H Hamano, S Kawa, A Horiuchi, H Unno, N Furuya, T Akamatsu, M Fukushima, T Nikaido, K Nakayama, N Usuda, K Kiyosawa
High serum IgG4 concentrations in patients with sclerosing pancreatitis.
N Engl J Med. 2001 Mar 8;344(10):732-8. doi: 10.1056/NEJM200103083441005.
Abstract/Text
BACKGROUND: Sclerosing pancreatitis is a unique form of pancreatitis that is characterized by irregular narrowing of the main pancreatic duct, lymphoplasmacytic inflammation of the pancreas, and hypergammaglobulinemia and that responds to glucocorticoid treatment. Preliminary studies suggested that serum IgG4 concentrations are elevated in this disease but not in other diseases of the pancreas or biliary tract.
METHODS: We measured serum IgG4 concentrations using single radial immunodiffusion and an enzyme-linked immunosorbent assay in 20 patients with sclerosing pancreatitis, 20 age- and sex-matched normal subjects, and 154 patients with pancreatic cancer, ordinary chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or Sjögren's syndrome. Serum concentrations of immune complexes and the IgG4 subclass of immune complexes were determined by means of an enzyme-linked immunosorbent assay with monoclonal rheumatoid factor.
RESULTS: The median serum IgG4 concentration in the patients with sclerosing pancreatitis was 663 mg per deciliter (5th and 95th percentiles, 136 and 1150), as compared with 51 mg per deciliter (5th and 95th percentiles, 15 and 128) in normal subjects (P<0.001). The serum IgG4 concentrations in the other groups of patients were similar to those in the normal subjects. In patients with sclerosing pancreatitis, serum concentrations of immune complexes and the IgG4 subclass of immune complexes were significantly higher before glucocorticoid therapy than after four weeks of such therapy. Glucocorticoid therapy induced clinical remissions and significantly decreased serum concentrations of IgG4, immune complexes, and the IgG4 subclass of immune complexes.
CONCLUSIONS: Patients with sclerosing pancreatitis have high serum IgG4 concentrations, providing a useful means of distinguishing this disorder from other diseases of the pancreas or biliary tract.
厚生労働省難治性膵疾患調査研究班・日本膵臓学会:自己免疫性膵炎診療ガイドライン2009. 膵臓 2009;24(特別号)..
Kensuke Kubota, Seitaro Watanabe, Takashi Uchiyama, Shingo Kato, Yusuke Sekino, Kaori Suzuki, Hironori Mawatari, Hiroshi Iida, Hiroki Endo, Koji Fujita, Masato Yoneda, Hirokazu Takahashi, Hiroyuki Kirikoshi, Noritoshi Kobayashi, Satoru Saito, Kazuya Sugimori, Kantaro Hisatomi, Nobuyuki Matsuhashi, Hirotaka Sato, Emiko Tanida, Takashi Sakaguchi, Nobutaka Fujisawa, Atsushi Nakajima
Factors predictive of relapse and spontaneous remission of autoimmune pancreatitis patients treated/not treated with corticosteroids.
J Gastroenterol. 2011 Jun;46(6):834-42. doi: 10.1007/s00535-011-0393-y. Epub 2011 Apr 15.
Abstract/Text
BACKGROUND: Relapse and spontaneous remission (SR) are characteristic features of autoimmune pancreatitis (AIP).
AIM AND METHODS: We conducted a study to determine if the predictive factors might be potentially related to the relapse in 70 consecutive AIP patients. Regarding SR, we studied the data of patients without corticosteroid treatment (CST).
RESULTS: CST was administered to 60% (42/70) of the patients; however, relapse was noted in 45.2% (19/42) of these patients. In 95% (18/19) of the AIP patients developing relapse, the relapse occurred within 3 years. The relapse rate was 80% (12/15) in the AIP patients administered CST for less than 12 months and 25.9% (7/27) in those administered CST for over 12 months (p < 0.01). The results of univariate analysis revealed significant association of relapse with the presence of jaundice, IgG4 seropositivity, presence of diffuse pancreas swelling, duodenal papillitis (DP), history of initial CST, and history of supportive treatment (p < 0.05), whereas multivariate analysis revealed that IgG4 seropositivity (OR 10.506, p = 0.0422) and the presence of jaundice (OR 6.945, p = 0.0174) are significant independent factors predictive of relapse in AIP patients. SR was recognized in 65.0% (13/20) of AIP patients without CST. The results of univariate analysis revealed that SR was associated with IgG4 seropositivity (p < 0.05), and multivariate analysis identified IgG4 seropositivity (OR 0.032, p = 0.0092) as a significant independent factor predictive of SR in these cases.
CONCLUSION: AIP patients with IgG4 seropositivity and jaundice are at a higher risk of relapse and they could therefore be candidates for over 3 years of maintenance CST. AIP patients with IgG4 seronegativity have a high likelihood of SR.
Immunologic Reference Values Johns Hopkins: The Harriet Lane Handbook, 19th ed.; Chapter 15 - Immunology and Allergy.
Amaar Ghazale, Suresh T Chari, Thomas C Smyrk, Michael J Levy, Mark D Topazian, Naoki Takahashi, Jonathan E Clain, Randall K Pearson, Mario Pelaez-Luna, Bret T Petersen, Santhi Swaroop Vege, Michael B Farnell
Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer.
Am J Gastroenterol. 2007 Aug;102(8):1646-53. doi: 10.1111/j.1572-0241.2007.01264.x. Epub 2007 Jun 6.
Abstract/Text
OBJECTIVES: To determine the sensitivity and specificity of elevated serum IgG4 level for the diagnosis of autoimmune pancreatitis (AIP) and its ability to distinguish AIP from pancreatic cancer, its main differential diagnosis.
METHODS: We measured serum IgG4 levels (normal 8-140 mg/dL) in 510 patients including 45 with AIP, 135 with pancreatic cancer, 62 with no pancreatic disease, and 268 with other pancreatic diseases.
RESULTS: Sensitivity, specificity, and positive predictive values for elevated serum IgG4 (>140 mg/dL) for diagnosis of AIP were 76%, 93%, and 36%, respectively, and 53%, 99%, and 75%, respectively, for IgG4 of >280 mg/dL. Among subjects with elevated IgG4, non-AIP subjects (N = 32) differed from AIP subjects (N = 34) in that they were more likely to be female (45%vs 9%, P < 0.001), less likely to have serum IgG4 >280 mg/dL (13%vs 71%, P < 0.001), or elevation of total IgG (16%vs 56%, P < 0.001). Serum IgG4 levels were elevated in 13/135 (10%) pancreatic cancer patients; however, only 1% had IgG4 levels >280 mg/dL compared with 53% of AIP. Compared with AIP, pancreatic cancer patients were more likely to have CA19-9 levels of >100 U/mL (71%vs 9%, P < 0.001).
CONCLUSION: Elevated serum IgG4 levels are characteristic of AIP. However, mild (<2-fold) elevations in serum IgG4 are seen in up to 10% of subjects without AIP including pancreatic cancer and cannot be used alone to distinguish AIP from pancreatic cancer. Because AIP is uncommon, IgG4 elevations in patients with low pretest probability of having AIP are likely to represent false positives.
厚生労働省IgG4関連全身硬化性疾患の診断法の確立と治療法に関する研究班、厚生労働省難治性の肝胆道疾患に関する調査研究班、日本胆道学会:IgG4関連硬化性胆管炎臨床診断基準2012.胆道 2012;26(1):59-63..
Hirotaka Ohara, Kazuichi Okazaki, Hirohito Tsubouchi, Kazuo Inui, Shigeyuki Kawa, Terumi Kamisawa, Susumu Tazuma, Kazushige Uchida, Kenji Hirano, Hitoshi Yoshida, Takayoshi Nishino, Shigeru B H Ko, Nobumasa Mizuno, Hideaki Hamano, Atsushi Kanno, Kenji Notohara, Osamu Hasebe, Takahiro Nakazawa, Yasuni Nakanuma, Hajime Takikawa, Research Committee of IgG4-related Diseases, Research Committee of Intractable Diseases of Liver and Biliary Tract, Ministry of Health, Labor and Welfare, Japan, Japan Biliary Association
Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012.
J Hepatobiliary Pancreat Sci. 2012 Sep;19(5):536-42. doi: 10.1007/s00534-012-0521-y.
Abstract/Text
BACKGROUND: IgG4-sclerosing cholangitis (IgG4-SC) patients have an increased level of serum IgG4, dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall, and a good response to steroid therapy. However, it is not easy to distinguish IgG4-SC from primary sclerosing cholangitis, pancreatic cancer, and cholangiocarcinoma on the basis of cholangiographic findings alone because various cholangiographic features of IgG4-SC are similar to those of the above progressive or malignant diseases.
METHODS: The Research Committee of IgG4-related Diseases and the Research Committee of Intractable Diseases of Liver and Biliary Tract in association with the Ministry of Health, Labor and Welfare, Japan and the Japan Biliary Association have set up a working group consisting of researchers specializing in IgG4-SC, and established the new clinical diagnostic criteria of IgG4-SC 2012.
RESULTS: The diagnosis of IgG4-SC is based on the combination of the following 4 criteria: (1) characteristic biliary imaging findings, (2) elevation of serum IgG4 concentrations, (3) the coexistence of IgG4-related diseases except those of the biliary tract, and (4) characteristic histopathological features. Furthermore, the effectiveness of steroid therapy is an optional extra diagnostic criterion to confirm accurate diagnosis of IgG4-SC.
CONCLUSION: These diagnostic criteria for IgG4-SC are useful in practice for general physicians and other nonspecialists.
厚生労働省難治性膵疾患調査研究班・日本膵臓学会:自己免疫性膵炎診療ガイドライン2013. 膵臓 2013;28(6): 724-783..
Feldman: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 9th ed.; Chapter 68 - Sclerosing Cholangitis and Recurrent Pyogenic Cholangitis .
Andreas Weber, Claus von Weyhern, Falko Fend, Jochen Schneider, Bruno Neu, Alexander Meining, Hans Weidenbach, Roland M Schmid, Christian Prinz
Endoscopic transpapillary brush cytology and forceps biopsy in patients with hilar cholangiocarcinoma.
World J Gastroenterol. 2008 Feb 21;14(7):1097-101.
Abstract/Text
AIM: To evaluate the sensitivity of brush cytology and forceps biopsy in a homogeneous patient group with hilar cholangiocarcinoma.
METHODS: Brush cytology and forceps biopsy were routinely performed in patients with suspected malignant biliary strictures. Fifty-eight consecutive patients undergoing endoscopic retrograde cholangio-pancreatography (ERCP) including forceps biopsy and brush cytology in patients with hilar cholangiocarcinoma between 1995-2005.
RESULTS: Positive results for malignancy were obtained in 24/58 patients (41.4%) by brush cytology and in 31/58 patients (53.4%) by forceps biopsy. The combination of both techniques brush cytology and forceps biopsy resulted only in a minor increase in diagnostic sensitivity to 60.3% (35/58 patients). In 20/58 patients (34.5%), diagnosis were obtained by both positive cytology and positive histology, in 11/58 (19%) by positive histology (negative cytology) and only 4/58 patients (6.9%) were confirmed by positive cytology (negative histology).
CONCLUSION: Brush cytology and forceps biopsy have only limited sensitivity for the diagnosis of malignant hilar tumors. In our eyes, additional diagnostic techniques should be evaluated and should become routine in patients with negative cytological and histological findings.
M Hattori, M Nagino, T Ebata, K Kato, K Okada, Y Shimoyama
Prospective study of biliary cytology in suspected perihilar cholangiocarcinoma.
Br J Surg. 2011 May;98(5):704-9. doi: 10.1002/bjs.7412. Epub 2011 Feb 3.
Abstract/Text
BACKGROUND: The diagnostic value of biliary cytology for hilar bile duct stricture is uncertain. This study prospectively examined three methods for the evaluation of biliary cytology in a consecutive group of patients.
METHODS: Preoperative bile sampling by aspiration through a drainage catheter (aspiration samples), saline flush through a drainage catheter (saline samples) or direct sampling from a drainage bag (bag samples) was performed in consecutive patients with suspected perihilar cholangiocarcinoma who underwent resection after endoscopic nasobiliary drainage or percutaneous transhepatic biliary drainage. All bile sampling was performed three times on separate days. The accuracy of cytology in the diagnosis of carcinoma was determined.
RESULTS: Of 100 consecutive patients with hilar strictures, 97 had histologically proven cholangiocarcinoma. The proportion of these 97 patients who had a positive finding on cytology in at least one of three sampling sessions was 55 per cent for aspiration samples, 48 per cent for bag samples and 38 per cent for saline samples (P = 0·021, aspiration versus saline). Tumour length correlated significantly with overall positivity. For aspiration samples, sensitivity was 55 per cent, specificity was 100 per cent and accuracy 56·0 per cent.
CONCLUSION: For biliary cytology, sampling by catheter aspiration is more effective than catheter flushing or sampling from a drainage bag. Repeated sampling increases sensitivity. Biliary cytology has modest diagnostic yield, but is easy to perform, highly specific, and can provide a definitive diagnosis.
Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
厚生労働省難治性膵疾患調査研究班・日本膵臓学会:自己免疫性膵炎診療ガイドライン2013. 膵臓 2013;28(6)..
厚生労働省 IgG4 関連全身硬化性疾患の診断法の確立と治療方法の開発に関する研究班. 厚生労働省難治性の肝胆道疾患に関する調査研究班. 日本胆道学会編:IgG4関連硬化性胆管炎臨床診断基準2012、胆道2012;26(1):59-63.
Lizhi Zhang, Jason T Lewis, Susan C Abraham, Thomas C Smyrk, Stanley Leung, Suresh T Chari, John J Poterucha, Charles B Rosen, Christine M Lohse, Jerry A Katzmann, Tsung-Teh Wu
IgG4+ plasma cell infiltrates in liver explants with primary sclerosing cholangitis.
Am J Surg Pathol. 2010 Jan;34(1):88-94. doi: 10.1097/PAS.0b013e3181c6c09a.
Abstract/Text
Sclerosing cholangitis can be primary (PSC) or secondary. One unusual cause of secondary sclerosing cholangitis is the newly recognized entity of IgG4-associated cholangitis. The prevalence and significance of IgG4 plasma cells in patients, who are clinically and radiologically classified as PSC, however, are unknown. Clinical information and histology of liver explants of 98 consecutive liver transplants performed for PSC were reviewed. IgG4 immunohistochemical stain was performed on sections from hilar areas that contained large bile ducts and corresponding cholecystectomy specimens (available in 74 cases). Serum IgG4 levels were measured in stored serum from 81 cases. Tissue IgG4 positivity (>or=10 IgG4+ plasma cells/high power field) was correlated with clinical features (age, sex, presence of inflammatory bowel disease and cholangiocarcinoma, pancreatogram, PSC duration, PSC recurrence after transplant, and number of acute rejection episodes) and histologic findings (periductal lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis) in the liver explants. Twenty-three (23%) liver explants showed periductal infiltration with IgG4+ plasma cells. Eighteen cases (22%) had elevated serum IgG4 levels, including 8 without tissue IgG4 positivity. All cases showed dense periductal fibrosis; none had storiform fibrosis or obliterative phlebitis. IgG4 positivity in the liver strongly correlated with moderate-to-marked periductal lymphoplasmacytic inflammation (P=0.002). Clinically, IgG4 positivity in tissue, but not in serum, was correlated with shorter PSC duration before transplant and higher risk of recurrence after transplant. Nearly one quarter of explanted livers that carry a clinical diagnosis of PSC contain increased IgG4+ periductal plasma cell infiltrates and positive serum IgG4 levels. However, none of the explants show histologic features diagnostic of IgG4-associated cholangitis. PSC with tissue IgG4 positivity has a more aggressive clinical course manifested by shorter time to transplant and a higher likelihood of recurrence than IgG4 negative PSC.
Masanori Koyabu, Kazushige Uchida, Norimasa Fukata, Takeo Kusuda, Tsukasa Ikeura, Yutaku Sakaguchi, Katsunori Yoshida, Masaaki Shimatani, Toshiro Fukui, Mitsunobu Matsushita, Yoshiko Uemura, Masaki Kaibori, Makoto Takaoka, Akiyoshi Nishio, Kazuichi Okazaki
Primary sclerosing cholangitis with elevated serum IgG4 levels and/or infiltration of abundant IgG4-positive plasma cells.
J Gastroenterol. 2010;45(1):122-9. doi: 10.1007/s00535-009-0130-y. Epub 2009 Sep 18.
Abstract/Text
Immunoglobin G4-related sclerosing cholangitis (IgG4-SC) is recognized as one of the systemic sclerosing diseases characterized by abundant IgG4-positive plasma cells with effective steroid therapy. On the other hand, primary sclerosing cholangitis (PSC), recognized as a sclerosing cholangitis of unknown origin without steroid efficacy, has been often clinically confused with IgG4-SC. To date, the prognosis of IgG4-SC is unclear, while the prognosis of PSC is well known to be poor. Therefore, it is clinically very important to be able to distinguish IgG4-SC from PSC. However, at the present time it still remains unclear whether PSC may sometimes be misdiagnosed as IgG4-SC or not. Herein, we report three rare cases of PSC with elevated serum IgG4 levels and/or an infiltration of abundant IgG4-positive plasma cells in the liver: a young male with ulcerative colitis (UC), and elderly female and a young female, each with elevated serum IgG4 levels. The first two patients showed infiltration of abundant IgG4-positive plasma cells in the portal area of the liver without response to steroid therapy. From our experiences, we emphasize that some patients with PSC, who do not respond to steroid therapy, show elevated serum IgG4 levels and/or infiltration of abundant IgG4-positive plasma cells, although the mechanism still remains unclear.
日本膵臓学会,厚生労働省難治性膵疾患に関する調査研究班:自己免疫性膵炎臨床診断基準2012.膵臓 2012;27:17-25..
厚労省研究班 「IgG4関連全身硬化性疾患の診断法の確立と治療方法の開発に関する研究班」,「新規疾患,IgG4関連多臓器リンパ増殖性疾患(IgG4+MOLPS)の確立のための研究班」:IgG4関連疾患包括診断基準2011.日本内科学会雑誌 2012:101(3):795-804..
T Kamisawa, T Shimosegawa, K Okazaki, T Nishino, H Watanabe, A Kanno, F Okumura, T Nishikawa, K Kobayashi, T Ichiya, H Takatori, K Yamakita, K Kubota, H Hamano, K Okamura, K Hirano, T Ito, S B H Ko, M Omata
Standard steroid treatment for autoimmune pancreatitis.
Gut. 2009 Nov;58(11):1504-7. doi: 10.1136/gut.2008.172908. Epub 2009 Apr 26.
Abstract/Text
OBJECTIVE: To establish an appropriate steroid treatment regimen for autoimmune pancreatitis (AIP).
METHODS: A retrospective survey of AIP treatment was conducted in 17 centres in Japan. The main outcome measures were rate of remission and relapse.
RESULTS: Of 563 patients with AIP, 459 (82%) received steroid treatment. The remission rate of steroid-treated AIP was 98%, which was significantly higher than that of patients without steroid treatment (74%, 77/104; p<0.001). Steroid treatment was given for obstructive jaundice (60%), abdominal pain (11%), associated extrapancreatic lesions except the biliary duct (11%), and diffuse enlargement of the pancreas (10%). There was no relationship between the period necessary to achieve remission and the initial dose (30 mg/day vs 40 mg/day) of prednisolone. Maintenance steroid treatment was given in 377 (82%) of 459 steroid-treated patients, and steroid treatment was stopped in 104 patients. The relapse rate of patients with AIP on maintenance treatment was 23% (63/273), which was significantly lower than that of patients who stopped maintenance treatment (34%, 35/104; p = 0.048). From the start of steroid treatment, 56% (55/99) relapsed within 1 year and 92% (91/99) relapsed within 3 years. Of the 89 relapsed patients, 83 (93%) received steroid re-treatment, and steroid re-treatment was effective in 97% of them.
CONCLUSIONS: The major indication for steroid treatment in AIP is the presence of symptoms. An initial prednisolone dose of 0.6 mg/kg/day, is recommend, which is then reduced to a maintenance dose over a period of 3-6 months. Maintenance treatment with low-dose steroid reduces but dose not eliminate relapses.