HLA class II serotypes DRB1*0405 and DQB1*0401 have been associated with increased disease susceptibility in Japan [18]. In contrast, this was not demonstrated in Korea, where disease relapse was associated with aspartic acid substitution at DQβ1-57 [19]. Single nucleotide polymorphisms (SNP) involved in disease susceptibility or recurrence have been reported to be present within genes encoding cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), tumour necrosis factor-alpha (TNFα) and Fc receptor-like 3 (FcR-3) [20–23] (Table 5.1). However, most genetic studies have centred on AIP in Asian patients and the applicability of this to other ethnic groups remains uncertain.

The involvement of the biliary tract, gallbladder and liver in many patients with AIP may suggest loco-regional factor(s) in pathogenesis. Peribiliary glands, which are physiologically distributed around the extrahepatic and intrahepatic large bile ducts [24] may be severely damaged in patients with IAC [25]. These glands are known to contain small amounts of exocrine pancreatic acini [26]. It has been postulated that a common antigen could be expressed in these glands, leading to the spectrum of manifestations observed in the hepato-biliary-pancreatic ductal system.

A role for gastric Helicobacter pylori in the pathogenesis of AIP was suggested in 2005 on the basis that H. pylori was associated with other autoimmune disorders and an increased detection of peptic ulcers in patients with AIP [27]. Significant homology between human carbonic anhydrase-II (CA-II) and α-carbonic anhydrase of H. pylori in segments containing the binding motif of the susceptibility HLA molecule DRB1_0405 was demonstrated [28], and the authors proposed that this pathogen may trigger AIP in genetically predisposed individuals by means of molecular mimicry. This hypothesis was supported by the detection of antibodies against plasminogen-binding protein of H. pylori in 94 % of patients in an Italian cohort with AIP [29]. In a recent study, no sequences of H. pylori DNA could be demonstrated in tissue or pancreatic juice from patients with AIP suggesting a direct infection was unlikely [30]. The role of this pathogen remains undetermined.

Several autoantigens have been investigated based on the theory that IgG4-RD is an autoimmune disorder. Non-specific antinuclear antibodies are identified in more than half of patients. Autoantibodies against lactoferrin (LF) and carbonic anhydrase (CA)-II, expressed in exocrine organs including the pancreas, salivary gland, bile duct, and renal tubules, can be detected in 73 and 54 % AIP patients, respectively [31]. A strong positive correlation between increased serum IgG4 levels and anti-CA-II antibody levels has been reported [32]. Anti-CA-IV antibodies, expressed in the epithelial cells of several organs, have also been detected in 34 % of AIP patients [33]. The wide distribution of LF and CA was suggested to provide a unifying explanation for the multisystem involvement in IgG4-RD, but these antibodies are non-specific for the disease. Antibodies against pancreatic secretory trypsin inhibitor (PSTI) were detected in 30–40 % of AIP patients [34] and autoantibodies against pancreatic exocrine enzymes and anti-PSTI antibodies were demonstrated by RNA microarray of pancreatic tissue and immunoassays in AIP patients from Europe [35]. In a proteomics study from Japan, a 13.1-kDa protein was identified as a candidate autoantigen, although the sequence has not been determined [36].

IgG4 is the least common IgG subclass representing less than 5 % of total IgG in the serum [37]. However, it can account for up to 80 % of total IgG after chronic exposure to certain antigens. IgG4 is a unique antibody with important amino acid differences to IgG1 in the CH2 domain resulting in an inability to activate complement via the classical pathway and reduced cellular immune responses due to decreased binding to the Fc-gamma receptors of effector cells [17, 38]. In the core hinge region, an amino acid switch allows IgG4 to undergo exchange of half-antibodies generating functionally monovalent antibodies which cannot cross-link antigens or form large immune complexes. IgG4 can bind the Fc portion of other IgG molecules at its constant domain, contributing to its anti-inflammatory function.

A direct role for IgG4 antibody in the pathogenesis of IgG4-RD has not been confirmed. IgG4 autoantibodies have not been detected in IgG4-RD although they have been shown to play an important role in unrelated immune-mediated disorders such as pemphigus vulgaris [39]. Interestingly, IgG4 in sera from patients with AIP can bind with normal human bile and pancreatic duct epithelia, a reaction that was abolished with steroid therapy [40]. The dense infiltration of the affected tissues with IgG4-positive plasma cells and the elevated levels of serum IgG4 seen in the majority of patients is still unexplained, but may be an epiphenomenon of the disease [10].

The immune-pathogenesis underlying the prominent lymphoplasmocytic infiltration with abundant IgG4 positive plasma cells in this disease is not fully understood. On immunohistochemistry, both CD20+ B cells and CD4+ T cells are present. In tissue and blood, a Th2 immune response predominates with increased expression of IL-4, IL-5 and IL-13 [41, 42], unlike other autoimmune disorders such as PSC and PBC where Th1 immune responses result in increased production of IFN-γ [43, 44]. These Th2 responses and related cytokine profile may explain some of the findings in IAC including the elevated serum IgE level, peripheral and tissue eosinophilia seen in some patients [45]. A role for Th2 cytokines in the bile of IAC patients in disrupting the biliary epithelial cell barrier function leading to chronic biliary inflammation in these patients has also been proposed [42]. There is a well-known association of Th2 responses with allergic disorders, and a history of allergy reported in over half of patients with AIP, although an allergic trigger has not been demonstrated so far.

Inducible-memory T regulatory cells (Tregs) and their regulatory cytokines were found to be up-regulated in both peripheral blood [46] and the affected tissues [41] of AIP and IAC patients. The reasons for this are not completely understood. Tregs are well known to play an important role in prevention of autoimmune disorders [47] and the attenuation of immune reactions associated with allergic and infectious disorders [48] by producing the regulatory cytokines IL-10 and tumour growth factor-b (TGF-b). The up-regulation of Tregs in IAC and AIP, therefore, may represent a secondary reaction to the excessive Th2 responses. It has been demonstrated previously that IL-10 can induce B cells to isotype switch to produce IgG4 [49] and that TGF-b is an important cytokine involved in tissue fibrogenesis. Therefore, the up-regulation of these two regulatory cytokines may mediate the two major histological manifestations of IgG4-RDs, i.e. infiltration of IgG4-positive plasma cells in affected tissues and storiform fibrosis.

Epidemiological data on the prevalence of IAC is scarce due to the lack of population-based studies. Most studies come from Japan and focus mainly on AIP. The estimated prevalence of AIP was reported to be 0.8 cases per 100,000 persons in Japan and the incidence was estimated to be 0.28–1.08/100,000, with approximately 336–1300 new cases per year [6]. Around 74 % of AIP patients are reported to have a concomitant IAC whereas isolated IAC is seen only in 8 % of cases [50]. Therefore, the prevalence of IAC may be estimated to be around three quarters that of AIP. Approximately 10 % of patients originally diagnosed with “sclerosing cholangitis” will have steroid-responsive strictures of the biliary tract with lymphoplasmocyticinfiltrates and IgG4-positive plasma cells in their bile ducts histology—these patients most likely have IAC rather than PSC, although diagnostic criteria should be adhered to when making this diagnosis [51].

The prevalence of IAC among patients diagnosed as PSC was evaluated by some previous studies that reported that approximately 7–9 % of patients presenting as PSC have features of IAC [52, 53]. In the largest two series of patients reported from Mayo Clinic [50] and King’s College in London [2], the majority of patients were adults, male and typically older than 50 years.

The spectrum of radiological features in IAC is variable and nonspecific. As only a few cases present with isolated biliary disease, pancreatic disease is usually evident on imaging. Dynamic computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) may show diffuse enlargement of the pancreas or a focal lesion that mimics pancreatic cancer [63] (Fig. 5.2). Other less commonly described findings include acute pancreatitis, pancreatic atrophy and diffuse enhancement [50] (Fig. 5.3). Although the ability of MRCP to delineate abnormalities of the main pancreatic duct is limited as compared to retrograde cholangiopancreatography (ERCP) in almost half of patients with diffuse type AIP [64], it continues to be a valuable non-invasive tool for the detection of pancreatic gland abnormalities as well as for follow-up of patients with IAC/AIP. Hilar space-occupying lesions or hepatic mass-like lesions mimicking CCA and HCC, respectively, are among other possible findings.

Strictures, wall thickening or both are the most frequently reported radiological abnormalities in patients with IAC. Circular and symmetrical thickening of the bile duct wall, smooth outer and inner margins, and a homogenous internal echo can be demonstrated on abdominal ultrasonography (US) [65], CT [66], MRCP, endoscopic ultrasound (EUS) and intraductal ultrasonography (IDUS). Interestingly, these features can be demonstrated in both stenotic and non-stenotic areas as well as in the gallbladder wall.

The distribution of the radiological changes in IAC is variable. Although a distal common bile duct (CBD) stricture is classical (Fig. 5.4), the involvement of both intrahepatic and extrahepatic bile ducts is evident in approximately 50 % of patients [55, 67] (Fig. 5.5). Inflammation and/or edema of the pancreas may contribute to the stricture; however, thickening of the bile duct itself can usually be demonstrated [68]. MRCP is helpful for delineating the distribution and the extent of the strictures; nevertheless, direct assessment by ERCP or percutaneous transhepatic cholangiography is usually indicated. Advantages of ECRP in this regard relate to its better sensitivity for the detection of subtle changes in the biliary tree and the main pancreatic duct as well as its therapeutic implications including obtaining brushings and biopsies for histopathology assessment and temporary stent insertion to relieve obstructive jaundice or cholangitis [38, 64]. EUS has a role to obtain fine needle aspirates (FNA) to exclude dysplasia and biopsy of a mass where possible.

Due to “similar” cholangiography findings, IAC was thought once to represent a PSC variant. There are however subtle differences on imaging [69]. Segmental strictures, long strictures with pre-stenotic dilatation and strictures of the distal common bile duct are typically seen in IAC whereas band-like strictures, beading, pruned-tree appearance and diverticulum-like out-pouching are more typical of classical PSC. Recently, Japanese investigators proposed a cholangiography-based classification for IAC [70]. According to this IAC can be classified into four types. IAC Type 1 is characterised by an isolated distal CBD stricture with chronic pancreatitis—pancreatic cancer and CCA being the most relevant differential diagnosis, which can be distinguished by IDUS [71], EUS-FNA [72] and/or biopsy of the bile duct [7, 71]. In IAC type 2, both the intrahepatic and extrahepatic bile ducts are involved and it must be differentiated from PSC. Based on the presence or absence of pre-stenotic dilatation with the intrahepatic strictures, this type is further subdivided into Type 2a and 2b respectively. The significance of these subtypes is unclear; however, Type 2b is thought to result from marked lymphoplasmocytic infiltration into the peripheral bile ducts. IAC Type 3 is characterised by hilar and distal CBD strictures whereas Type 4 shows only hilar strictures and both should be distinguished from CCA by means of EUS, IDUS, cytology and/or biopsy of the bile duct. It must be mentioned, however, that the cholangiography findings in some patients with IAC do not fit into any of these four types and the clinical utility of this approach has not been validated.

Although the microanatomy of the affected organs and probably the age of the lesions may cause some variability, the histological findings in IAC are generally similar to those seen in other organs involved in IgG4-RD. The large bile ducts are usually affected; however, changes in the small intrahepatic bile ducts can be occasionally demonstrated on liver biopsy.

There is no pathognomonic feature of IAC. Common features seen in IAC such as pancreatic duct abnormalities (7–15 %), increased serum IgG4 (9–36 %) and IgG4-positive plasma cells (23 %) were reported to occur also in patients with PSC and other disorders [3]. Therefore, IAC diagnosis must be based on a combination of clinical, serologic, imaging, and histologic findings [4]. Multiple diagnostic criteria have been proposed in order to distinguish IAC from other conditions that may share similar features. The HISORt (histology, imaging, serology, other organ involvement and response to corticosteroid) criteria for AIP [63] and its IAC version [50] (Table 5.2), Asian consensus criteria [79] and most recently new Japanese criteria [80] (Table 5.3) are the most widely applied. Although these criteria share almost the same diagnostic items, the combination of criteria required to establish a definite diagnosis is variable. For example, a definite diagnosis can be established in the presence of either typical histology from a previous resection or biopsy or classic imaging of AIP/IAC with increased serum IgG4 levels according to the HISORtcriteria [50]. In patients who have do not meet these criteria and have a high index of suspicion, every effort should be made to rule out malignancy. This is followed by a re-evaluation after 4 weeks of corticosteroids therapy and if a response is observed the diagnosis of IAC can be confirmed. In contrast, response to steroids is considered as an optional criterion by the Asian and Japanese criteria and its presence cannot establish a definite diagnosis in the absence of other criteria that are considered crucial for definite diagnosis [79, 80].