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1
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Notohara K. Histological features of autoimmune pancreatitis and IgG4-related sclerosing cholangitis with a correlation with imaging findings. J Med Ultrason (2001) 2021; 48:581-594. [PMID: 34669070 DOI: 10.1007/s10396-021-01148-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022]
Abstract
Autoimmune pancreatitis (AIP) is characterized by a tumefactive inflammatory lesion resembling pancreatic carcinoma. Type 1 AIP is a pancreatic manifestation of IgG4-related disease characterized by unique histological features that can be identified on imaging. The capsule-like rim, which is a collar of hypertrophic lesion surrounding the pancreas, consists of lymphoplasmacytic infiltration and fibrosis, and storiform fibrosis is often identified. Hypertrophic lesions of various microscopic architectures such as the ducts, veins (obliterative phlebitis), arteries (periarteritis), and nerves are observed without parenchymal damage. The pancreatic lobules keep their contours, but the acinar cells are diminished and replaced by numerous inflammatory cells. These features provide clues to arrive at a diagnosis of type 1 AIP and to distinguish it from pancreatic carcinoma on imaging. In contrast, type 2 AIP is an epithelium-centered inflammation involving the ducts and lobules. Neutrophilic infiltration in the epithelium and/or lumens (granulocytic epithelial lesion) is a characteristic finding. Lobular swelling due to inflammation is the cause of pancreatic enlargement. IgG4-related sclerosing cholangitis is histologically similar to the hypertrophic ductal lesion in type 1 AIP and characterized by wall thickening due to inflammation and luminal stenosis. The epithelium is intact, which is different from bile duct carcinomas and primary sclerosing cholangitis, the latter of which is characterized by inflammation targeting the epithelium. Although the histological features of type 1 AIP and IgG4-related sclerosing cholangitis are unique, the biopsy diagnosis of these diseases has limitations, which should be recognized by clinicians.
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Affiliation(s)
- Kenji Notohara
- Department of Anatomic Pathology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602, Japan.
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2
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Nakata R, Uehara T, Iwaya M, Asaka S, Kobayashi S, Sugano M, Higuchi K, Kusama Y, Nakazawa K, Nakaguro M, Kobayashi M, Tateishi A, Makino M, Kawaguchi K, Maejima T, Ishii K, Sano K, Shimojo H, Hori A, Otsuki T, Hamano H, Kawa S, Ota H. Immunostaining With Immunoglobulin G Subclass Antibody Cocktail for Diagnosis of Type 1 Autoimmune Pancreatitis. Int J Surg Pathol 2020; 28:844-849. [PMID: 32456567 DOI: 10.1177/1066896920924781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND. Immunoglobulin (Ig) G4-related diseases (RDs) are systemic diseases in which serum IgG4 levels are frequently elevated. They can cause diffuse or focal tumor formation, organ swelling, and tissue thickening in organs infiltrated by IgG4+ plasma cells. The diagnostic criteria for IgG4-RDs include an IgG4/IgG ratio >40%, but counting IgG+ cells can be difficult because of the weakness of IgG staining density. We hypothesized that an antibody cocktail of mixed IgG1, IgG2, IgG3, and IgG4 (AC-IgG) might give immunohistochemistry results comparable with those of IgG in IgG4-RD. METHODS. We compared AC-IgG reactivity with IgG expression in type 1 autoimmune pancreatitis (AIP), a representative IgG4-RD. We compared immunohistochemistry results using AC-IgG and IgG-only in 10 cases of AIP. The coefficient of variation (Cv) was used to analyze differences between AC-IgG and IgG findings in AIP by 13 board-certified pathologists. RESULTS. Although mean values for IgG+ cells did not significantly differ between AC-IgG (34.3; range = 27.4-37.1) and IgG (30.0; range = 23.0-45.6; P = .6254), Cv was lower for AC-IgG (33.4%) than for IgG (51.4%; regression equation; y[IgG] = 0.988x + 0.982; correlation coefficient = 0.907). The data showed that the results of both methods were largely consistent. CONCLUSION. AC-IgG could replace IgG to count IgG+ cells because of its lower Cv.
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Affiliation(s)
- Rie Nakata
- 168943Matsumoto Kyoritsu Hospital, Matsumoto, Japan
| | | | - Mai Iwaya
- 13056Shinshu University, Matsumoto, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Kenji Sano
- 36910Iida Municipal Hospital, Iida, Japan
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3
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Aljishi M, Thet Z, Han T, Madhan K. Acute Tubulointerstitial Nephritis as a Sole Manifestation of Immunoglobulin G4-Related Disease. J Med Cases 2019; 10:348-353. [PMID: 34434307 PMCID: PMC8383568 DOI: 10.14740/jmc3395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 12/10/2019] [Indexed: 11/23/2022] Open
Abstract
This is a case report of a patient who developed severe acute kidney disease with kidney biopsy showing interstitial nephritis, plasma cell infiltration and immunoglobulin G4 (IgG4) expression consistent with IgG4-related kidney disease. There were no other systemic features of IgG4-related disease. The patient was treated with corticosteroids and mycophenolate. This case highlights the need to consider IgG4-related kidney disease even in the absence of other systemic features. Isolated renal involvement is underrecognized and can lead to missed diagnosis. It also illustrates that mycophenolate can be used as a steroid sparing agent in this condition; an observation that adds to the limited literature in this field.
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Affiliation(s)
- Manaf Aljishi
- Renal Department, Rockhampton Hospital, Queensland, Australia.,University of Queensland, St Lucia QLD 4072, Australia
| | - Zaw Thet
- Renal Department, Rockhampton Hospital, Queensland, Australia
| | - Thin Han
- Medicine and Nephrology, Rockhampton Hospital, Rockhampton QLD 4700, Australia
| | - Krishan Madhan
- Renal Medicine Department, Hervey Bay Hospital, Queensland, Australia
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Kamisawa T, Nakazawa T, Tazuma S, Zen Y, Tanaka A, Ohara H, Muraki T, Inui K, Inoue D, Nishino T, Naitoh I, Itoi T, Notohara K, Kanno A, Kubota K, Hirano K, Isayama H, Shimizu K, Tsuyuguchi T, Shimosegawa T, Kawa S, Chiba T, Okazaki K, Takikawa H, Kimura W, Unno M, Yoshida M. Clinical practice guidelines for IgG4-related sclerosing cholangitis. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2019; 26:9-42. [PMID: 30575336 PMCID: PMC6590186 DOI: 10.1002/jhbp.596] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IgG4‐related sclerosing cholangitis (IgG4‐SC) is a distinct type of cholangitis frequently associated with autoimmune pancreatitis and currently recognized as a biliary manifestation of IgG4‐related disease. Although clinical diagnostic criteria of IgG4‐SC were established in 2012, differential diagnosis from primary sclerosing cholangitis and cholangiocarcinoma is sometimes difficult. Furthermore, no practical guidelines for IgG4‐SC are available. Because the evidence level of most articles retrieved through searching the PubMed, Cochrane Library, and Igaku Chuo Zasshi databases was below C based on the systematic review evaluation system of clinical practice guidelines MINDS 2014, we developed consensus guidelines using the modified Delphi approach. Three committees (a guideline creating committee, an expert panelist committee for rating statements according to the modified Delphi method, and an evaluating committee) were organized. Eighteen clinical questions (CQs) with clinical statements were developed regarding diagnosis (14 CQs) and treatment (4 CQs). Recommendation levels for clinical statements were set using the modified Delphi approach. The guidelines explain methods for accurate diagnosis, and safe and appropriate treatment of IgG4‐SC.
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Affiliation(s)
- Terumi Kamisawa
- Department of Internal Medicine, Tokyo Metropolitan, Komagome Hospital, Tokyo, Japan
| | - Takahiro Nakazawa
- Department of Gastroenterology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan
| | - Susumu Tazuma
- Department of General Internal Medicine, Hiroshima University Graduate School of Biomedical & Health Science, Hiroshima, Japan
| | - Yoh Zen
- Department of Diagnostic Pathology, Kobe University, Kobe, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Hirotaka Ohara
- Department of Community-Based Medical Education, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takashi Muraki
- Department of Medicine, Gastroenterology, Shinshu University, Matsumoto, Nagano, Japan
| | - Kazuo Inui
- Department of Gastroenterology, Second Teaching Hospital, Fujita Health University, Nagoya, Japan
| | - Dai Inoue
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Takayoshi Nishino
- Department of Gastroenterology, Tokyo Womens' Medical University Yachiyo Medical Center, Yachiyo, Japan
| | - Itaru Naitoh
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takao Itoi
- Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan
| | - Kenji Notohara
- Department of Anatomic Pathology, Kurashiki Central Hospital, Kurashiki, Japan
| | - Atsushi Kanno
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kensuke Kubota
- Department of Endoscopy, Yokohama City University Hospital, Yokohama, Japan
| | - Kenji Hirano
- Department of Gastroenterology, Tokyo Takanawa Hospital, Tokyo, Japan
| | - Hiroyuki Isayama
- Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Kyoko Shimizu
- Department of Gastroenterology, Tokyo Womens' Medical University, Tokyo, Japan
| | | | - Tooru Shimosegawa
- Division of Gastroenterology, South-Miyagi Medical Center, Ohgawara, Japan
| | - Shigeyuki Kawa
- Department of Internal Medicine, Matsumoto Dental University, Matsumoto, Japan
| | | | - Kazuichi Okazaki
- The Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Moriguchi, Japan
| | - Hajime Takikawa
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Wataru Kimura
- Faculty of Medicine, Departments of Gastroenterology and Gastroenterological, General, Breast, and Thyroid Surgery, Yamagata University, Yamagata, Japan
| | - Michiaki Unno
- Division of Hepato-Biliary Pancreatic Surgery, Tohoku University Graduate School, of Medicine, Sendai, Japan
| | - Masahiro Yoshida
- Department of Hepato-Biliary-Pancreatic and Gastrointestinal Surgery, School of Medicine, International University of Health and Welfare, Ichikawa, Japan
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5
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Detlefsen S, de Vos JD, Tanassi JT, Heegaard NHH, Fristrup C, Schaffalitzky de Muckadell OB. Value of anti-plasminogen binding peptide, anti-carbonic anhydrase II, immunoglobulin G4, and other serological markers for the differentiation of autoimmune pancreatitis and pancreatic cancer. Medicine (Baltimore) 2018; 97:e11641. [PMID: 30075546 PMCID: PMC6081052 DOI: 10.1097/md.0000000000011641] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The diagnosis of autoimmune pancreatitis (AIP) and its differential diagnosis from pancreatic cancer (PC) can be challenging. In this retrospective study, we aimed to evaluate the value of anti-plasminogen binding peptide (a-PBP), immunoglobulin G4 (IgG4), and anti-carbonic anhydrase-II (a-CA-II), together with other serological markers whose value is not fully elucidated.The serum levels of a-PBP, IgG4, IgG, anti-nuclear antibodies (ANA), anti-lactoferrin (a-LF), a-CA-II, and rheumatoid factor (RF) were evaluated in patients with AIP (n = 29), PC (n = 17), pancreatic neuroendocrine neoplasm (P-NEN, n = 12), and alcoholic chronic pancreatitis (ACP, n = 41). ANCA were measured in the AIP patients.There was no statistically significant difference in mean a-PBP values in AIP compared with PC. A ROC curve showed that, when using a cut-off of 38.3 U, low values of a-PBP had a sensitivity and specificity of 45% and 71% for differentiating AIP from PC. The sensitivity and specificity of IgG4 (cut-off 1.4 g/L) for differentiating AIP from PC was 45% and 88%, but rose to 52% and 88% when using a cut-off of 1.09 g/L. When using this cut-off, the sensitivity and specificity for differentiating type 1 AIP from PC was 68% and 88%. None of the other markers were significantly changed in AIP versus PC. For differentiation of type 1 and type 2 AIP, the only significant differences were IgG4 in type 1 AIP (P < .01), with a sensitivity of 68% and a specificity of 80%, and c-ANCA elevations found in some type 2 AIP patients (P < .05).The only serological marker for which we found a statistically significant difference in mean values between AIP and PC was IgG4. However, the value of IgG4 for the distinction of AIP from PC was limited, probably in part due to the relatively high number of type 2 AIP patients in our study. In accord with recent publications, our data do not support a role of increased serum a-PBP for the diagnosis of AIP.
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Affiliation(s)
- Sönke Detlefsen
- Department of Pathology
- Odense Pancreas Center (OPAC), Odense University Hospital
- Institute of Clinical Research, University of Southern Denmark
| | - Jesper D. de Vos
- Institute of Clinical Research, University of Southern Denmark
- Department of Medical Gastroenterology, Odense University Hospital, Odense
| | - Julia T. Tanassi
- Department of Autoimmunology and Biomarkers, Statens Serum Institute, Copenhagen
| | - Niels H. H. Heegaard
- Department of Autoimmunology and Biomarkers, Statens Serum Institute, Copenhagen
- Department of Clinical Biochemistry and Pharmacology
| | - Claus Fristrup
- Odense Pancreas Center (OPAC), Odense University Hospital
- Department of Surgery, Odense University Hospital, Odense, Denmark
| | - Ove B. Schaffalitzky de Muckadell
- Institute of Clinical Research, University of Southern Denmark
- Department of Medical Gastroenterology, Odense University Hospital, Odense
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Hamano H, Tanaka E, Ishizaka N, Kawa S. IgG4-related Disease - A Systemic Disease that Deserves Attention Regardless of One's Subspecialty. Intern Med 2018; 57:1201-1207. [PMID: 29279491 PMCID: PMC5980798 DOI: 10.2169/internalmedicine.9533-17] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
IgG4-related disease (IgG4-RD) is an inflammatory condition characterized by a high serum IgG4 concentration and the abundant infiltration of lymphocytes and IgG4-positive plasma cells in the tissue, as well as spatial (diverse clinical manifestations) and temporal (the possibility of recurrence) multiplicities. Since the initial documentation of IgG4-related disease in patients with autoimmune pancreatitis in 2001, a growing body of evidence has been accumulating to suggest that various-virtually all-organs can be affected by IgG4-RD. In general, steroid therapy is effective and is considered to be the first-line treatment for IgG4-RD. The precise mechanism underlying this systemic disorder has remained unknown. Considering that IgG4-RD was specified as being an intractable disease in 2015, further studies are needed to clarify whether IgG4-RD is indeed a distinct disease entity or a complex of disorders of different etiologies and clinical conditions.
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Affiliation(s)
- Hideaki Hamano
- Division of Medical Informatics, Shinshu University Hospital, Japan
- Department of Internal Medicine, Gastroenterology, Shinshu University School of Medicine, Japan
| | - Eiji Tanaka
- Department of Internal Medicine, Gastroenterology, Shinshu University School of Medicine, Japan
| | | | - Shigeyuki Kawa
- Department of Internal Medicine, Matsumoto Dental University, Japan
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7
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Xiao J, Xu P, Li B, Hong T, Liu W, He X, Zheng C, Zhao Y. Analysis of clinical characteristics and treatment of immunoglobulin G4-associated cholangitis: A retrospective cohort study of 39 IAC patients. Medicine (Baltimore) 2018; 97:e9767. [PMID: 29465558 PMCID: PMC5842017 DOI: 10.1097/md.0000000000009767] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Immunoglobulin (Ig)G4-associated cholangitis (IAC) is one of the common organ manifestations of IgG4-related systemic disease (ISD). IAC and autoimmune pancreatitis (AIP) may mimic sclerosing cholangitis, cholangiocarcinoma, or pancreatic carcinoma. Diagnosis is based on a combination of clinical, biochemical, radiological, and histological findings.To study the clinical presentation of and treatment strategy for IAC, we reviewed clinical, serologic, and imaging characteristics, as well as treatment response, in 39 patients with IAC. The majority of patients were men (82%). Clinical features on presentation included obstructive jaundice in 26 patients (67%) and abdominal pain in 20 (51%). Positive IgG4 immunostaining was seen in 27 patients. The median serum IgG4 level before treatment was 769.4 mg/dL (range, 309.1-1229.7 mg/dL). After the steroid therapy, the median serum IgG4 level in 23 patients was 247.0 mg/dL (range, 139.0-355.0 mg/dL). Cholangiograms were available in 36 (92%) patients. Stenosis of the lower part of the common bile duct was found in 26 of 39 patients. Stenosis was diffusely distributed in the intra- and extrahepatic bile ducts in 14 of 39 patients. Additionally, strictures of the bile duct were detected in the hilar hepatic lesions in 27 of 39 patients. AIP was the most frequent comorbidity (35/39 in this study) of IAC. Other affected organs included eyes (n = 6), salivary glands (sialadenitis, n = 10), lymph nodes (mediastinal and axillary, n = 3), kidneys (n = 2), and the retroperitoneum (retroperitoneal fibrosis, n = 2).Regarding treatment, 29 patients were treated with steroids, of whom one underwent pancreatoduodenectomy, and one underwent choledochojejunostomy. Eight patients were treated with biliary stents. The remaining 19 patients took prednisolone alone. Eight patients achieved spontaneous resolution. Four patients with suspected pancreatic cancer or cholangiocarcinoma underwent surgery, including 2 patients who also received postoperative steroids. All patients were regularly followed up for 9 to 36 months. Only 2 patients in the steroids treatment group relapsed to manifest obstructive jaundice and high serum IgG4 levels. These 2 patients were treated with steroids and biliary stents, resulting in complete remission.We also review the diagnostic and therapeutic management and discuss recent pathophysiological findings, which might aid in understanding the molecular mechanisms contributing to IAC and other manifestations of IgG4-related diseases (IgG4-RD). Biomarkers that are more accurate are needed to correctly diagnose IAC and prevent misdiagnoses and unnecessary therapeutic interventions.
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8
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Xu WL, Ling YC, Wang ZK, Deng F. Diagnostic performance of serum IgG4 level for IgG4-related disease: a meta-analysis. Sci Rep 2016; 6:32035. [PMID: 27558881 PMCID: PMC4997323 DOI: 10.1038/srep32035] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 08/02/2016] [Indexed: 12/13/2022] Open
Abstract
An elevated serum IgG4 level is one of the most useful factors in the diagnosis of IgG4-related disease (IgG4-RD). In this study, we performed a meta-analysis of the published articles assessing the diagnostic accuracy of serum IgG4 concentrations for IgG4-RD. The databases of MEDLINE/PubMed, EMBASE and Web of Science were systematically searched for relevant studies. Sensitivities and specificities of serum IgG4 in each study were calculated, and the hierarchical summary receiver operating characteristic (HSROC) model with a random effects model were employed to obtain the individual and pooled estimates of sensitivities and specificities. In total, twenty-three studies comprising 6048 patients with IgG4-RD were included in the meta-analysis. The pooled sensitivity was 85% with a 95% confidence interval (CI) of 78-90%; the pooled specificity was 93% with a 95% CI of 90-95%. The HSROC curve for quantitative serum IgG4 lies closer to the upper left corner of the plot, and the area under the curve (AUC) was 0.95 (95% CI 0.93, 0.97), which suggested a high diagnostic accuracy of serum IgG4 for the entity of IgG4-RD. Our study suggests that serum IgG4 has high sensitivity and specificity in the diagnosis of IgG4-RD.
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Affiliation(s)
- Wen-Long Xu
- Department of Clinical Laboratory, Baoshan Branch of Shanghai Huashan Hospital, Baoshan Renhe Hospital, Shanghai 200431, China
| | - Ying-Chun Ling
- Department of Clinical Laboratory, Shaoxing Seventh People's Hospital, Zhejiang Shaoxing 312000, China
| | - Zhi-Kai Wang
- Department of Clinical Laboratory, Shanghai Family Planning Hospital, Shanghai 200032, China
| | - Fang Deng
- Department of Clinical Laboratory, Anhui Provincial Tumor Hospital, Anhui Hefei 230031, China
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Smit WL, Culver EL, Chapman RW. New Thoughts on Immunoglobulin G4-Related Sclerosing Cholangitis. Clin Liver Dis 2016; 20:47-65. [PMID: 26593290 DOI: 10.1016/j.cld.2015.08.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Immunoglobulin G4 (IgG4)-related sclerosing cholangitis (IgG4-SC) is the biliary manifestation of the multisystem IgG4-related disease. IgG4-SC presents with biliary strictures and/or masses that can bear a striking similarity to other malignant and inflammatory diseases. Diagnosis is based on a combination of clinical, biochemical, radiological, and histologic findings with careful exclusion of malignant disease. Corticosteroids are the mainstay of treatment with good clinical, biochemical, and radiological responses. This review provides a comprehensive overview of the current knowledge of the prevalence, clinical features, radiology and histology findings, diagnosis, treatment, natural history, and pathophysiology of IgG4-SC.
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Affiliation(s)
- Wouter L Smit
- Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands; Nuffield Department of Medicine, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK
| | - Emma L Culver
- Translational Gastroenterology Unit, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK; Nuffield Department of Medicine, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK
| | - Roger W Chapman
- Translational Gastroenterology Unit, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK; Nuffield Department of Medicine, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK.
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Uehara T, Hamano H, Kawa S, Kobayashi Y, Yoshizawa A, Oki K, Nakata R, Kobayashi A, Sano K, Ota H. Comparison of histopathological features of pancreatic carcinoma and type 1 autoimmune pancreatitis. Pathol Int 2015; 64:51-7. [PMID: 24629172 DOI: 10.1111/pin.12136] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 01/13/2014] [Indexed: 12/24/2022]
Abstract
Type 1 autoimmune pancreatitis (AIP-1) is an immunoglobulin G (IgG)-4-related disease (IgG4-RD), characterized by elevated serum immunoglobulin G4 (IgG4) and infiltration by IgG4(+) plasma cells. Pancreatic carcinoma (PC) sometimes shows infiltration by IgG4(+) plasma cells, but details have been unclear. We compared pathological findings and expression of IgG4 and IgG in fibroses in 18 PC patients to those from 9 AIP-1 patients. Fibroses were divided into areas of ductal adenocarcinoma (DA) and obstructive pancreatitis (OP). Serum IgG4 levels were lower than the cut-off value in all PC patients with no IgG4-RD. Diffuse lymphoplasmacytic infiltration and eosinophil infiltration were characteristic of fibroses in PC. Though AIP-1 samples often had storiform fibrosis even in biopsies, PC did not show storiform fibrosis. Ratios of IgG4(+) plasma cells/IgG(+) plasma cells (IgG4/IgG ratios) in DA and OP were significantly lower than in AIP-1. However, high-density IgG4(+) plasma cell foci were detected in PC fibroses, particularly around peripheral nerves, vessels, and lymphoid follicles; between lobules and invasion fronts; and within neutrophilic abscesses. In conclusion, the IgG4/IgG ratio is useful in distinguishing PC from AIP-1, and should be evaluated in three or more areas, as PC can show localized high-density IgG4(+) plasma cell areas.
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Affiliation(s)
- Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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Amendment of the Japanese Consensus Guidelines for Autoimmune Pancreatitis, 2013 II. Extrapancreatic lesions, differential diagnosis. J Gastroenterol 2014; 49:765-84. [PMID: 24664402 DOI: 10.1007/s00535-014-0944-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 02/06/2014] [Indexed: 02/04/2023]
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Comparative MRI analysis of morphologic patterns of bile duct disease in IgG4-related systemic disease versus primary sclerosing cholangitis. AJR Am J Roentgenol 2014; 202:536-43. [PMID: 24555589 DOI: 10.2214/ajr.12.10360] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The purpose of this study was to perform a retrospective MRI-based comparative analysis of the morphologic patterns of bile duct disease in IgG4-related systemic disease (ISD, also called autoimmune pancreatitis) compared with primary sclerosing cholangitis (PSC) and the autoimmune liver diseases autoimmune hepatitis and primary biliary cirrhosis. MATERIALS AND METHODS This study included 162 consecutively registered patients (47 with ISD, 73 with PSC, and 42 with autoimmune liver diseases). Two abdominal radiologists retrospectively reviewed MR images in consensus. Imaging findings on the bile ducts, liver, pancreas, and other organs were analyzed to establish disease patterns. RESULTS ISD was associated with contiguous thickening of intrahepatic and extrahepatic bile ducts (p<0.001), pancreatic parenchymal abnormalities (p<0.001), renal abnormalities (p<0.001), and gallbladder wall thickening (p<0.03). The severity of common bile duct wall thickness was significantly different in ISD (p<0.001). The mean single wall thickness in the ISD group was 3.00 (SD, 1.47) mm, in the PSC group was 1.89 (SD, 0.73) mm, and in the autoimmune liver disease group was 1.80 (SD, 0.67) mm. PSC was associated with liver parenchymal abnormalities (p<0.001). We did not find statistical significance between the three groups in location (p=0.220) or length (p=0.703) of extrahepatic bile duct strictures, enhancement of bile duct stricture (p=0.033), upper abdominal lymphadenopathy, or retroperitoneal fibrosis. Although presence of intrahepatic bile duct stricture was statistically significant when all three groups were compared, it was not useful for differentiating ISD from PSC. CONCLUSION The presence of continuous as opposed to skip disease in the bile ducts, gallbladder involvement, and single-wall common bile duct thickness greater than 2.5 mm supports a diagnosis of ISD over PSC. ISD and PSC could not be differentiated on the basis of location and length of common bile duct stricture.
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Uehara T, Hamano H, Suga T, Kawa S, Yoshizawa A, Kobayashi Y, Murata K, Oki K, Sano K, Onodera R, Ota H. Inflammation of colon adenoma in the setting of type 1 autoimmune pancreatitis. Pathol Int 2014; 64:67-74. [DOI: 10.1111/pin.12139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Accepted: 01/19/2014] [Indexed: 12/24/2022]
Affiliation(s)
- Takeshi Uehara
- Department of Laboratory Medicine; Shinshu University School of Medicine; Matsumoto Japan
| | - Hideaki Hamano
- Division of Medical Informatics; Shinshu University Hospital; Matsumoto Japan
| | - Tomoaki Suga
- Gastroenterology, Department of Medicine; Shinshu University School of Medicine; Matsumoto Japan
| | - Shigeyuki Kawa
- Center for Health, Safety and Environmental Management; Shinshu University; Matsumoto Japan
| | - Akihiko Yoshizawa
- Department of Laboratory Medicine; Shinshu University School of Medicine; Matsumoto Japan
| | - Yukihiro Kobayashi
- Department of Laboratory Medicine; Shinshu University School of Medicine; Matsumoto Japan
| | - Kazuya Murata
- Department of Laboratory Medicine; Shinshu University School of Medicine; Matsumoto Japan
| | - Keiko Oki
- Department of Laboratory Medicine; Shinshu University Hospital; Matsumoto Japan
| | - Kenji Sano
- Department of Laboratory Medicine; Shinshu University School of Medicine; Matsumoto Japan
| | - Rie Onodera
- Department of Biomedical Laboratory Medicine; Shinshu University School of Medicine; Matsumoto Japan
| | - Hiroyoshi Ota
- Department of Laboratory Medicine; Shinshu University School of Medicine; Matsumoto Japan
- Department of Laboratory Medicine; Iwate Medical University School of Medicine; Morioka Japan
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Pezzilli R, Morselli-Labate AM. The concept of autoimmune pancreatitis and its immunological backgrounds. Expert Rev Clin Immunol 2014; 6:125-36. [DOI: 10.1586/eci.09.68] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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15
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Mizutani S, Suzuki H, Yoshida H, Arima Y, Kitayama Y, Uchida E. Case of IgG4-related sclerosing cholangitis with a normal serum IgG4 level: report of a case. J NIPPON MED SCH 2013; 79:367-72. [PMID: 23123394 DOI: 10.1272/jnms.79.367] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Although hilar cholangioma is the most common cause of stricture of the hilar bile duct, several diseases can contribute to stenosis. Here, we report on a patient with immunoglobulin (Ig) G4-related sclerosing cholangitis (IgG4-SC) of the hilar bile duct arising from obstructive jaundice. The patient had undergone laparoscopic cholecystectomy for the removal of gallstones. The differential diagnosis for icterus included hilar cholangiocarcinoma, primary sclerosing cholangitis, IgG4 sclerosing cholangitis, ischemic bile duct stenosis, a complication of cholecystitis, amputation neuroma, and iatrogenic stenosis. Numerous examinations were performed, but a definite diagnosis remained elusive. Because cholangiocarcinoma could not be ruled out, we proposed surgical resection. The patient subsequently underwent extended right liver lobectomy and intrahepatic cholangiojejunostomy. Pathological examination revealed numerous inflammatory cell infiltrates resembling IgG4-positive antibody plasma cells in the stromal layer of the stenotic bile duct walls. Hypertrophy of the nerve fiber fascicles was not observed. The serum IgG4 level of the patient was within the normal range. Few reports of IgG4-SC with a normal serum IgG4 level have been published. When this condition presents as it did in the present case, establishing a definite diagnosis can be difficult.
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Affiliation(s)
- Satoshi Mizutani
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School Musashi Kosugi Hospital, Nakahara-ku, Kawasaki, Kanagawa, Japan.
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Tanaka A, Tazuma S, Okazaki K, Tsubouchi H, Inui K, Takikawa H. Nationwide survey for primary sclerosing cholangitis and IgG4-related sclerosing cholangitis in Japan. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2013; 21:43-50. [PMID: 24353071 DOI: 10.1002/jhbp.50] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND We previously conducted nationwide surveys for primary sclerosing cholangitis (PSC) in Japan, and demonstrated several characteristic features of Japanese PSC patients, yet patients with IgG4-related sclerosing cholangitis (IgG4-SC) might be misdiagnosed as PSC. Since the clinical diagnostic criteria of IgG4-SC were established in 2012, we again conducted a nationwide survey to investigate the characteristics of PSC and IgG4-SC lacking pancreatic involvement. METHODS The design was a questionnaire-based, multi-center retrospective study. The enrolled subjects were patients with PSC and IgG4-SC without pancreatic involvement diagnosed after 2005. RESULTS We enrolled 197 PSC and 43 IgG4-SC patients without pancreatic lesions. The male dominance was significantly evident in IgG4-SC (P = 0.006). In patients with PSC, two peaks in age distribution were clearly observed. IgG4-SC was not detected in any patient younger than 45 years of age. At presentation, serum albumin and IgM were significantly higher in PSC, while serum IgG and IgG4 were significantly elevated in IgG4-SC. Inflammatory bowel disease (IBD) was detected in only 68/197 PSC patients (34%). The prognosis of IgG4-SC was considerably better than that of PSC. CONCLUSION We confirmed several interesting clinical details of PSC in Japanese patients: two peaks in the age distribution and lower prevalence of IBD.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan.
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Tanaka A, Takikawa H. Geoepidemiology of primary sclerosing cholangitis: A critical review. J Autoimmun 2013; 46:35-40. [DOI: 10.1016/j.jaut.2013.07.005] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 07/11/2013] [Indexed: 12/20/2022]
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Kim JH, Byun JH, Kim SY, Lee SS, Kim HJ, Kim MH, Lee MG. Sclerosing cholangitis with autoimmune pancreatitis versus primary sclerosing cholangitis: comparison on endoscopic retrograde cholangiography, MR cholangiography, CT, and MRI. Acta Radiol 2013; 54:601-7. [PMID: 23528564 DOI: 10.1177/0284185113481018] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND It is essential to differentiate sclerosing cholangitis with autoimmune pancreatitis (SC-AIP) from primary sclerosing cholangitis (PSC) as the treatment and prognosis of the two diseases are totally different. PURPOSE To compare image findings of SC-AIP and PSC on endoscopic retrograde cholangiography (ERC), magnetic resonance cholangiography (MRC), computed tomography (CT), and magnetic resonance imaging (MRI). MATERIAL AND METHODS Two radiologists retrospectively reviewed ERC, MRC, CT, and MRI in 28 SC-AIP and 23 PSC patients in consensus. Factors evaluated included the length, location, and multiplicity of bile duct stricture, the presence of characteristic cholangiographic features of PSC on ERC and MRC, and the presence, location, thickness, and pattern of bile duct wall thickening on CT and MRI. RESULTS On ERC, focal stricture, multifocal and intrahepatic bile duct stricture, and beaded, pruned-tree, and diverticulum-like appearance were more frequent in PSC than in SC-AIP patients (P ≤ 0.006). On MRC, multifocal and intrahepatic bile duct stricture and pruned-tree appearance were more frequent in PSC than in SC-AIP patients (P ≤ 0.044). On CT and MRI, the bile duct wall was thicker (5.1 mm vs. 3.1 mm; P = 0.033 and 4.3 mm vs. 3.0 mm; P = 0.01, respectively) in SC-AIP than in PSC patients. PSC was more frequently associated with intrahepatic bile duct wall thickening on both CT (93% vs. 50%; P = 0.024) and MRI (100% vs. 50%; P = 0.023) than SC-AIP. CONCLUSION The combination of ERC or MRC with cross-sectional images, including CT and MRI, may be helpful in differentiating between SC-AIP and PSC.
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Affiliation(s)
- Jin Hee Kim
- Department of Radiology and Research Institute of Radiology
| | - Jae Ho Byun
- Department of Radiology and Research Institute of Radiology
| | - So Yeon Kim
- Department of Radiology and Research Institute of Radiology
| | - Seung Soo Lee
- Department of Radiology and Research Institute of Radiology
| | | | - Myung-Hwan Kim
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Moon-Gyu Lee
- Department of Radiology and Research Institute of Radiology
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IgG4-related disease-like fibrosis as an indicator of IgG4-related lymphadenopathy. Ann Diagn Pathol 2013; 17:416-20. [PMID: 23702322 DOI: 10.1016/j.anndiagpath.2013.04.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Revised: 03/30/2013] [Accepted: 04/18/2013] [Indexed: 01/06/2023]
Abstract
The significance of IgG4-related diseases including IgG4-related lymphadenopathy has recently been recognized worldwide. Inflammatory pseudotumors in lymph nodes, as well as in other organs, are also recognized as IgG4-related diseases. Only a few case reports have described IgG4-related lymphadenopathy with fibrosis (IgG4-fibrosing lymphadenopathy), and IgG4-fibrosing lymphadenopathy has not been compared clinicopathologically with non-IgG4-related lymphadenopathy with fibrosis. We have evaluated the pathologic features in 13 patients with IgG4-fibrosing lymphadenopathy, including IgG4 and IgG expression in lymph nodes, and compared these features with those of patients with non-IgG4-related lymphadenopathy with fibrosis with reactive inguinal lymphadenopathy and focal fibrosis and lymph nodes at least 10 mm in diameter. IgG4-fibrosing lymphadenopathy was characterized by lymphoplasmacytic and eosinophilic infiltration, many IgG4-positive plasma cells in fibrotic areas, and high serum IgG4 concentrations. The IgG4-positive/IgG-positive plasma cell ratio was significantly higher in the IgG4-fibrosing lymphadenopathy than in the non-IgG4-fibrosing lymphadenopathy group. The presence of even minor fibrosis with characteristics of IgG4-related disease such as IgG4-fibrosing lymphadenopathy may facilitate the diagnosis of IgG4-related lymphadenopathy.
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Khosroshahi A, Carruthers MN, Stone JH, Shinagare S, Sainani N, Hasserjian RP, Deshpande V. Rethinking Ormond's disease: "idiopathic" retroperitoneal fibrosis in the era of IgG4-related disease. Medicine (Baltimore) 2013; 92:82-91. [PMID: 23429355 PMCID: PMC4553983 DOI: 10.1097/md.0b013e318289610f] [Citation(s) in RCA: 139] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Idiopathic retroperitoneal fibrosis (RPF) is a periaortic sclerotic disease that encases adjacent retroperitoneal structures, particularly the ureters. A subset of idiopathic RPF cases can be associated with IgG4-related disease, but the frequency of this association is not clear. We selected 23 cases of idiopathic RPF and identified IgG4-related RPF cases based on the presence of IgG4+ plasma cells in the tissue, using an IgG4/IgG ratio cutoff of >40%. We then compared the IgG4-related RPF patients and the non-IgG4-related RPF patients in terms of both the presence of histopathologic features typical of IgG4-related disease and the simultaneous occurrence (or history) of other organ manifestations typical of IgG4-related disease. The IgG4-related RPF and non-IgG4-related RPF groups were also analyzed in terms of clinical, laboratory, and radiologic features and treatment review. We identified 13 cases of IgG4-related RPF (57% of the total cohort). The distinguishing features of IgG4-related RPF were histopathologic and extra-organ manifestations of IgG4-related disease. The IgG4-related RPF patients were statistically more likely than non-IgG4-related RPF patients to have retroperitoneal biopsies showing lymphoplasmacytic infiltrate (p = 0.006), storiform fibrosis (p = 0.006), or tissue eosinophilia (p = 0.0002). Demographics of the 2 groups, including a middle-aged, male predominance (mean age, 58 yr; 73% male), were similar. IgG4-related disease accounts for a substantial percentage of patients with "idiopathic" RPF. Histopathologic features such as storiform fibrosis, obliterative phlebitis, and tissue eosinophilia are critical to identifying this disease association. Extraretroperitoneal manifestations of IgG4-related disease are also often present among patients with IgG4-related RPF. Elevated IgG4/total IgG ratios in tissue biopsies are more useful than the number of IgG4+ plasma cells per high-power field in cases of RPF that are highly fibrotic.
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Affiliation(s)
- Arezou Khosroshahi
- From Rheumatology Unit (AK, MNC, JHS), Division of Rheumatology, Allergy, and Immunology, Department of Medicine; Department of Pathology (SS, RPH, VD); and Department of Radiology (NS), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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Atypical manifestations of IgG4-related sclerosing disease in the abdomen: imaging findings and pathologic correlations. AJR Am J Roentgenol 2013; 200:102-12. [PMID: 23255748 DOI: 10.2214/ajr.12.8783] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE The purpose of this essay is to illustrate a variety of atypical imaging manifestations of IgG4-related sclerosing disease in the abdomen and to correlate the imaging and pathologic findings. CONCLUSION In rare instances, IgG4-related sclerosing disease manifests atypical features in various organs in the abdomen. It is important that radiologists be aware of the typical and atypical features of this disease to provide timely effective treatment.
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Oseini AM, Chaiteerakij R, Shire AM, Ghazale A, Kaiya J, Moser CD, Aderca I, Mettler TA, Therneau TM, Zhang L, Takahashi N, Chari ST, Roberts LR. Utility of serum immunoglobulin G4 in distinguishing immunoglobulin G4-associated cholangitis from cholangiocarcinoma. Hepatology 2011; 54:940-8. [PMID: 21674559 PMCID: PMC3253343 DOI: 10.1002/hep.24487] [Citation(s) in RCA: 134] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Accepted: 05/27/2011] [Indexed: 12/12/2022]
Abstract
UNLABELLED Elevated serum immunoglobulin G4 (sIgG4) is a feature of autoimmune pancreatitis (AIP) and IgG4-associated cholangitis (IAC); a >2-fold increase in sIgG4 is considered highly specific for these disorders. Many patients with IAC present with biliary strictures and obstructive jaundice, making cholangiocarcinoma (CCA) an important differential diagnosis. We determined the value of sIgG4 in distinguishing IAC from CCA. sIgG4 levels were measured in a test cohort of 126 CCA and 50 IAC patients. The results were confirmed in a validation cohort of 161 CCA and 47 IAC patients. Of the 126 CCA patients in the test cohort, 17 (13.5%) had elevated sIgG4 (>140 mg/dL) and four (3.2%) had a >2-fold (>280 mg/dL) increase. Primary sclerosing cholangitis (PSC) was present in 31/126 CCA patients, of whom seven (22.6%) had elevated sIgG4 and two (6.5%) had a >2-fold elevation. Of the 50 IAC patients, 39 (78.0%) had elevated sIgG4 and 25 (50.0%) had a >2-fold increase. The results in the validation cohort were consistent with those of the test cohort. CONCLUSION Although elevated sIgG4 levels are characteristic of IAC, some patients with CCA, particularly with PSC, have elevated sIgG4 levels, including a small percentage with a more than a 2-fold increase in sIgG4. Therefore, sIgG4 elevation alone does not exclude the diagnosis of CCA. Depending on the prevalence of the two diagnoses, the use of a 2-fold cutoff for sIgG4 may not reliably distinguish IAC from CCA. At a cutoff of 4 times the upper limit of normal, sIgG4 is 100% specific for IAC.
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Affiliation(s)
- Abdul M. Oseini
- Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Roongruedee Chaiteerakij
- Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Abdirashid M. Shire
- Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Amaar Ghazale
- Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Joseph Kaiya
- Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Catherine D. Moser
- Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Ileana Aderca
- Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Teresa A. Mettler
- Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Terry M. Therneau
- Department of Health Sciences Research, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Lizhi Zhang
- Department of Laboratory Medicine and Pathology, College of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Naoki Takahashi
- Department of Radiology, College of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Suresh T. Chari
- Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota
| | - Lewis R. Roberts
- Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota
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Ito M, Naruke Y, Mihara Y, So K, Miyashita T, Origuchi T, Nakashima M, LiVolsi V. Thyroid papillary carcinoma with solid sclerosing change in IgG4-related sclerosing disease. Pathol Int 2011; 61:589-92. [DOI: 10.1111/j.1440-1827.2011.02701.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Raissian Y, Nasr SH, Larsen CP, Colvin RB, Smyrk TC, Takahashi N, Bhalodia A, Sohani AR, Zhang L, Chari S, Sethi S, Fidler ME, Cornell LD. Diagnosis of IgG4-related tubulointerstitial nephritis. J Am Soc Nephrol 2011; 22:1343-52. [PMID: 21719792 DOI: 10.1681/asn.2011010062] [Citation(s) in RCA: 233] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
IgG4-related systemic disease is an autoimmune disease that was first recognized in the pancreas but also affects other organs. This disease may manifest as tubulointerstitial nephritis (IgG4-TIN), but its clinicopathologic features in the kidney are not well described. Of the 35 patients with IgG4-TIN whose renal tissue specimens we examined, 27 (77%) had acute or progressive chronic renal failure, 29 (83%) had involvement of other organ systems, and 18 of 23 (78%) had radiographic abnormalities. Elevated total IgG or IgG4 serum levels were present in 79%. All pathologic specimens featured plasma cell-rich TIN, with most showing diffuse, expansile interstitial fibrosis. Immune complexes along the tubular basement membranes were present in 25 of 30 (83%). All specimens had a moderate to marked increase in IgG4+ plasma cells by immunohistochemistry. We used a control group of 175 pathologic specimens with plasma cell-rich interstitial infiltrates that can mimic IgG4-TIN to examine the diagnostic utility of IgG4 immunostaining. Excluding pauci-immune necrotizing and crescentic glomerulonephritis, IgG4 immunohistochemistry had a sensitivity of 100% (95% CI 90-100%) and a specificity of 92% (95% CI 86-95%) for IgG4-TIN. Of the 19 patients with renal failure for whom treatment and follow-up data were available, 17 (89%) responded to prednisone. In summary, because no single test definitively diagnoses IgG4-related systemic disease, we rely on a combination of histologic, immunophenotypic, clinical, radiographic, and laboratory features. When the disease manifests in the kidney, our data support diagnostic criteria that can distinguish IgG4-TIN from other types of TIN.
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Affiliation(s)
- Yassaman Raissian
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 1 Street SW, Rochester, MN 55905, USA
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Abstract
PURPOSE OF REVIEW To summarize the existing knowledge of various clinical presentations of IgG4-related systemic disease (IgG4-RSD) and to review the evolving list of organs affected by IgG4-RSD. RECENT FINDINGS The term IgG4-RSD encompasses a variety of clinical entities once regarded as being entirely separate diseases. The list of organs associated with this condition is growing steadily. Tissue biopsies reveal striking histopathological similarity, regardless of which organ is involved, although subtle differences across organs exist. Diffuse lymphoplasmacytic infiltrates, presence of abundant IgG4-positive plasma cells and extensive fibrosis are the hallmark pathology findings. Tumorous swelling, eosinophilia, and obliterative phlebitis are other frequently observed features. Polyclonal elevations of serum IgG4 are found in most but not all patients. SUMMARY IgG4-RSD is an underrecognized condition about which knowledge is now growing rapidly. Yet there remain many unknowns with regard to its cause, pathogenesis, various clinical presentations, approach to treatment, disease monitoring, and long-term outcomes. A wide variety of organs can be involved in IgG4-RSD. Clinicians should be aware of this entity and consider the diagnosis in the appropriate settings.
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Abstract
PURPOSE OF REVIEW IgG4-related systemic disease (ISD) is a recently recognized syndrome affecting multiple organs. Autoimmune pancreatitis (AIP) is the pancreatic manifestation of ISD and mimics pancreatic cancer. Current data show frequent association with serum IgG4 elevation and other serologic abnormalities. Here we explore the diagnostic and possible prognostic utility and pathogenetic implications of serologic abnormalities in ISD. RECENT FINDINGS Serum IgG4 elevations (>140 mg/dl) are seen in 70-80% of AIP patients and also in 5% of normal population and 10% of pancreatic cancer making it an unsuitable single marker for diagnosis. However, when combined with other features of AIP, it can be of great diagnostic value though its utility in monitoring of therapy or as a marker or predictor of relapse is limited. Several other antibodies have been identified in AIP against pancreas-specific antigens like trypsinogens I and II, pancreatic secretory trypsin inhibitor (PSTI) and plasminogen binding protein (PBP) and other nonpancreas-specific antigens. Anti-PBP antibodies appear to have potential diagnostic utility but require further validation. SUMMARY No single serologic marker is diagnostic of ISD. Serum IgG4 elevation has convincing diagnostic utility when combined with other disease features although its value in disease monitoring may be limited.
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Lin YJ, Chen PC, Chen HA, Li CF. IgG4-related retroperitoneal fibrosis: the first reported case in a Chinese population. Int J Rheum Dis 2010; 13:e70-e73. [PMID: 21199458 DOI: 10.1111/j.1756-185x.2010.01543.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Immunoglobulin G4 (IgG4)-related sclerosing disease is a newly recognized clinicopathological entity characterized by lymphoplasmacytic infiltration and varying degrees of fibrosis in various organs, with abundant IgG4-positive plasma cells in tissues. Patients usually exhibit multisystem involvement and often respond well to steroid and immunosuppressive therapy. However, this disease has been rarely reported in a Chinese population. We herein report a case of IgG4-related sclerosing disease solely presenting with retroperitoneal fibrosis that was effectively treated with systemic steroid therapy. To the best of our knowledge, this is the first reported case of IgG4-related retroperitoneal fibrosis in a Chinese population.
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Affiliation(s)
- Yeong-Jang Lin
- Divisions of Allergy, Chi-Mei Medical Center, Tainan, Taiwan
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Uehara T, Hamano H, Kawa S, Sano K, Oki K, Kobayashi Y, Nagaya T, Akamatsu T, Kurozumi M, Fujinaga Y, Tanaka E, Honda T, Ota H. Chronic gastritis in the setting of autoimmune pancreatitis. Am J Surg Pathol 2010; 34:1241-9. [PMID: 20697253 DOI: 10.1097/pas.0b013e3181ec07ee] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Autoimmune pancreatitis (AIP) is a recently recognized disease entity. In some patients, this disease is associated with other inflammatory diseases. In this study, we aimed to elucidate the pathologic characteristics of AIP-associated gastritis (AIP-G). We evaluated and compared the pathologic findings and immunohistochemical expressions of immunoglobulin G (IgG)4 and IgG in gastric biopsy specimens from 13 AIP-G patients with those from patients of 2 control groups. We divided the AIP-G patients who did not receive steroid therapy [AIP-G-ST(-)] into the following 2 groups: without Helicobacter pylori (HP) infection [AIP-G-HP(-)] and with HP infection [AIP-G-HP(+)]. The control groups comprised 19 patients who were diagnosed with chronic active gastritis associated with HP infection and 7 patients with nonsteroidal anti-inflammatory drug-induced gastritis. We classified the findings for the gastric mucosa into those for the upper and the lower lamina propria. The characteristic finding of AIP-G groups was diffusely lymphoplasmacytic infiltration in the lamina propria. The IgG4-positive plasma cell/IgG-positive plasma cell ratios (IgG4/IgG ratios) in both the upper and lower lamina propria in the AIP-G-ST(-) groups were predominantly higher than the corresponding values in the other groups. In the AIP-G-ST(-) groups, the IgG4/IgG ratio in the lower lamina propria was predominantly higher than that in the upper lamina propria, irrespective of the HP status. In conclusion, diffuse lymphoplasmacytic infiltration in the lamina propria and increased IgG4/IgG ratio in the gastric mucosa (notably in the lower lamina propria) may be the characteristic findings of AIP-G.
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Affiliation(s)
- Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
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Koyabu M, Uchida K, Miyoshi H, Sakaguchi Y, Fukui T, Ikeda H, Takaoka M, Hirohara J, Nishio A, Uemura Y, Uemoto S, Okazaki K. Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases. J Gastroenterol 2010; 45:732-41. [PMID: 20087609 DOI: 10.1007/s00535-010-0199-3] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2009] [Accepted: 12/23/2009] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Patients with autoimmune pancreatitis (AIP) characteristically show elevated serum levels of immunoglobulin G4 (IgG4) and abundant infiltration of IgG4-positive plasmacytes in the involved organs. The most common involved organ showing extrapancreatic lesions is the bile duct, which exhibits sclerosing cholangitis (SC). However, the role of IgG4 in the development of IgG4-related SC (IgG4-SC) remains unclear. To clarify the role of IgG4 in IgG4-SC, we have performed an immunohistochemical analysis of the bile duct. METHODS Laboratory and immunohistochemical findings of liver biopsy specimens obtained from patients with IgG4-SC, primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), and primary biliary cirrhosis (PBC) were compared. The biopsy specimens were first stained with anti-IgG1, anti-IgG4, and anti-Foxp3 (forkhead box P3) antibodies, and the ratio of IgG4-, IgG1-, and Foxp3-positive cells, respectively, to infiltrated mononuclear cells (IgG4/Mono, IgG1/Mono, Foxp3/Mono) was assessed. RESULTS The ratio of IgG4/IgG1-positive plasma cells was significantly higher in specimens obtained from patients with IgG4-SC than in those from patients with PSC, AIH, and PBC. The Foxp3/Mono ratio in patients with PBC was significantly higher than that in patients with IgG4-SC and PSC. In patients with IgG4-SC, the number of Foxp3-positive cells was significantly correlated with the number of IgG4-positive cells; in the other patient groups, there was no correlation. CONCLUSIONS The IgG4/IgG1 ratio in the liver may be a useful marker for differential diagnosis of IgG4-SC and PSC. In IgG4-SC, abundant infiltration of regulatory T cells (Tregs) may affect the switching of B cells to IgG4-producing plasmacytes, and there is a possibility that the function of Tregs is different in IgG4-SC and other liver diseases (PSC, AIH, and PBC).
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Affiliation(s)
- Masanori Koyabu
- Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono, Moriguchi, Osaka, 570-8507, Japan
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Koyabu M, Uchida K, Fukata N, Kusuda T, Ikeura T, Sakaguchi Y, Yoshida K, Shimatani M, Fukui T, Matsushita M, Uemura Y, Kaibori M, Takaoka M, Nishio A, Okazaki K. Primary sclerosing cholangitis with elevated serum IgG4 levels and/or infiltration of abundant IgG4-positive plasma cells. J Gastroenterol 2010; 45:122-9. [PMID: 19760481 DOI: 10.1007/s00535-009-0130-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2009] [Accepted: 08/19/2009] [Indexed: 02/04/2023]
Abstract
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.
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Affiliation(s)
- Masanori Koyabu
- The Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Moriguchi, Japan
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Japanese consensus guidelines for management of autoimmune pancreatitis: II. Extrapancreatic lesions, differential diagnosis. J Gastroenterol 2010; 45:355-69. [PMID: 20127119 DOI: 10.1007/s00535-009-0197-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2009] [Accepted: 12/17/2009] [Indexed: 02/04/2023]
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Abstract
BACKGROUND Autoimmune pancreatitis (AIP) is a relatively newly recognized type of pancreatitis that is characterized by diffuse or focal swelling of the pancreas due to lymphoplasmacytic infiltration and fibrosis of the pancreatic parenchyma. MATERIAL AND METHODS A PubMed literature search was performed using the keywords "autoimmune pancreatitis". Sometimes, bibliographies were cross-referenced and related article searches were performed once an article of interest was identified. RESULTS Pathologically, AIP shows narrowing of the pancreatic ducts and the intrapancreatic portion of the common bile duct. Obstructive jaundice is a common symptom at presentation, and pancreatic cancer represents an important clinical differential diagnosis. In late stages of the disease, the normal pancreatic parenchyma is often replaced by large amounts of fibrosis. Histologically, there seem to be two subtypes of the disease-one showing infiltration with IgG4-positive plasma cells but lacking granulocytic epithelial lesions (GELs), the other showing GELs but lacking strong IgG4 positivity. AIP is in at least some instances the pancreatic manifestation of a clinicopathological entity of IgG4-related systemic sclerosing disease. On the basis of pancreatic imaging, together with serological measurement of IgG4 and evaluation of other organ involvement, many AIP patients can be identified. The remaining patients require further diagnostic work-up. In these patients, pancreatic core needle biopsy and, as AIP responds to steroid treatment, also a trial with steroids, can help to differentiate AIP from pancreatic cancer. OUTLOOK AND DISCUSSION: This review presents the pathological, radiologic and laboratory findings of AIP. Moreover, the treatment and pathogenesis are discussed.
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Affiliation(s)
- Sönke Detlefsen
- Department of Pathology, Odense University Hospital, Odense, Denmark.
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Padilla D, Menéndez P, Villarejo P, Cubo T, Martín J. [Autoimmune sclerosing cholangitis after hepatobiliary-pancreatic surgery]. Cir Esp 2010; 87:391-3. [PMID: 20206922 DOI: 10.1016/j.ciresp.2009.01.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2008] [Accepted: 01/29/2009] [Indexed: 10/19/2022]
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Abstract
OBJECTIVES As the patients with autoimmune pancreatitis (AIP) are increasing in Japan, the practical guideline for managing AIP is required to be established. METHODS Three committees (the professional committee for making clinical questions [CQs] and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators) were organized. Fifteen specialists for AIP extracted the specific clinical statements from a total of 871 literatures by PubMed search (approximately 1963-2008) and from a secondary database and made 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. RESULTS The professional committee made 13, 6, 6, and 11 CQs and statements for the concept and diagnosis, extrapancreatic lesions, differential diagnosis, and treatment, respectively. The expert panelists regarded them as valid after a 2-round modified Delphi approach. CONCLUSIONS After evaluation by the moderators, the Japanese clinical guideline for AIP has been established. Further studies for the international guideline are needed after international consensus for diagnosis and treatment.
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Li Y, Bai Y, Liu Z, Ozaki T, Taniguchi E, Mori I, Nagayama K, Nakamura H, Kakudo K. Immunohistochemistry of IgG4 can help subclassify Hashimoto's autoimmune thyroiditis. Pathol Int 2009; 59:636-41. [PMID: 19712131 DOI: 10.1111/j.1440-1827.2009.02419.x] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
IgG4-related sclerosing disease has been recently recognized as a systemic disease entity characterized by an elevated serum IgG4 level, sclerosing fibrosis and diffuse lymphoplasmacytic infiltration by many IgG4-positive plasma cells. Similar histopathological features have often been noted in the fibrous variant of Hashimoto's autoimmune thyroiditis, but thyroid gland involvement has been only briefly mentioned with regard to IgG4, and no immunohistochemistry for IgG4 has been reported in Hashimoto's autoimmune thyroiditis. Herein, the purpose of the present study was to investigate the infiltration of IgG- and IgG4-positive plasma cells on immunohistochemistry for a panel of thyroiditis samples (Hashimoto's autoimmune thyroiditis, n= 13; subacute thyroiditis, n= 2; lymphocytic thyroiditis, n= 2). Cases of Hashimoto's thyroiditis could be classified into two groups based on immunostaining of IgG4: IgG4 thyroiditis (IgG4-related, IgG4-positive plasma cell-rich thyroiditis) and non-IgG4 thyroiditis (non-IgG4-related, IgG4-positive plasma cell-poor thyroiditis). IgG4 thyroiditis presents with severe lymphoplasmacytic infiltration, dense fibrosis, marked follicular cell degeneration, oxyphilic change and lymphoid follicle formation, while non-IgG4 thyroiditis presents with relatively mild or absent histopathological characteristics. In conclusion, immunostaining of IgG4 can help subclassify Hashimoto's thyroiditis; and IgG4 thyroiditis may have a close relationship with IgG4-related sclerosing disease.
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Affiliation(s)
- Yaqiong Li
- Department of Human Pathology, Wakayama Medical University, Wakayama 641-8509, Japan
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Bateman AC, Deheragoda MG. IgG4-related systemic sclerosing disease - an emerging and under-diagnosed condition. Histopathology 2009; 55:373-83. [DOI: 10.1111/j.1365-2559.2008.03217.x] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Itoh S, Nagasaka T, Suzuki K, Satake H, Ota T, Naganawa S. Lymphoplasmacytic sclerosing cholangitis: assessment of clinical, CT, and pathological findings. Clin Radiol 2009; 64:1104-14. [PMID: 19822244 DOI: 10.1016/j.crad.2009.07.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2009] [Revised: 07/16/2009] [Accepted: 07/20/2009] [Indexed: 12/24/2022]
Abstract
AIM To assess the clinical, computed tomography (CT), and pathological findings in patients with lymphoplasmacytic sclerosing cholangitis. MATERIALS AND METHODS Fifteen consecutive patients (four women and 11 men, mean age 71 years) with lymphoplasmacytic sclerosing cholangitis and without the characteristic features of underlying disorders causing benign biliary strictures were retrospectively recruited. Two radiologists evaluated multiphase contrast-enhanced CT images acquired with 0.5 or 1-mm collimation. One pathologist performed all histological examinations, including IgG4 immunostaining. RESULTS The intrahepatic biliary ducts showed dilatation in all 15 patients, but only seven presented with jaundice. Although laboratory data were not available in all patients, serum gammaglobulin and IgG levels were elevated in five of six patients and six of eight patients, respectively. Anti-nuclear antibody was detected in three of six patients. The involved biliary ducts showed the following CT findings: involvement of the hilar biliary duct (14/15), a mean wall thickness of 4.9 mm, a smooth margin (10/15), a narrow but visible lumen (6/15), hyper-attenuation during the late arterial phase (9/15), homogeneous hyper-attenuation during the delayed phase (11/11), and no vascular invasion (14/15). Abnormal findings in the pancreas and urinary tract were detected in eight of 15 patients. In 13 patients with adequate specimens, moderate to severe lymphoplasmacytic infiltration associated with dense fibrosis was observed. Infiltration of IgG4-positive plasma cells was moderate or severe in nine patients and minimal or absent in four patients. CONCLUSION Lymphoplasmacytic sclerosing cholangitis exhibits relatively characteristic clinical and CT findings, although they are not sufficiently specific for differentiation from other biliary diseases.
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Affiliation(s)
- S Itoh
- Department of Technical Radiology, Nagoya University School of Health Sciences, Nagoya, Japan.
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Fujinaga Y, Kadoya M, Kawa S, Hamano H, Ueda K, Momose M, Kawakami S, Yamazaki S, Hatta T, Sugiyama Y. Characteristic findings in images of extra-pancreatic lesions associated with autoimmune pancreatitis. Eur J Radiol 2009; 76:228-38. [PMID: 19581062 DOI: 10.1016/j.ejrad.2009.06.010] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2009] [Accepted: 06/09/2009] [Indexed: 12/17/2022]
Abstract
PURPOSE Autoimmune pancreatitis is a unique form of chronic pancreatitis characterized by a variety of extra-pancreatic involvements which are frequently misdiagnosed as lesions of corresponding organs. The purpose of this study was to clarify the diagnostic imaging features of extra-pancreatic lesions associated with autoimmune pancreatitis. MATERIALS AND METHODS We retrospectively analyzed diagnostic images of 90 patients with autoimmune pancreatitis who underwent computer-assisted tomography, magnetic resonance imaging, and/or gallium-67 scintigraphy before steroid therapy was initiated. RESULTS AIP was frequently (92.2%) accompanied by a variety of extra-pancreatic lesions, including swelling of lachrymal and salivary gland lesions (47.5%), lung hilar lymphadenopathy (78.3%), a variety of lung lesions (51.2%), wall thickening of bile ducts (77.8%), peri-pancreatic or para-aortic lymphadenopathy (56.0%), retroperitoneal fibrosis (19.8%), a variety of renal lesions (14.4%), and mass lesions of the ligamentum teres (2.2%). Characteristic findings in CT and MRI included lymphadenopathies of the hilar, peri-pancreatic, and para-aortic regions; wall thickening of the bile duct; and soft tissue masses in the kidney, ureters, aorta, paravertebral region, ligamentum teres, and orbit. CONCLUSIONS Recognition of the diagnostic features in the images of various involved organs will assist in the diagnosis of autoimmune pancreatitis and in differential diagnoses between autoimmune pancreatitis-associated extra-pancreatic lesions and lesions due to other pathologies.
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Affiliation(s)
- Yasunari Fujinaga
- Department of Radiology, Shinshu University School of Medicine, Asahi, Matsumoto, Japan.
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Nishimori I, Otsuki M. Autoimmune pancreatitis and IgG4-associated sclerosing cholangitis. Best Pract Res Clin Gastroenterol 2009; 23:11-23. [PMID: 19258183 DOI: 10.1016/j.bpg.2008.11.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis characterised by a high serum IgG4 concentration and complications that include various extrapancreatic manifestations, one of which is sclerosing cholangitis. In AIP patients, infiltration of abundant IgG4-positive plasma cells and dense fibrosis are commonly observed in the pancreas and wall of the bile duct and gallbladder. The major symptom at onset of AIP is obstructive jaundice caused by stricture of the bile duct, and this requires differential diagnosis of AIP from pancreato-biliary malignancies and primary sclerosing cholangitis (PSC). Recently, there have been reports of particular cases of sclerosing cholangitis with a high serum IgG4 level and cholangiographic and pathological findings comparable to those observed in AIP patients. Being apparently different from PSC and similar to that in AIP, sclerosing cholangitis with and without AIP shows a clinical response to steroid therapy and thus is designated as 'IgG4-associated sclerosing cholangitis'. The pathogenesis of AIP and IgG4-associated sclerosing cholangitis remains at yet undetermined.
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Affiliation(s)
- Isao Nishimori
- Department of Gastroenterology and Hepatology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.
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Recognizing immunoglobulin G4 related overlap syndromes in patients with pancreatic and hepatobiliary diseases. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2009; 22:840-6. [PMID: 18925309 DOI: 10.1155/2008/586173] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The first description of autoimmune pancreatitis and elevated serum immunoglobulin-G4 (IgG4) in 2001 heralded further reports of several related autoimmune diseases with raised IgG4 levels. It is now recognized that a spectrum of overlap syndromes associated with increased IgG4 and biopsy evidence of IgG4-producing plasma cells, which has now been convincingly linked with cholangitis, autoimmune hepatitis, Sjögren's syndrome, nephritis and retroperitoneal fibrosis. Collectively, this disease cluster is referred to as IgG4-related systemic disease. The importance of making the correct diagnosis is underscored by the management of individuals with IgG4-related systemic disease. In the first instance, patients generally have a dramatic response to immunosuppressive therapy, whereas patients with other forms of cholangitis and pancreatitis do not. Also, surgical management of pancreatic malignancy can be avoided once the correct diagnosis of IgG4-related disease has been made. In the present review, an overview of the current information regarding the role of IgG4 and IgG4-positive cells affecting the biliary system, pancreas and liver is provided.
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Morselli-Labate AM, Pezzilli R. Usefulness of serum IgG4 in the diagnosis and follow up of autoimmune pancreatitis: A systematic literature review and meta-analysis. J Gastroenterol Hepatol 2009; 24:15-36. [PMID: 19067780 DOI: 10.1111/j.1440-1746.2008.05676.x] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
High circulating serum immunoglobulin G4 (IgG4) levels have been proposed as a marker of autoimmune pancreatitis (AIP). The aim of the present study was to review the data existing in the English literature on the usefulness of the IgG4 serum levels in the diagnosis and follow up of patients with AIP. A total of 159 patients with AIP and 1099 controls were described in seven selected papers reporting the usefulness of serum IgG4 in diagnosing AIP. In total, 304 controls had pancreatic cancer, 96 had autoimmune diseases, and the remaining 699 had other conditions. The summary receiver-operating characteristic curve analysis was carried out by means of Meta-DiSc open-access software. Serum IgG4 showed good accuracy in distinguishing between AIP and the overall controls, pancreatic cancer and other autoimmune diseases (area under the curve [+/- SE]: 0.920 +/- 0.073, 0.914 +/- 0.191, and 0.949 +/- 0.024, respectively). The studies analyzed showed significantly heterogeneous specificity values in each of the three analyses performed. The analysis of the four studies comparing AIP and pancreatic cancers also showed significantly heterogeneous values of sensitivities and odds ratios. Regarding the usefulness of IgG4 as a marker of efficacy of steroid treatment, a decrease in the serum concentrations of IgG4 was found in the four available studies. The serum IgG4 subclass is a good marker of AIP, and its determination should be included in the diagnostic workup of this disease. However, the heterogeneity of the studies published until now means that more studies are necessary in order to better evaluate the true accuracy of IgG4 in discriminating AIP versus other autoimmune diseases.
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Lymphoplasmacytic granuloma localized to the ampulla of Vater: an ampullary lesion of IgG4-related systemic disease? Gastrointest Endosc 2008; 68:1229-32. [PMID: 18547570 DOI: 10.1016/j.gie.2008.02.079] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2007] [Accepted: 02/23/2008] [Indexed: 02/08/2023]
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Tanaka A, Takamori Y, Toda G, Ohnishi S, Takikawa H. Outcome and prognostic factors of 391 Japanese patients with primary sclerosing cholangitis. Liver Int 2008; 28:983-9. [PMID: 18397233 DOI: 10.1111/j.1478-3231.2008.01726.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES We performed a national survey in 2003, and demonstrated characteristic features of primary sclerosing cholangitis (PSC) patients in Japan. In this study, we aimed to clarify the outcome and prognostic factors of Japanese PSC patients. METHODS Questionnaires were sent to gastroenterologists in Japan, and 391 patients with PSC were registered and enrolled in the current study. The median follow-up was 5.3 years (range 0.1-20.8 years). The cumulative incidence for survival was analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox-proportional hazards regression model for determining prognostic variables. RESULTS The estimated median survival of all patients was 13.1 years, with a 5-year survival rate of 74.5%. Thirty-eight patients (9.7%) who underwent liver transplantation (LT) had a 5-year survival rate of 92.0%. Both univariate and multivariate analysis demonstrated that younger age [below 49 years old; odds ratio (OR)=1.76, 1.12-2.76, P=0.0136] and lower total bilirubin (below 3.0 mg/dl; OR=2.50, 1.60-3.89, P<or=0.0001) were independent prognostic factors for LT-free survival of PSC patients in Japan. Cholangiocarcinoma (CCA) was found in 14 (3.6%) patients, and only two out of 125 PSC patients exhibited a history of inflammatory bowel diseases. CONCLUSIONS Although several characteristic features existed, the outcome as well as prognostic factors of Japanese PSC patients appeared to be similar to those from the United States and European countries. In contrast, the incidence of CCA in PSC appeared to be lower in Japan.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
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Kobayashi G, Fujita N, Noda Y, Ito K, Horaguchi J. Autoimmune pancreatitis: with special reference to a localized variant. J Med Ultrason (2001) 2008; 35:41-50. [PMID: 27278690 DOI: 10.1007/s10396-008-0177-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2007] [Accepted: 03/07/2008] [Indexed: 12/24/2022]
Abstract
In 2006, the Japan Pancreas Society revised the diagnostic criteria for autoimmune pancreatitis (AIP) so as to more clearly define its morphological, pathological, and immunological features, as follows: (1) diffuse or segmental narrowing of the main pancreatic duct with an irregular wall and diffuse or localized enlargement of the pancreas recognized by imaging studies; (2) high serum gamma globulin, IgG, or IgG4 levels, or the presence of autoantibodies; and (3) marked interlobular fibrosis and prominent infiltration of lymphocytes and plasma cells in the periductal area, occasionally with lymphoid follicles in the pancreas. Establishing a diagnosis of AIP has become easier with knowledge of its immunological abnormalities, including serum IgG4 levels. However, the localized form of AIP sometimes mimics pancreatic cancer. The rate of focal mass formation in patients with AIP is reportedly 24%-43%; however, there have been few reports on the histological findings of localized AIP, in contrast to mass-forming pancreatitis (MFP). Our review of patients who had undergone resection due to a preoperative diagnosis of MFP with possible cancer revealed 72% to be patients with localized AIP. For the discrimination of these conditions, it is important to recognize the characteristic ultrasonographic findings of AIP, i.e., (1) diffuse or localized enlargement and hypoechogenicity of the pancreas; (2) rarity of calcification, cystic lesions, and peripancreatic fluid collection; (3) thickened layer structure of the bile duct wall; (4) iso/hypervascularity in the swollen portion of the pancreas; (5) attenuation of pancreatic swelling and bile duct wall thickening after steroid therapy; and (6) multiple hypoechoic masses in various organs, including the pancreas. Contrast-enhanced endoscopic ultrasonography is potentially a useful tool in the differential diagnosis and for assessment of the efficacy of steroid therapy by enabling evaluation of the vascularity of the lesions. Along with the presence of IgG4-positive plasma cells, verification of obliterative phlebitis is highly specific for the histological diagnosis of AIP.
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Affiliation(s)
- Go Kobayashi
- Department of Gastroenterology, Sendai City Medical Center, 5-22-1 Tsurugaya, Miyagino-ku, Sendai, 983-0824, Japan.
| | - Naotaka Fujita
- Department of Gastroenterology, Sendai City Medical Center, 5-22-1 Tsurugaya, Miyagino-ku, Sendai, 983-0824, Japan
| | - Yutaka Noda
- Department of Gastroenterology, Sendai City Medical Center, 5-22-1 Tsurugaya, Miyagino-ku, Sendai, 983-0824, Japan
| | - Kei Ito
- Department of Gastroenterology, Sendai City Medical Center, 5-22-1 Tsurugaya, Miyagino-ku, Sendai, 983-0824, Japan
| | - Jun Horaguchi
- Department of Gastroenterology, Sendai City Medical Center, 5-22-1 Tsurugaya, Miyagino-ku, Sendai, 983-0824, Japan
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology but lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for this disease. Associations with inflammatory bowel disease (IBD) especially ulcerative colitis (UC), and with particular autoimmune diseases, as well as the genetic associations further suggest PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research and several HLA and non-HLA associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease. PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and hence evoking an abnormal immune response.
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Abstract
Aims of treatment for primary sclerosing cholangitis are as follows: prevention of progression of hepatobiliary disease, reduction of symptoms and consequences of cholestasis (pruritus, osteoporosis), and prevention of complications (colorectal cancer, hepatobiliary cancer). Ursodeoxycholic acid (UDCA) improves biliary secretion and laboratory parameters of cholestasis, but its effects on liver histology and survival are not clear. It reduces the incidence of dysplasias and carcinomas of the colon in patients with colitis and possibly has a beneficial effect on the incidence of bile duct carcinomas. At present, UDCA represents the most promising therapeutic option. Immunosuppressive treatment has not been proven to be effective; it appears to be indicated in the overlap syndrome with autoimmune hepatitis but may be harmful in bacterial cholangitis. Bacterial cholangitis is common in patients with dominant stenoses and requires antibiotic treatment. Endoscopic treatment of dominant stenoses improves cholestasis and prolongs survival in comparison to predicted survival. Pruritus represents a problem in some patients, and cholestyramine represents the first-line treatment. If ineffective, opioid antagonists, rifampin, or ondansetron may be tried. For treatment of osteoporosis and osteopenia, calcium and vitamin D supplementation are recommended, and in selected cases, bisphosphonates may be indicated. In patients with severe cholestasis and coagulation defects, parenteral supplementation of vitamin K may be indicated. During treatment, all patients should be regularly screened for colonic and bile duct carcinomas. Patients with cirrhosis of the liver and its complications are treated accordingly, and in end-stage disease, liver transplantation is indicated.
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Ghazale A, Chari ST, Zhang L, Smyrk TC, Takahashi N, Levy MJ, Topazian MD, Clain JE, Pearson RK, Petersen BT, Vege SS, Lindor K, Farnell MB. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology 2008; 134:706-15. [PMID: 18222442 DOI: 10.1053/j.gastro.2007.12.009] [Citation(s) in RCA: 584] [Impact Index Per Article: 34.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2007] [Accepted: 11/26/2007] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Immunoglobulin (Ig)G4-associated cholangitis (IAC) is the biliary manifestation of a steroid-responsive multisystem fibroinflammatory disorder in which affected organs have a characteristic lymphoplasmacytic infiltrate rich in IgG4-positive cells. We describe clinical features, treatment response, and predictors of relapse in IAC and compare relapse rates in IAC with intrapancreatic vs proximal bile duct strictures. METHODS We reviewed clinical, serologic, and imaging characteristics and treatment response in 53 IAC patients. RESULTS IAC patients generally were older (mean age, 62 y) men (85%), presenting with obstructive jaundice (77%) associated with autoimmune pancreatitis (92%), increased serum IgG4 levels (74%), and abundant IgG4-positive cells in bile duct biopsy specimens (88%). At presentation, biliary strictures were confined to the intrapancreatic bile duct in 51%; the proximal extrahepatic/intrahepatic ducts were involved in 49%. Initial presentation was treated with steroids (n = 30; median follow-up period, 29.5 months), surgical resection (n = 18; median follow-up period, 58 months), or was conservative (n = 5; median follow-up period, 35 months). Relapses occurred in 53% after steroid withdrawal; 44% relapsed after surgery and were treated with steroids. The presence of proximal extrahepatic/intrahepatic strictures was predictive of relapse. Steroid therapy normalized liver enzyme levels in 61%; biliary stents could be removed in 17 of 18 patients. Fifteen patients treated with steroids for relapse after steroid withdrawal responded; 7 patients on additional immunomodulatory drugs remain in steroid-free remission (median follow-up period, 6 months). CONCLUSIONS IAC should be suspected in unexplained biliary strictures associated with increased serum IgG4 and unexplained pancreatic disease. Relapses are common after steroid withdrawal, especially with proximal strictures. The role of immunomodulatory drugs for relapses needs further study.
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Affiliation(s)
- Amaar Ghazale
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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Vierling JM. Clinical Use of Immunosuppressive Drugs to Control the Immune Response. LIVER IMMUNOLOGY 2008:391-407. [DOI: 10.1007/978-1-59745-518-3_31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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50
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Uehara T, Hamano H, Kawakami M, Koyama M, Kawa S, Sano K, Honda T, Oki K, Ota H. Autoimmune pancreatitis-associated prostatitis: Distinct clinicopathological entity. Pathol Int 2008; 58:118-25. [DOI: 10.1111/j.1440-1827.2007.02199.x] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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