Sarles et al. 
Idiopathic chronic pancreatitis associated with hypergammaglobulinemia;suggested an autoimmune mechanism
Kawaguchi et al. 
Lymphoplasmacytic sclerosing pancreatitis (LPSP)
Yoshida et al. 
Proposal of the concept of autoimmune pancreatitis (AIP)
Hamano et al. 
Elevated serum IgG4 levels in AIP patients
Japan Pancreas Society 
First diagnostic criteria for AIP
Kamisawa et al. 
Proposal of IgG4-related systemic disease
Notohara et al. 
Idiopathic duct-centric pancreatitis (IDCP)
Zamboni et al. 
AIP with granulocyte epithelial lesion (GEL)
Chari et al. 
HISORt criteria for AIP
Kim et al. 
Korean diagnostic criteria for AIP
Otsuki et al. 
Asian diagnostic criteria for AIP
Kamisawa et al. 
Standard steroid treatment for AIP
Chari et al. 
International consensus on classification of AIP into type 1 and type 2
Sah et al.
Clinical differences between type 1 and 2 AIP
Shimosegawa et al. 
International Consensus Diagnostic Criteria
Kamisawa et al. 
International survey of AIP
Hart et al. 
International survey about long-term outcomes of AIP
The First Report of AIP
A 68-year-old woman developed jaundice and was admitted to another hospital in 1993. Radiographic examinations showed pancreatic enlargement and common bile duct (CBD) obstruction. A tentative diagnosis of pancreatic cancer was made, and exploratory laparotomy was performed. The intraoperative diagnosis was advanced pancreatic cancer, and surgery was concluded without resecting the tumor or performing a biliary bypass procedure, and no biopsy specimens of the tumor were taken. After discharge, the patient presented at Tokyo Women’s Medical University Hospital for further examination and treatment.
The patient had no history of alcohol abuse and no family history of pancreatic disease. She had no manifestations of sicca syndrome or any other collagen diseases. On physical examination, a hard, elastic mass with mild tenderness was palpated in the left upper quadrant of the abdomen in the area of the pancreas. The jaundice remitted spontaneously in the absence of any treatment. Though blood chemistry examinations showed evidence of cholestatic liver dysfunction, the total bilirubin level was normal. The pancreatic enzyme data showed an increased elastase-1 level with a low trypsin level, but she had normal lipase and pancreatic amylase levels. Levels of the tumor markers CA19.9, CEA, and Dupan-II were all within their normal ranges. Antinuclear antibody (ANA), anti-thyroglobulin antibody, and anti-microsomal antibody tests were positive. Her IgG level (2,960 mg/dL) was markedly elevated, with slight elevation of the IgE level (452 IU/mL). Though a 75-g oral glucose tolerance test showed a diabetic pattern, her HbA1c value was normal. An abnormally low value was obtained on the secretin test of exocrine pancreatic function.
Ultrasonography showed diffuse enlargement of the pancreas with a slight hypoechoic pattern and CBD dilatation. On CT scans, diffuse pancreatic enlargement was seen, with homogeneous staining of the pancreas on contrast CT. On endoscopic retrograde pancreatography (ERP), the main pancreatic duct showed diffuse narrowing, and the main pancreatic duct wall was irregular (Fig. 1.1a). Histological examination of a needle biopsy specimen of the pancreas showed severe fibrotic change and lymphocyte and plasma cell infiltration.
Based on the above findings, chronic pancreatitis was diagnosed, an autoimmune mechanism was suspected to be involved in its pathogenesis, and it was suggested that steroid therapy would be effective. The patient was given oral prednisolone 40 mg/day for 1 week, followed by gradual tapering. The pancreas showed a dramatic decrease in size 8 weeks after the start of steroid therapy, and the CBD dilatation decreased from 11 to 8 mm. ERP done 4 weeks after the start of steroid therapy showed resolution of the narrowing of the main pancreatic duct, though mild irregularity of its wall remained (Fig. 1.1b). The IgG levels became normal, and the ANA, anti-thyroglobulin antibody, and anti-microsomal antibody titers decreased. The cholestatic liver dysfunction and exocrine pancreatic dysfunction showed complete resolution, and the patient was discharged after an uneventful course.
Based on the findings described above, AIP would have been considered today, but AIP did not exist as a concept at that time. Although the patient had an abdominal mass, pancreatic cancer was unlikely, because her general condition was good, she had no abdominal pain, and spontaneous resolution of her jaundice occurred over a 1-month period in the absence of any treatment. The presence of “diffuse irregular narrowing of the main pancreatic duct” on ERP had been noticed in several previous chronic pancreatitis patients, but its cause was unknown. However, the case reported above suggested that an autoimmune mechanism may have also been involved in the pathogenesis of previous cases.
This is the first case of AIP ever reported, and it was the first case treated with a steroid, and because of the steroid therapy’s remarkable efficacy, surgery based on suspicion of pancreatic cancer has become unnecessary in cases with similar findings. Although this was only a report of a single case, the concept of AIP as a new clinical entity was proposed .
Type 1 AIP
AIP is frequent in elderly males. According to a nationwide survey  in Japan, the male-to-female ratio of AIP patients was 3.7, with a mean age of 63.0 years. In the USA, the mean age was 61 years, and 85 % was male . Obstructive jaundice induced by sclerosing cholangitis is the predominant initial symptom (74 % in the Komagome Hospital series ), and the jaundice sometimes fluctuates. Other symptoms include abdominal or back pain, weight loss, and anorexia. Diabetes mellitus (DM), usually type 2, is found in about half of AIP patients. The diagnoses of DM and AIP are made simultaneously in most patients, but some patients show exacerbation of preexisting DM with the onset of AIP [24, 25]. Mild or moderate pancreatic exocrine dysfunction is frequently detected . Signs of associated extrapancreatic lesions, such as swelling of the salivary glands, hydronephrosis, and lymphadenopathy, are sometimes seen.
Liver and biliary enzymes and total bilirubin are frequently increased. Elevation of serum pancreatic enzymes was sometimes detected, but their levels were rarely abnormally high. Peripheral eosinophilia (≥600 cells/mm3) and elevation of serum IgE levels were present in 11 and 34 %, respectively . Elevation of serum IgG levels, positive antinuclear antibody (ANA), and positive rheumatoid factor (RF) were seen in 56.9, 33.6, and 27.3 %, respectively . Serum IgG4 levels are frequently increased (77 % in the Komagome Hospital series , 81 % in the USA , and 68 % in Korea ). However, serum IgG4 levels are also elevated in some patients with pancreatic cancer (4 % (5/116) in the Komagome Hospital series  and 7 % (5/71) in the University of Pittsburgh Medical Center series ).
The typical pancreatic imaging of AIP is diffuse enlargement and effacement of the lobular contour of the pancreas, with enhancement of the enlarged pancreas in the delayed phase of dynamic CT and MRI. A capsule-like rim that surrounds the pancreas is rather specific to AIP patients [30, 31]. On diffusion-weighted magnetic resonance imaging, AIP and pancreatic cancer are seen as high signal intensity areas, which are frequently diffuse or multiple in AIP patients, while they are solitary in pancreatic cancer patients .
Ultrasound examination shows an enlarged hypoechoic pancreas with hyperechoic spots . Irregular narrowing (<3 mm in diameter) of the main pancreatic duct is a characteristic pancreatographic finding of AIP. The degree of narrowing of the main pancreatic duct can sometimes differ in the same patient [33–35]. MRCP cannot demonstrate the narrowing of the main pancreatic duct in many cases, but AIP is suggested by the presence of less upstream dilatation of the main pancreatic duct . On fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), both AIP and pancreatic cancer patients showed FDG uptake in the pancreas, but abnormal extrapancreatic FDG uptake, such as extensive lymphadenopathy or swollen salivary gland, is highly suggestive of AIP .
The histological findings in the pancreas of AIP (LPSP) are abundant infiltration of T lymphocytes and IgG4-positive plasma cells and fibrosis in a periductal and interlobular distribution. The epithelium of the narrowed pancreatic duct is usually well preserved. Obliterative phlebitis is frequently seen in the variably sized pancreatic veins [2, 38, 39].
Diagnostic Criteria and Differential Diagnosis
Recently, the ICDC  for AIP were developed to diagnose AIP safely, avoid misdiagnosing pancreatic cancer as AIP, and diagnose AIP when it presents acutely. The criteria for type 1 and type 2 AIP were developed independently, and the diagnosis of AIP is made based on one or more of the following cardinal features: imaging characteristics of the pancreatic parenchyma and pancreatic duct, serology, other organ involvement, pancreatic histology, and the optional criterion of response to steroid therapy. Each feature has been categorized as either level 1 or 2 depending on its diagnostic reliability.
The most important disease to rule out when considering a diagnosis of AIP is pancreatic cancer. CT findings (a capsule-like rim, delayed enhancement of the swollen pancreas, and presence of extrapancreatic lesions) and ERP findings (≥3-cm-long narrowed main pancreatic duct, maximal upstream main pancreatic duct <5 mm, side branch derivation from the narrowed portion, and skipped lesions) suggest AIP rather than pancreatic cancer [33, 35, 40]. However, especially in segmental-type AIP, a histological approach with endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) plays an important role in confirming the diagnosis and excluding malignancy . IgG4-immunostaining of biopsy specimens taken from the major duodenal papilla of AIP patients is useful to support the diagnosis of AIP [41–43].
Although spontaneous improvement of AIP is seen in some patients, the standard therapy for AIP is oral steroid [17, 44, 45]. It is vitally important to distinguish AIP from pancreatic cancer before steroid therapy is started. In the Japanese standard regimen [44, 45] of steroid therapy for AIP, the indications for steroid therapy are principally symptoms such as obstructive jaundice and hydronephrosis. Before steroid therapy, the blood glucose level should be controlled using insulin in patients with DM, and in patients with obstructive jaundice, the jaundice is usually managed by endoscopic or transhepatic biliary drainage. The recommended initial dose of oral prednisolone is 0.6 mg/kg/day. Morphological and serological evaluations of the effectiveness of steroid treatment are performed 2 weeks after its start. A poor response to steroid therapy should raise the possibility of pancreatic cancer and the need to reevaluate the diagnosis. When steroid therapy is effective, the steroid dose is tapered by 5 mg every 1–2 weeks to a maintenance dose over a period of 3–6 months, while the patient’s symptoms, as well as the biochemical, serological, and imaging findings, are carefully monitored. Relapses of AIP are frequent (around 30 %) [19, 20]. To prevent relapse, steroid maintenance therapy (5 mg/day) is recommended for at least about 6 months. Predictors of disease relapse include the presence of proximal bile duct involvement [20, 46] and persistent elevation of serum IgG4 levels . In relapsed cases, re-administration or dose-up of steroid [17, 44, 45] and administration of immunosuppressive drugs such as azathioprine [47, 48] or rituximab [48, 49] are effective.