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Immunoglobulin G4 Levels

Educational Objective
Based on this clinical scenario and the accompanying image, understand how to arrive at a correct diagnosis.
1 Credit CME

A 67-year-old man with type 2 diabetes mellitus and hyperlipidemia was evaluated for unintentional weight loss of 28 lb (12.7 kg) and increasing fasting blood glucose values over the past 6 months. A computed tomography scan showed diffuse enlargement of the pancreas with peripheral hypoenhancement but no discrete mass. Soft tissue surrounded the infrarenal abdominal aorta, extended along the common iliac arteries, and obstructed the left ureter, causing hydronephrosis. He was referred for evaluation of possible malignancy. Laboratory studies including immunoglobulin G subgroup 4 (IgG4) levels are shown in the Table. Fine-needle aspiration of the pancreas showed no malignancy. Colonoscopy results 8 months ago were normal.

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A. Test results indicate presence of IgG4-related disease.

IgG4-related disease is a relapsing, immune-mediated, multiorgan, fibroinflammatory disease (characterized by intense inflammation and fibrosis) that presents similarly to a nonspecific malignant, infectious, and inflammatory condition. IgG4 is a subclass of IgG that accounts for less than 5% of the total IgG in healthy adults.1,2 The sensitivity of any elevation of IgG4 for diagnosing IgG4-related disease is approximately 70% and the specificity is 85%. Some criteria for diagnosing IgG4-related disease use a 2-fold elevation of IgG4 levels as the threshold for a positive test, in which case the sensitivity is approximately 60% and the specificity is 90%.1,3,4 Because the prevalence of IgG4-related disease is low (4.6 cases per 100 000),5 the positive predictive value of IgG4 elevation is only 36%.3 IgG4 may be elevated in conditions other than IgG4-related disease. For example, IgG4-related disease is elevated in 7% to 10% of patients with pancreatic cancer, cholangiocarcinoma, primary sclerosing cholangitis, acute pancreatitis, and healthy individuals.3 The precise role of IgG4 in the pathogenesis of IgG4-related disease remains unknown. Elevated IgG4 levels in IgG4-related disease may result from type 2 helper cell activation, in response to prolonged exposure to an unknown antigen.2,6 The 2018 Medicare reimbursement for the IgG4 assay is $9.90.

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Article Information

Corresponding Author: Suresh T. Chari, MD, College of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (chari.suresh@mayo.edu).

Published Online: December 20, 2018. doi:10.1001/jama.2018.16665

Conflict of Interest Disclosures: The authors report no disclosures.

Additional Contribution: We thank the patient for sharing his experience and for granting permission to publish it.

References
1.
Kamisawa  T, Zen  Y, Pillai  S, Stone  JH.  IgG4-related disease.  Lancet. 2015;385(9976):1460-1471. doi:10.1016/S0140-6736(14)60720-0PubMedGoogle ScholarCrossref
2.
Stone  JH, Zen  Y, Deshpande  V.  IgG4-related disease.  N Engl J Med. 2012;366(6):539-551. doi:10.1056/NEJMra1104650PubMedGoogle ScholarCrossref
3.
Ghazale  A, Chari  ST, Smyrk  TC,  et al.  Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer.  Am J Gastroenterol. 2007;102(8):1646-1653. doi:10.1111/j.1572-0241.2007.01264.xPubMedGoogle ScholarCrossref
4.
Stone  JH, Brito-Zerón  P, Bosch  X, Ramos-Casals  M.  Diagnostic Approach to the Complexity of IgG4-Related Disease.  Mayo Clin Proc. 2015;90(7):927-939. doi:10.1016/j.mayocp.2015.03.020PubMedGoogle ScholarCrossref
5.
Kanno  A, Masamune  A, Okazaki  K,  et al; Research Committee of Intractable Diseases of the Pancreas.  Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2011.  Pancreas. 2015;44(4):535-539. doi:10.1097/MPA.0000000000000325PubMedGoogle ScholarCrossref
6.
de Boer  BA, Kruize  YC, Rotmans  PJ, Yazdanbakhsh  M.  Interleukin-12 suppresses immunoglobulin E production but enhances immunoglobulin G4 production by human peripheral blood mononuclear cells.  Infect Immun. 1997;65(3):1122-1125.PubMedGoogle Scholar
7.
Chari  ST, Takahashi  N, Levy  MJ,  et al.  A diagnostic strategy to distinguish autoimmune pancreatitis from pancreatic cancer.  Clin Gastroenterol Hepatol. 2009;7(10):1097-1103. doi:10.1016/j.cgh.2009.04.020PubMedGoogle ScholarCrossref
8.
Umehara  H, Okazaki  K, Masaki  Y,  et al.  Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.  Mod Rheumatol. 2012;22(1):21-30. doi:10.3109/s10165-011-0571-zPubMedGoogle ScholarCrossref
9.
Kamisawa  T, Shimosegawa  T, Okazaki  K,  et al.  Standard steroid treatment for autoimmune pancreatitis.  Gut. 2009;58(11):1504-1507. doi:10.1136/gut.2008.172908PubMedGoogle ScholarCrossref
10.
Gardner  TB, Levy  MJ, Takahashi  N, Smyrk  TC, Chari  ST.  Misdiagnosis of autoimmune pancreatitis: a caution to clinicians.  Am J Gastroenterol. 2009;104(7):1620-1623. doi:10.1038/ajg.2008.89PubMedGoogle ScholarCrossref
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