In 1961, Sarles et al the term idiopathic chronic pancreatitis in patients that presented with obstructive jaundice and hypergammaglobulinemia.1 In 1995, the term “autoimmune pancreatitis” was adapted to common literature, introduced by Yoshida et al.2 Today, Autoimmune pancreatitis (AIP) can be defined as a chronic fibroinflammatory steroid-responsive disease of the pancreas. Type I AIP refers to lymphoplasmacytic sclerosing pancreatitis (LPSP) that is more common among East Asians, typically characterized by IgG4-positive plasma cells in extrapancreatic organs, as described by Kamisawa. 3 Type II AIP refers to idiopathic duct-centric chronic pancreatitis (IDCP) typically seen in younger patients in a Western society like Europe and the US, characterized by the presence of granulocyte epithelial lesions proposed to lead to duct destruction. 4 AIP has also shown to have a strong association with inflammatory bowel disease (IBD), particularly with type II AIP versus Type I AIP that generally carries a worse prognosis and greater disease severity. 5 AIP has been used to describe these two separate disease entities that have various overlapping clinical and histological features. However, there are significant differences in the clinical course, diagnostic approach and management strategies that must be addressed to achieve improved clinical outcomes. Because of these two subtypes and their distinct features, it has been proposed to describe the two phenotypes as AIP referring to LPSP and IDCP as its own separate category as IDCP. The diagnostic challenge with AIP, particularly in the Western nations, is the apparent prevalence of IgG4-seronegative AIP along with extrapancreatic manifestations that could affect diagnostic accuracy. Another diagnostic hurdle is the similar presentations and mimicry of AIP to pancreatic neoplasm, which warrants urgent evaluation and diagnosis. The short-term prognosis of AIP is generally favorable as evidenced by radiological and clinical improvement after steroid therapy. However, there is limited data when it comes to long-term sequelae associated with AIP given the relatively recent discovery of high IgG4 serum levels in patients with AIP. In this article, we will examine the two different subtypes of AIP, their diagnostic criteria, and outline the treatment strategies recently employed for these diseases. We will reflect on the importance of early recognition of AIP and make the distinction between AIP and pancreatic cancer. We will also provide a comprehensive overview of the long-term outcomes of AIP including pancreatic stone formation, pancreatic exocrine/endocrine dysfunction, concurrent malignancy, and mortality rates.

Subtypes of Autoimmune Pancreatitis

Recent studies have elucidated to the fact that there are two main subtypes of AIP. Type 1 AIP, per Mackay in 1969, is defined by the presence of IgG4 autoantibodies, hypergammaglobulinemia, the deposition of immunoglobulins, and is steroid responsive.6  Type II AIP differs from its counterpart in that there are no serologic markers associated with Type II AIP.  However, there is a deposition of C3c and IgG within the basement membrane of pancreatic ducts and acini suggesting immune-mediated complex destruction of these structure in Type II AIP making the classification of type II AIP as a true AIP unclear.7





Clinical manifestations of LPSP


Patients with LPSP typically present at an older age compared to IDCP. In a multinational analysis of a total of 1064 patients from 23 different institutions found that the average age of diagnosis for LPSP is 61.4 (as compared to patients with IDCP who presented on average at the age of 39.9).8 Although painless obstructive jaundice is a similar presentation that can be found in both LPSP and IDCP, the most common clinical presentation in LPSP is obstructive jaundice. In a cohort study of 731 patients, 75% of patients with LPSP presented initially with jaundice compared to 47% of patients with IDCP. Patients with LPSP also were found to have more incidences of diffuse swelling of the pancreas compared to IDCP.9 Obstructive jaundice observed could be related to pancreatic swelling and subsequent biliary tree compression or proximal extrahepatic and intrahepatic biliary stricture, which can also be associated with IgG4-mediated colangitis.10 LPSP can also present in a variety of extrapancreatic lesions, including lacrimal and salivary gland lesions, hilar lymphadenopathy and pulmonary lesions, sclerosing cholangitis, retroperitoneal fibrosis, and tubulointerstitial nephritis.11-13 LPSP seems to be the pancreatic manifestation of IgG4-related disease, characterized by swelling of the pancreas, elevated serum IgG4 levels, and extrapancreatic lesions associated with the infiltration of IgG4+ plasma cells.14


Serology of LPSP

IgG4 + plasma cells have been studied extensively and may play a role in the pathogenesis of LPSP. In a cohort study from Mayo Clinic of 45 patients with LPSP, patients with a serum IgG4 level >140mg/dl had a sensitivity of 76% and specificity of 93% in diagnosing LPSP.15 The median IgG4 level in patients with LPSP in a cohort study of 20 patients with sclerosing pancreatitis was 663 mg/dL as compared to normal patients who had median IgG4 levels of 51 mg/dL.16 IgG4 titers, however, can be nonspecific and can be elevated in pancreatic cancer as well.17 Therefore, serology alone should not be routinely used to diagnosis LPSP.

Radiology of LPSP

Contrast-enhanced computed tomography (CECT) is the optimal imaging study to assess parenchymal changes within the pancreas as well as to exclude malignancy. Magnetic resonance cholangiopancreatography (MRCP) or endoscopic cholangiography (ERCP) are useful in assessing the biliary and pancreatic duct abnormalities that can arise from LPSP. Diffuse parenchymal enlargement is a characteristic radiologic finding seen in patients with LPSP described as “sausage-shaped” with featureless and effaced normal lobular architecture of the pancreas.18 For focal LPSP that presents with a homogeneous enhancement of the lesion in the delayed phase (likely due to retention of contrast), MRCP or EUS may show the main pancreatic duct penetrating through the mass lesion, called a positive duct penetrating sign. Long (>1/3 duct length) segment involvement or focal narrowing of the pancreatic duct and multiple strictures in the affected segment without significant upstream dilatation (10 cells/HPF) is a widely accepted diagnostic marker for LPSP.17 IgG4 immunostaining can be used as supportive evidence for the diagnosis. However, it is non-specific and can be found in several other conditions, such as pancreatic malignancy and pancreatitis. 


Clinical Presentation of IDCP

The most common clinical presentation in these patients is acute pancreatitis, occurring in 1/3 to nearly 2/3 of patients with IDCP.22-23 Other common clinical features of IDCP also include painless obstructive jaundice, focal pancreatic mass, and symptomatic pancreatic duct stricture formation.24 IDCP typically affects younger patients with a mean age at diagnosis being 39.9 years (compared to 61.4 years in Type I AIP) as proposed by one of the largest case series on AIP.25 In a case series of 43 patients at Mayo Clinic diagnosed with IDCP, the median age for patients diagnosed with IDCP was 31 years of age and about half of the patients were found to be women.26 For IDCP, there appears to be no difference in prevalence among men and women with a nearly equal male-female ratio.25 IDCP is more common amongst European and US populations, accounting for 20-40% of AIP cases in Europe and the US.27 Several reports have also concluded that there is a significant association with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC) where there is an increased risk of developing UC compared to the general population.28 Among Western countries, the prevalence of AIP-UC is between 30-35% and Eastern countries like Japan and Korea report a prevalence rate of 16% and 5.8% respectively.5 When AIP and IBD occur concurrently, the disease severity is more severe and the prognosis is poorer compared to patients with IBD alone. In a retrospective study comparing patients who underwent a colonoscopy showed more extensive colitis in patients diagnosed with AIP-UC compared to the UC only group with 66.7% of patients from the AIP-US group underwent surgery due to refractory colitis.29

Serological Markers of IDCP

Features of LPSP serologic markers such as elevated IgG4 level and multiorgan involvement are not present in IDCP, making diagnosis difficult unless histological features are examined and tested for.30

Radiological Features of IDCP

The presence of a distinct focal mass on radiographic imaging is the most common feature of IDCP, found in up to one-third of patients with IDCP. Another common radiographic finding is diffuse pancreatic enlargement, particularly in the absence of peripancreatic fat stranding which can be useful in distinguishing between other etiologies of acute pancreatitis. Little is known about perfusion abnormalities and pancreatic duct changes given the relative rarity of the condition compared to LPSP and therefore would require further investigation to differentiate the two subtypes radiologically.24

Histological manifestations of IDCP

There are similar histological patterns that are shared between LPSP and IDCP, including periductal lymphoplasmacytic infiltrate and storiform fibrosis.12 However, the hallmark histologic feature of IDCP not seen in LPSP is the granulocyte epithelial lesion (GEL), described as intraepithelial and intraluminal neutrophils that infiltrate the small and medium-sized ducts, can form microabscesses, and is often associated with duct destruction.19,1 IDCP also usually has none or very few (