JOP. J Pancreas (Online) 2015 Jul 08; 16(4):326-334 REVIEW ARTICLE Review Article: Diagnosis and Management of Igg4 Autoimmune Pancreatitis Ahmed Salem, Diaa Hamouda, Alyssa Parian Johns Hopkins University School of Medicine, Baltimore, Maryland, USA ABSTRACT Autoimmune pancreatitis is a rare form of chronic pancreatitis that has only recently been recognized as a separate type of pancreatitis French Henry Sarles. in the last two decades. The histopathological features of this distinct form of pancreatitis was first described as early as 1961 when the INTRODUCTION Autoimmune pancreatitis (AIP) is a rare form of chronic [8] found intensely positive IgG4 cells in extrapancreatic pancreatitis that has only recently been recognized as organ systems in AIP patients. Thus, the concept of IgG4- a separate type of pancreatitis in the last two decades. diseaserelated systemicwhereas typedisease 2 AIPemerged. appears Type to be1 AIPa pancreas is now The histopathological features of this distinct form of considered to be a pancreatic manifestation IgG4-related specificEPIDEMIOLOGY disorder. pancreatitis was first described as early as 1961 when pancreatitis associated with hypergammaglobulinemia. Up till now the true incidence of AIP is in the United the French Henry Sarles [1] described a type of sclerosing Subsequently, most of the early literature about AIP came States is unknown with reports limited to case series from Japan where the concept of Autoimmune Pancreatitis and descriptions of tertiary referrals. The estimated et al. many authors had reported a form of chronic pancreatitis (AIP)was first proposed in 1995 by Yoshida [2] after estimatedprevalence the in prevalenceJapan, where of autoimmune AIP was first pancreatitis described, in AIP was widely accepted and AIP was differentiated from is 0.82 per 100,000 persons [9]. Japanese series have otherassociated types with of chronic Sjögren's-like pancreatitis. syndrome. An increasing The definition awareness of and further research of AIP has found it is a heterogeneous patients with chronic pancreatitis to be between 5% and disorder with variations in pathophysiology, genetic 6%. Several series in the United States have reported that 2% to 3% of pancreatic resections had evidence of thatautoimmune underwent pancreatitis pancreatic at pathologic resection analysis for suspected [10-12]. predisposition and extra-pancreatic manifestations AIP was diagnosed in approximately 2%-6% of patients Asian and European observations were reported compared to chronic pancreatitis [3, 4]. form worldwide, accounting for almost all cases in Japan differently. Reports from Asia described a disease pancreatic cancer [13, 14].Type 1 AIP is the most common affecting elderly males with pancreatic histology showing and Korea and more than 80% of cases in Europe and the twiceUnited as States common [15, 16].in men Type as 1 AIPin women. has a peak It is incidence frequently in alymphoplasmacytic disease that affects sclerosing both genders pancreatitis equally (LPSP)with pancreatic [5], later the sixth or seventh decade of life [9, 16] and is at least histologycalled type characterized 1 AIP. Reports by fromgranulocytic Europe andepithelial US described lesions associated with sclerosing extra-pancreatic lesions such pancreatitis (IDCP) or type 2 AIP. 2as AIPsclerosing seems to cholangitis, affect a younger retroperitoneal subset of patientsfibrosis withand (GEL) [6], later called idiopathic duct-centric chronic sclerosing sialadenitis [17, 19]. On the other hand, Type et al. a peak incidence typically about a decade younger than aIn critical2001, milestoneHamano was reached[7] reported when increasedKamisawa serum et al. There also appears to be an association between type 2 levels of IgG4 in patients with AIP. Subsequently in 2004 those with type 1 AIP with no gender preponderance [16]. Received Accepted AIP and inflammatory bowel diseases especially ulcerative Keywords Pancreatitis; Pancreatic Neoplasms colitisCLINICAL [20-22]. PRESENTATION CorrespondenceMarch 16th, Ahmed 2014- Salem May 04th, 2015 Johns Hopkins University School of Medicine Gastroenterology Department, USA Phone phase, The presentation the most common of AIP canclinical be variable presentation [23]. Itfor can both be E-mail [email protected] subtypesdivided into of AIPan acuteis obstructive and a sub-acute jaundice, phase. typically In the painless acute +1-410-733-2204 JOP. Journal of the Pancreas - http://www.serena.unina.it/index.php/jop - Vol. 16 No. 4 – Jul 2015. [ISSN 1590-8577] 326 JOP. J Pancreas (Online) 2015 Jul 08; 16(4):326-334 Further evidence suggesting an autoimmune pathophysiology is the variety of autoantibodies against or with mild epigastric pain. The jaundice of type 1 typically carbonic anhydrase, antinuclear antibody, rheumatoid pancreatitishas a fluctuating such course as abdominal and spontaneous pain and resolution elevation has of factor, lactoferrin, trypsinogen and pancreatic secretory serumbeen reported pancreatic [13, enzymes 24]. Features greater suggestive than three of timesacute upper limit of normal are more often observed in type 2 exclusive to AIP. Animal models of AIP have been limited, trypsin inhibitor [31, 46-48], although none of these are AIP [15, 24-28]. Another key feature that can characterize but have suggested AIP may be T-cell mediated since type 1 AIP is other organ involvement (OOI) [21]. As agents that increase regulatory T-cell population and canpreviously be involved mentioned, prior, type concomitant, 1 AIP is considered or subsequent to be part to molecularactivity (sirolimus, mimicry rapamycin) in genetically had significantpredisposed benefits persons [4]. of systemic IgG4-related disease, therefore, other organs One proroposed mechanism for the pathogenesis of AIP is present with manifestations , such as biliary disease, DIAGNOSIS symptomspancreatic ofinvolvement. Sjogren’s disease,Thus type lung 1 nodules,patients interstitial can also [31, 46]. An accurate diagnosis of AIP remains challenging. The and diffuse or focal lymphadenopathy among others nephritis, retroperitoneal fibrosis, orbital pseudotumors, AIPclinical is andmisdiagnosed radiographic as findingspancreatic of AIPcancer and pancreaticand only In the subacute phase, after initial treatment, AIP can [29, 30]. realizedmalignancy after have pathology a significant from Whippleoverlap surgeryand frequently returns present with pancreatic atrophy leading to steatorrhea More concerning though, is mistaking a diagnosis of pancreaticas lymphoplasmotic malignancy infiltrates for AIP and as nodelay sign in of diagnosis carcinoma. is patientsresembling with chronic AIP. Interestingly, pancreatitis glycemic [21]. Diabetes control improves mellitus likely to close the already narrow window of curative in(DM) a subset or impaired of AIP fastingpatients glucose following is seen the intreatment up to 50% with of surgical options in these patients [50]. Many diagnostic corticosteroidPATHOPHYSIOLOGY therapy [31, 32]. different approaches of medical practice between East and criteria have evolved over the last 15 years and reflected The exact pathophysiology of AIP has yet to be fully West. The first sets of diagnostic criteria were established by the Japanese Pancreatic Society in 2002 and 2006 (JPS autoimmuneelucidated. It causeis an ofinflammatory AIP has been and inferred fibrosing due disease to the 2002, 2006) [51, 52] and consisted of three main items: profoundmarked by response pancreatic to steroidlymphoplasmacytic therapy and theinfiltrates. pancreatic An retrograde pancreatocholangiography), serology tests, characteristic radiographic findings (including endoscopic infiltrates of various types of immune cells, including CD4- and Europehistopathological diagnostic findingsERCP is used.IgG4 lesswas commonly added to duethe serological evaluation in JPS 2006. In the United States thepositive pathogenesis T-cells, IgG4-producing of AIP has been plasma studied cells mainly (in type from 1 to the risk of pancreatitis, therefore a different diagnostic anAIP), immunological and granulocytes approach (in type and 2focused AIP)[21, mainly 33-35]. on Thus, type et al.. of the approach (HISORt ) was proposed by Chari Mayo Clinic in 2006 [53] . HISORt criteria (Figure 1) constitutes1 AIP. The themost smallest striking fraction observation of total is theIgG associationin plasma imaging and serology, other organ involvement, and between serum IgG4 and AIP [7]. In healthy subjects, IgG4 responseconsisted toof corticosteroid five cardinal therapyfeatures and of newlyAIP in introduced histology, (usually less than 5%) [36, 37] and elevation in serum (Rt) as diagnostic parameters whereas ERCP was excluded IgG4 is seen in only a limited number of autoimmune asother a major organ factor. involvement (OOI) and response to steroid and parasitic diseases [37-41]. It has been demonstrated that IgG4 antibodies are unable to activate the classical the International Association of Pancreatology, the complement pathway and have limited binding to Fc- InternationalSubsequently inConsensus 2010 during Diagnostic the 14th Criteria Congress (ICDC) of gamma receptor [42]. This can be explained by the fact that IgG4 antibodiesare involved in a continuous process referred to as ‘Fab-arm exchange’ or “half antibody [21] were proposed in attempt to globally unify the AIP exchange” by swapping a heavy-light chain pair with a exceptiondiagnostic criteria.of steroid ICDC responsiveness were similar to considered the original optional HISORt