Keywords

Introduction

Autoimmune pancreatitis (AIP) represents a rare form of chronic pancreatitis having distinct and characteristic clinical, radiologic, chemical, and histological features. The pancreas has no organ-residing immune system like the hollow gut system (MALT). However, in acute and even more so in chronic pancreatitis as well as in pancreatic cancer, a dense inflammatory infiltrate can be observed [1]. While the autoimmune diseases of the liver have been known for decades and their particular immunopathology is rather well understood [2], AIP seems to have appeared at the end of the last century as a novel disease. However, 50 years ago Henry Sarles had already discovered autoantibodies in some of his patients with chronic pancreatitis [3, 4], and sometime later associations of pancreatitis with primary biliary cirrhosis (PBC) [5] and Sjögren’s syndrome [6, 7] were described. Furthermore, pancreatitis is part of some syndromes of polyglandular autoimmune diseases (PGAD) [8]. In the 1990s, a “lymphoplasmacellular sclerosing pancreatitis” in conjunction with cholangitis was described [9] and in 1995 the term “autoimmune pancreatitis” was introduced [10]. AIP can be considered an enigmatic disease, widening the possible spectrum of inflammatory diseases of the pancreas. This might explain the unforeseen interest in the disease, where the number of publications exceeds the number of patients [11].

After the formation of national guidelines, which were sometimes conflicting [12–17], the three major societies [i.e., JPS (Japan), APA (USA), and EPC (Europe)] came together for an “International Consortium for Diagnostic Criteria” (ICDC) of autoimmune pancreatitis [18]. As a major result, two subtypes of AIP were acknowledged that are defined both by histology and by clinical picture [19] (Table 5.1). Type 1 is IgG/IgG4-positive (both serum and tissue) [20] with more “other organ involvement” (OOI) as it represents a systemic “immunogammopathy” [21]. AIP type 2 is eosinophilic infiltration in the pancreas (see below).

Table 5.1 ICDC diagnostic criteria of definite and probable AIP type 1
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Etiology and Pathogenesis

The pathogenesis of AIP is unclear in contrast to other forms of pancreatitis [22]. Similar to Sjögren’s syndrome and primary sclerosing cholangitis (PSC), CD4+ Th1 cells dominate. Patients with AIP, especially in Japan, demonstrate HLA loci [23], with two of them carrying an increased risk of developing AIP: HLA class II haplotype DRB1 * 0405-DBQB1 * 0401, and the ABCF1 gene, localized on the proximal part of the telomere region C3-2-11 in HLA-E class I [23, 24].

As is the nature of any autoimmune disease, several common autoantibodies have been detected, such as antinuclear autoantibodies (ANA) . Disease-specific autoantibodies in AIP are against ductal antigens such as lactoferrin (ALF) and carbonic anhydrase type 2 (ACA-II) [25] as well as against acinar antigens such as SPINK1 [26, 27], ubiquitin-protein ligase E3 component n-recognin 2 (UBR2) [28], and trypsinogens [27]. Most of these autoantibodies will be of IgG as this Ig class is elevated, especially IgG4 [20]. Lactoferrin and carbonic anhydrase type 2 are characteristic for so-called specialized secretory epithelium that, besides the pancreas, also is found in the salivary glands, the lung, the renal tubule, and the bile ducts—tissues that can all become sites of systemic autoimmune disease [29] as “other organ involvement” in type 1 AIP with a lymphoplasma cellular IgG4-positive inflammatory infiltrate [30]. As in other immune-triggered systemic diseases such as mixed connective tissue disease (MCTD) or soft-tissue rheumatism, the spectrum of organ manifestations is wide. There is a limitation: Not all patients with an IgG4+ infiltrate in the pancreas (or elsewhere) present with increased blood levels of IgG4 [20, 31–33].

The autoimmune character of the disease is not fully understood: Thymectomy in neonatal mice and immunization with lactoferrin and carbonic anhydrase type II led to AIP [34]. Lymphotoxin can induce AIP [35]. While T-cell-negative I-A-chain−/−(Ab0) mice develop AIP spontaneously, HLA-DRB1*0405 is the predisposing factor [36]. In the MRL/Mp model, suppressing regulatory T cells increases the severity of AIP [37]. However, the triggering factors are unclear. The histology seems suggestive of exogenous factors. Consequently, viral and other xenobiotic factors have been studied. With a murine retrovirus, an “exocrinopathy” could be developed, including pancreatitis and Sjögren-like changes [27, 38], resembling AIP. Immunization of mice with apathogenic E. coli caused autoantibodies against carbonic anhydrase type II [39].

One of the most fascinating theories is proposing Helicobacter pylori as being the causative agent [40], the rationale being a “molecular mimicry” [41] between the H. pylori enzyme CA and the human carbonic anhydrase type II (CA-II), the lead enzyme of pancreatic duct cells [42] and one of the described autoantibodies in AIP. Interestingly, this sequence incorporates a binding motif of HLA DRB1*0405 that is associated with some patients with AIP [23, 24]. However, H. pylori DNA or RNA could not be detected in the pancreas of patients with AIP [43]. Another host protein, UBR2 (ubiquitin-protein ligase E3 component n-recognin 2), shows a high homology with the cagA protein of H. pylori [28]. Even if H. pylori itself could not be found in pancreatic tissue in AIP, the concept of “molecular mimicry” is suggestive for the pathogenesis of AIP. Another attempt to hit an exogenous, disease-causing agent failed as well in that varicella zoster virus (VZV) could not be detected in the tissue of patients with AIP [44].

Pathology

Macropathology

Upon gross pathology, AIP may resemble pancreatic ductal adenocarcinoma (PDAC). In 50–80 % of AIP, a tumorous mass is described in the pancreatic head. Together with obstructive jaundice [30] and enlarged lymph nodes, the diagnosis of PDAC is highly suggestive. It must be noted that the typical dilation of the main pancreatic duct (MPD) is missing in AIP and the pancreas typically lacks pseudocysts and calcifications, which are described rarely.

Histopathology

A histological grading system has been proposed [30] and reevaluated [45] (Table 5.2). The histopathological features of AIP are lymphoplasmacellular infiltrates, destroying ductal and later even acinar tissue. The exocrine pancreas is replaced by fibrotic tissue (Fig. 5.1). Granulocytic epithelial lesions (GEL) mark a specific histopathological finding. Focal destructions of the epithelial lining are caused by neutrophilic granulocytes. GEL also incorporate eosinophils.

Table 5.2 ICDC Levels 1 and 2 diagnostic criteria for AIP type 1 according to ICDC
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Fig. 5.1
figure 1

Overview of autoimmune pancreatitis (H&E staining) with the typical lymphocellular infiltrates around a pancreatic duct and storiform fibrosis

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As a major result of the ICDC [18], AIP was classified in two distinct subtypes [46]: a lymphoplasmacytic sclerosing pancreatitis (LPSP, type 1) with IgG4-positive cells (Fig. 5.2) and an idiopathic ductocentric chronic pancreatitis (IDCP, type 2) with GEL and eosinophils.

Fig. 5.2
figure 2

Immunohistochemistry for IgG in AIP type 1

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Epidemiology

There are no reliable data on the incidence and prevalence of AIP; however, AIP can be considered a rare disease. Depending on the reference group of patients (acute or chronic pancreatitis), the prevalence was described between 4.7 and 10 % [14, 31, 32, 47].

AIP is more common among males, even more pronounced in the Asia-Pacific population. The peak seems to be above the age of 50 [48], but with a wide range spanning essentially all ages.

Clinical Picture

As a spinoff of ICDC, the data of close to 1000 patients were gathered. The clinical picture and initial presentation can vary widely. Abdominal pain seems to be the major symptom [19]. Another feature, albeit sometimes misleading the diagnosis, is painless jaundice, found in 48–86 % of cases [47, 49]. Cholangitis can be the leading symptom, preceding the diagnosis of IAP by months. AIP can present as acute pancreatitis as well [50], maybe more often in younger patients [51]. Nausea and weight loss are also typical, the latter in about a third of cases. The inflammatory pancreatic head tumor can be the cause of a gastric outlet syndrome (obstruction). The disease is sometimes diagnosed best by analyzing the associated diseases (OOI), at least in type 1 AIP, as these may be the dominant symptoms.

Association with Other Autoimmune Diseases/Organ Involvement

Other organ involvement is a typical feature of type 1 AIP [19], found in 37–50 % of all patients (Fig. 5.3).

Fig. 5.3
figure 3

Possible affection of other organs (other organ involvement, OOI) in autoimmune pancreatitis

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Crohn’s disease (CD) and ulcerative colitis (UC) are associated with AIP [52]; it looks as if UC is more associated with type 1 and CD with type 2 AIP [19]. Inflammatory bowel disease (IBD) is the next most frequent OOI following cholangitis. The association between AIP and CD is more frequently observed in younger patients [52, 53]. Pancreatic exocrine insufficiency is present in most AIP patients and in about 40 % of IBD patients [54].

Diabetes mellitus (DM) is an autoimmune disease on its own but is also observed frequently in AIP. Most of these patients exhibit the typical criteria of DM type 1 with autoantibodies against islet cells (ICA), glutamic acid decarboxylase (GAD), and the tyrosine phosphatase-like protein [19]. It has been reported that diabetes mellitus in AIP ameliorates under steroid therapy [55].

Associations between AIP and autoimmune hepatitis or primary biliary cirrhosis are rare [19].

Affection of the biliary tract by IgG4-associated cholangitis (IAC) is the most frequent overall OOI in AIP, naturally occurring in type 1AIP, hence warranting special attention [19]. IAC occurs both in the intra- and extrahepatic bile ducts as well as in the gallbladder wall [56]. The findings in the bile ducts in AIP may mimic PSC [57]. Due to the fact that IAC/AIP responds well to steroids, in contrast to PSC, the differential diagnosis is pivotal.

Extraintestinal manifestations of the AIP include lung and kidney lesions (Fig. 5.3). The pulmonary lesions are made up of diffuse small nodules, infiltrates, and/or hilar adenopathy that can clinically impress as interstitial pneumonia. Lesions in the kidney appear as tubulointerstitial nephritis leading to mild renal insufficiency. Renal lesions have a distinct morphology on multidetector CT (MDCT) [58].

Further OOI as manifestations of IgG immunopathy in AIP type 1 are idiopathic retroperitoneal fibrosis, scleroderma, lymphadenopathy, as well as inflammatory pseudotumors of the hypophysis, lungs, and liver [59]. Rare autoimmune conditions accompanying AIP are systemic lupus erythematosus (SLE), autoimmune hepatitis (AIH), idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis (RA), and thyroiditis [60].

Diagnosis

Laboratory Diagnostics

Serum amylase and lipase in AIP are normal or slightly elevated. Patients may have signs of obstructive jaundice (transaminases, bilirubin, alkaline phosphatase, GGT) [19, 47]. Eosinophilia and increased serum IgE can be found [50]. A pathological glucose tolerance (OGTT) or type II diabetes can be diagnosed in conjunction with AIP (54–76 %) [19, 47]. Pancreatic exocrine insufficiency can develop [19] and may be transient [61, 62].

Serology

The most predominant findings in AIP are elevated serum IgG and IgG4 [20], also found in other autoimmune diseases [63]. The specificity of IgG4 to discriminate AIP from PDAC is said to be 98 %, with a sensitivity of 90.4 %. The sensitivity of total gamma globulin (IgG) in serum was estimated between 59.1 and 73.3 % [33]. Further generic autoantibodies are antinuclear antibodies (ANA) (76 %; n = 13/17), rheumatoid factor (RF) (29 %; n = 5/17), and antibodies against smooth muscle (ASMA) (18 %; n = 3/17).

As mentioned above, there are several specific autoantibodies described. Those are directed against antigens in the pancreatic ducts such as lactoferrin and carbonic anhydrase type II (ACA-II) [25]. Further autoantibodies have been described against acinar antigens, such as SPINK1 [26, 27], ubiquitin-protein ligase E3 component n-recognin 2 (UBR2) [28], and trypsinogens [27]. The frequency described in the few studies varies: lactoferrin (ALF) in 76 % (n = 13/17) and carbonic anhydrase type II in 59 % (n = 10/17) [64]. It seems as if patients in Europe do not express these autoantibodies as often as patients from the Asia-Pacific region [65]. The acinar antigens or respective autoantigens cannot be tested with commercial kits. Therefore, as confirmatory studies are currently lacking (but are under way), these autoantibodies, which could greatly simplify the diagnosis of AIP, have no clinical impact at present.

Imaging

AIP presents in about 60 % of patients with a pancreatic head tumor; therefore, PDAC is the most important differential diagnosis in cross-sectional imaging [58, 66, 67]. Nevertheless, there is a distinct, not to say pathognomonic picture of AIP: In both MRI and MDCT, a capsular enhancement can be detected [68] (Fig. 5.4). Sometimes a peripheral hypoattenuation (“halo”) can be seen. Another typical picture is a diffuse swelling of the entire pancreas (“German bratwurst”) or parts thereof that can be accompanied by obliteration or affection of the MPD and/or distal bile duct (Fig. 5.4). In both magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP), a small MPD with strictures can be seen. A typical finding is a distinct contrast enhancement of the distal bile duct as a sign of the AIP-associated cholangitis (IAC) [69].

Fig. 5.4
figure 4

Imaging in autoimmune pancreatitis. (a) MDCT with contrast and a hypodense swelling of the pancreatic tail. (b) T2-weighted MRI, demonstrating the segmental vanishing of the MPD and a reduction of signal. (c) T1-weighted MRI with contrast, demonstrating reduced uptake in the pancreatic tail similar to MDCT (all images are from the same patient)

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Any possible finding in the pancreas may occur: from acute pancreatitis to atrophy of the gland. Pancreatic pseudocysts and MPD dilatations, however, are atypical, as are calcifications. Ordinary transabdominal ultrasound seems not to be helpful; however, both contrast-enhanced ultrasound as well as elastography are claimed to allow for a more robust diagnosis and distinction from PDAC [70].

Endoscopic ultrasound (EUS) will show a hypoechogenic, sausage-like enlarged pancreas [71, 72]. The parenchymal pattern is said to be typical of contrast-enhanced ultrasound as well as elastography. EUS offers the option of taking a biopsy [45, 73]. A histological diagnosis is an important part of establishing the diagnosis according to ICDC (Figs. 5.1 and 5.2). The yield of EUS-guided FNA or Trucut biopsy in establishing the diagnosis of AIP or IAC is around 50 % [74, 75].

In Japan, ERCP is still used as a diagnostic tool. It would show the same findings as in MRCP: segmental, irregular narrowing of the MPD and stenosis of the CBD. ERCP, however, has little or no value in the differential diagnosis of autoimmune cholangitis (IAC) versus PSC [76].

Classification and Diagnostic Criteria

There have been several proposals to classify and diagnose chronic pancreatitis. All had their impact in their respective time. For AIP, a panel of experts reached a consensus (ICDC), addressing both the diagnosis and the classification of AIP [18]. In addition, we developed a scoring system for chronic pancreatitis allowing for the grading of disease activity [77]. This tool can be used to monitor disease activity according to therapy.

The classification of AIP requires clear criteria for diagnosis according to ICDC. According to the clinical reality, two categories are formed: “definite” versus “probable” with morphological criteria (histology, imaging) (Tables 5.1 and 5.3). These criteria have been further detailed (Tables 5.2 and 5.4). The criteria are described separately for AIP type 1 (Tables 5.1 and 5.3) and AIP type 2 (Tables 5.2 and 5.4). Based on these criteria, diagnostic algorithms are proposed, separately for AIP type 1 (Figs. 5.5 and 5.6) and AIP type 2 (Fig. 5.7). Application of these ICDC in the years to come will prove whether they are adequate to diagnose and classify AIP [78].

Table 5.3 ICDC diagnostic criteria for AIP type 2 (definitive and probable)
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Table 5.4 ICDC levels 1 and 2 diagnostic criteria for AIP type 2
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Fig. 5.5
figure 5

ICDC algorithm to diagnose AIP type 1 in patients with jaundice and typical findings (level 1) [18]

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Fig. 5.6
figure 6

ICDC algorithm to diagnose AIP type 1 in patients with jaundice and atypical imaging (level 2) [18]

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Fig. 5.7
figure 7

ICDC algorithm to diagnose AIP type 2 in patients with jaundice and both typical and atypical imaging (levels 1 and 2) [18]

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Therapy

Treatment with steroids should be considered in patients who fulfill the ICDC criteria and who are symptomatic (pain, jaundice). It should be noted that even if there is a significant bile duct stricture leading to obstructive jaundice but the diagnosis of AIP is secured, patients can be treated with steroids first without the need for immediate stenting. The changes in the MPD as well as focal lesions in the lungs and kidney will respond quickly to steroid treatment. A pancreatic head tumor will also respond; however, if there is any doubt about the diagnosis of AIP according to the ICDC, cross-sectional imaging must be performed after 2 weeks to ensure appropriate shrinking of the inflammatory pancreatic head tumor—and not missing a pancreatic cancer.

Prednisone is the corticosteroid of choice. The recommended initial dose is 40 mg once daily (≈0.5 mg/kg BW) for 4 weeks, with tapering thereafter in 10-mg steps [79–81]. The scheme is following the recommendations for Crohn’s disease (Table 5.5).

Table 5.5 General treatment scheme for steroid therapy in AIP
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A significant proportion of patients will experience a relapse of AIP during the steroid taper. The recurrence rate is around 30 %, higher in type 1 AIP, especially in those where the initially elevated IgG/IgG4 is not normalized [62]. Those patients may be in need of maintenance therapy with low-dose steroids (5–10 mg prednisone daily) [47]. The OOI will also respond well to steroid therapy [49]. As an alternative, other immune suppressants can be used [81, 82]. Azathioprine would be the first choice, even if this drug itself rarely could cause pancreatitis.

In AIP with cholangitis (IAC) [83] steroids may not suffice. Relapse rates seem to be higher, especially after (unintentional) operation [84]. Jaundice as a presenting symptom is a determining factor for relapse after successful steroid medication [49], making the use of other immunosuppressive drugs necessary, such as azathioprine or mycophenolate mofetil [81, 82]. The addition of ursodesoxycholic acid (UDA) is recommended in analogy to other forms of cholangitis [45].

Natural Course and Prognosis

In contrast to pancreatic cancer, AIP is a benign diagnosis. However, the diagnosis must be safely established. There are no long-term studies on AIP at present. It is generally accepted that AIP has a good prognosis. There are case reports on pancreatic cancer in AIP. Most of the cancers occurred within a 1–2-year period of the diagnosis of AIP. In principle, it is feasible to assume that AIP could develop into PDAC, in analogy to colorectal cancer in UC; however, we are far from calling AIP a premalignant lesion [19]. Nevertheless, this differential diagnosis must be taken seriously in order to leave all patients with the option of surgical removal of a malignant tumor. PDAC as a differential diagnosis must be considered in IgG/IgG4-negative disease, i.e., type 2 AIP. If in doubt, surgery must be the choice of treatment, especially if EUS-guided biopsy is inconclusive [85].