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Japanese consensus guidelines for management of autoimmune pancreatitis: I. Concept and diagnosis of autoimmune pancreatitis

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Abstract

As the number of patients with autoimmune pancreatitis (AIP) is increasing in Japan, practical guidelines for managing AIP need to be established. Three committees [the professional committee for developing clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee of moderators] were organized. Fifteen AIP specialists extracted specific clinical statements from a total of 871 articles in the literature using a PubMed search (1963–2008) and a secondary database, and developed the CQs and statements. The expert panelists individually rated these clinical statements using a modified Delphi approach in which a clinical statement receiving a median score greater than 7 on a 9-point scale from the panel was regarded as valid. The professional committee developed 13, 6, 6, and 11 CQs and statements for the concept and diagnosis, extra-pancreatic lesions, differential diagnosis and treatment, respectively. The expert panelists regarded them as valid after two-round modified Delphi approaches. After evaluation by the moderators, the Japanese clinical guidelines for AIP were established. The digest versions of the present guidelines have been published in the official journal of the Japan Pancreas Society, “Pancreas.” Full versions divided into three series are scheduled to be published in the present and followings two issues in the Journal of Gastroenterology with approval of Professor Go VLW, the Editor-in-Chief of "Pancreas.”

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Acknowledgment

This study was supported by the grant-in-aid for the Intractable Pancreatic Diseases, supported by the Ministry of Health, Labor, and Welfare of Japan.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Kansai Medical University, 2-3-1 Shinmachi, Hirakata, Osaka, 573-1191, Japan

    Kazuichi Okazaki

  2. Center for Health, Safety and Environmental Management, Shinshu University, Matsumoto, Japan

    Shigeyuki Kawa

  3. Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

    Terumi Kamisawa

  4. Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Toru Shimosegawa

  5. Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Masao Tanaka

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  1. Kazuichi Okazaki
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  4. Toru Shimosegawa
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Working members of Research Committee for Intractable Pancreatic Disease and Japan Pancreas Society

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Correspondence to Kazuichi Okazaki.

Appendices

Appendix: Clinical Diagnostic Criteria of Autoimmune Pancreatitis (revised proposal) (proposed by the Research Committee of Intractable Diseases of the Pancreas supported by the Japanese Ministry of Health, Labor, and Welfare, and Japan Pancreas Society)

It is suspected that the pathogenesis of autoimmune pancreatitis (AIP) involves autoimmune mechanisms. Currently, the main cases observed for characteristic findings of AIP are the diffuse enlargement of the pancreas and the narrowing of the pancreatic duct, which are associated with the findings that are suggestive of the involvement of autoimmune mechanisms such as increased levels of γ-globulin and IgG, the presence of autoantibodies, and the effective response to steroid therapy. In some cases, AIP shows extra-pancreatic manifestations such as sclerosing cholangitis, sclerosing sialadenitis, and retroperitoneal fibrosis, suggesting that AIP is a systemic disease. In Western countries, AIP is occasionally observed in association with ulcerative colitis and the formation of tumors, which suggests that it is somewhat contrary to the definition and concept of the disease adopted in Japan.

Patients with AIP often show discomfort in the epigastrium, obstructive jaundice due to bile duct stricture, and diabetes mellitus. AIP is more common in middle-aged and elderly males. Although the long-term prognosis of the disease is not clear, pancreatic stone formation has been found in some cases.

When diagnosing AIP, it is important to differentiate it from neoplastic lesions, such as pancreatic or biliary cancers, and to avoid facile therapeutic diagnosis by steroid administration. The present criteria, therefore, are based on the minimum consensus about AIP to avoid misdiagnosing pancreatic or biliary cancer as far as possible, but not for screening AIP.

Clinical diagnostic criteria

  1. 1.

    Diffuse or segmental narrowing of the main pancreatic duct with irregular wall and diffuse or localized enlargement of the pancreas by imaging studies, such as abdominal ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI).

  2. 2.

    High serum γ-globulin, IgG or IgG4, or the presence of autoantibodies, such as antinuclear antibodies and rheumatoid factor.

  3. 3.

    Marked inter-lobular fibrosis and prominent infiltration of lymphocytes and plasma cells in the peri-ductal area, occasionally with lymphoid follicles in the pancreas.

For diagnosis, criterion 1 must be present, together with criterion 2 and/or 3.

Diagnosis of autoimmune pancreatitis is established when criterion 1, together with criterion 2 and/or 3, are fulfilled.

However, it is necessary to exclude malignant diseases such as pancreatic or biliary cancers.

Imaging studies

  1. 1.

    Diffuse or localized swelling of the pancreas

Abdominal ultrasonography (US), computed tomography (CT), and/or magnetic resonance imaging (MRI) show diffuse or localized swelling of the pancreas.

  1. (a)

    The US feature of pancreatic swelling is usually hypoechoic, sometimes with scattered echogenic spots.

  2. (b)

    Contrast-enhanced CT generally shows delayed enhancement similar to a normal pancreas with sausage-like enlargement and/or a capsular-like low density rim.

  3. (c)

    MRI shows diffuse or localized enlargement of the pancreas with lower density in T1-weighed images and higher density in T2-weighed images compared with each of the liver images.

  4. 2.

    Narrowing of the pancreatic duct

The main pancreatic duct shows diffuse or localized narrowing.

  1. (a)

    Unlike obstruction or stricture, narrowing of the pancreatic duct extends over a larger range where the duct is narrowed with irregular walls. In typical cases, more than one-third of the entire length of the pancreatic duct is narrowed. Even in cases where the narrowing is segmental and extends to less than one-third, the upper stream of the main pancreatic duct rarely shows notable dilatation.

  2. (b)

    When the pancreatic images do show typical findings but laboratory data do not, there is a possibility of AIP. However, without histopathological examinations, it is difficult to distinguish AIP from pancreatic cancer.

  3. (c)

    To obtain images of the pancreatic duct, it is necessary to use endoscopic retrograde cholangiopancreatography (ERCP) and additionally the direct images taken during the operation or on specimens. Currently, it is difficult to depend on magnetic resonance cholangiopancreatography (MRCP) for the diagnosis.

  4. 3.

    The pancreatic image findings described above may be observed retrospectively from the time of diagnosis.

Laboratory data

  1. 1.

    In many cases, patients with AIP show increased levels of serum γ-globulin, IgG, or IgG4. High serum IgG4, however, is not specific to AIP, since it is also observed in other disorders such as atopic dermatitis, pemphigus, or asthma. Currently, the significance of high serum IgG4 in the pathogenesis and the pathophysiology of AIP is unclear.

  2. 2.

    Although increased levels of serum γ-globulin (≥2.0 g/dl), IgG (≥1,800 mg/dl), and IgG4 (≥135 mg/dl) may be used as criteria for the diagnosis of AIP, further studies are necessary. Health insurance in Japan does not cover the cost of measuring serum IgG4 levels in AIP.

  3. 3.

    Autoantibodies such as antinuclear antibody and rheumatoid factor are often detected in patients with AIP.

Pathohistological findings of the pancreas

  1. 1.

    Fibrotic changes associated with prominent infiltration of lymphocytes and plasma cells, occasionally with lymphoid follicles, are observed. In many cases, infiltration of IgG4-positive plasma cells is observed.

  2. 2.

    Lymphocytic infiltration is prominent in the peri-ductal area, together with and inter-lobular fibrosis, occasionally including intra-lobular fibrosis.

  3. 3.

    Inflammatory cell infiltration involves the ducts and results in diffuse narrowing of the pancreatic duct with atrophy of acini.

  4. 4.

    Obliterative phlebitis is often observed.

  5. 5.

    Although fine-needle biopsy under ultrasonic endoscopy (EUS-FNA) is useful in differentiating AIP from malignant tumors, the diagnosis may be difficult if the specimen is too small.

Endocrine and exocrine function of the pancreas

Some patients with AIP show a decline of exocrine pancreatic function and diabetes mellitus. In some cases, steroid therapy improves endocrine and exocrine pancreatic dysfunction.

Relationship to extra-pancreatic lesions and other associated disorders

AIP may be associated with sclerosing cholangitis, sclerosing sialadenitis, or retroperitoneal fibrosis. Most AIP patients with sclerosing sialadenitis are negative for both anti-SSA and anti-SSB antibodies, which may suggest that AIP is different from Sjogren’s syndrome. Scleroing cholangitis-like lesions accompanying AIP and primary sclerosing cholangitis (PSC) respond differently to steroid therapy and follow different prognoses, which suggests that they are not the same disorder. Further studies are necessary to clarify the role of autoimmune mechanisms in AIP.

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Okazaki, K., Kawa, S., Kamisawa, T. et al. Japanese consensus guidelines for management of autoimmune pancreatitis: I. Concept and diagnosis of autoimmune pancreatitis. J Gastroenterol 45, 249–265 (2010). https://doi.org/10.1007/s00535-009-0184-x

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  • DOI: https://doi.org/10.1007/s00535-009-0184-x

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