552 Kamisawa T, et al. , 2011; 10 (4): 552-555EDITORIAL October-December, Vol. 10 No.4, 2011: 552-555 IgG4-related sclerosing cholangitis Terumi Kamisawa,* Taku Tabata* * Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan. Autoimmune pancreatitis (AIP) is a unique form of cally, and histopathologically. Average age of clini- inflammatory disorders that affect this organ.1,2 cal onset for IgG4-related sclerosing cholangitis is Histopathology reveals dense infiltration of T lym- approximately two decades older than for PSC, which phocytes and IgG4-positive plasma cells with fibrosis occurs during in 30 to-40-year-olds.7,8,12 Obstructive and obliterative phlebitis, termed lymphoplasmacytic jaundice is the most frequent chief complaint, seen sclerosing pancreatitis (LPSP).1-3 Various extrapan- in 75-77%13,14 of patients with IgG4-related sclero- creatic lesions associated with AIP have similar his- sing cholangitis, whereas many PSC patients are tological features.4,5 Therefore, AIP is currently asymptomatic, presenting after liver injury is identi- considered a pancreatic manifestation of an IgG4-re- fied on routine physical examination. Inflammatory lated systemic disease. In some cases, there is clinical bowel disease is sometimes comorbid with (41- involvement of only 1 or 2 organs, while in others 3 or 63%),13,14 while various sclerosing lesions (such as 4 are affected.2,5,6 However, precise pathogenetic me- sclerosing cholecystitis, sclerosing sialadenitis, and chanisms, including the role of IgG4, remain unclear. retroperitoneal fibrosis) are sometimes seen in pa- Stenosis of the bile duct is frequently observed in tients with IgG4-related sclerosing cholangitis. AIP patients; histologically, IgG4-related sclerosing Serum IgG4 levels are frequently and significantly cholangitis, a bile duct lesion of the systemic disea- elevated in patients with IgG4-related sclerosing se, is revealed.2,6 Stenosis is seen most frequently cholangitis7,8,13,14 (Table 1). Mendes, et al.15 repor- (70-79%)7,8 in the lower bile duct of AIP patients, ted elevated serum IgG4 levels in 9% (12 of 127) of but this may be due in part to compression caused PSC patients, who experienced a more severe disease by pancreatic edema, in addition to biliary wall thick- course, including shorter time to liver transplanta- ening.9 When stenosis develops in the hilar or intra- tion. However, some may have had IgG4-related hepatic bile duct, the cholangiographic appearance sclerosing cholangitis without pancreatic involve- is similar to that of primary sclerosing cholangitis ment. According to Nakazawa’s classification16 (PSC).7,8 PSC is a progressive disease that eventua- of cholangiograms in IgG4-related sclerosing cho- lly involves intra- and extra-hepatic bile ducts, and langitis, type 1 stenosis, located exclusively in the which sometimes leads to liver cirrhosis.10,11 The va- lower part of the common bile duct, can often lead to lue of steroid therapy is questionable, and liver a misdiagnosis of pancreatic cancer; type 2 stenosis, transplantation is the only effective curative treat- diffusely distributed throughout the intra- and ex- ment. Since IgG4-related sclerosing cholangitis res- trahepatic bile ducts, is similar to that seen in PSC; ponds well to steroid therapy, it is necessary to while it is type 3 stenosis, of the hilar hepatic region differentiate this from PSC in order to provide the and the lower part of the common bile duct, and most appropriate treatment regimen. type 4 stenosis, detected only in the hilar hepatic IgG4-related sclerosing cholangitis and PSC can region, that should be differentiated from cholangio- be discriminated clinically, serologically, radiologi- carcinoma. As revealed by cholangiogram, IgG4-rela- ted sclerosing cholangitis involves lower bile duct stenosis and a relatively long stricture extending Correspondence and reprint request: Terumi Kamisawa, M.D., Ph.D. from the hilar to intrahepatic biliary system with Department of Internal Medicine. Tokyo Metropolitan Komagome Hospital simple distal dilatation, whereas PSC produces 3-18-22 Honkomagome characteristic findings, including band-like stricture, Bunkyo-ku, Tokyo 113-8677, Japan beaded appearance, pruned tree appearance, and Tel.: +81-3-3823-2101. Fax: +81-3-3824-1552 16 E-mail: [email protected] diverticulum-like outpouching (Figure 1). In IgG4- Manuscript received: June 20, 2011. related sclerosing cholangitis, intraductal or endos- Manuscript accepted: June 20, 2011. copic ultrasonography can detect wall thickening of 553 IgG4-related sclerosing cholangitis.. , 2011; 10 (4): 552-555 Table 1. Differences between IgG4-related sclerosing cholangitis and primary sclerosing cholangitis (PSC). IgG4-related sclerosing cholangitis PSC • Age Elderly Young • Initial symptom Obstructive jaundice Liver dysfunction • Associated diseases º Inflammatory bowel disease Rare Sometimes º Sclerosing diseases Frequent Rare • Elevation of serum IgG4 Frequent Rare • Infiltration of IgG4-positive cells Many Scarce • Steroid responsiveness Good Poor • Prognosis Good Progressive PSC Sclerosing cholangitis with AIP 5 3 1 4 2 6 9 Figure 1. Schematic illus- 1. Band-like stricture. 2. Segmental stricture tration of cholangiographic di- 4. Beaded appearance. 3. Dilation after confluent stricture fferences between primary 5. Pruned-tree appearance 9. Stricture of lower CBD sclerosing cholangitis and 6. Diverticulum-like outpouching IgG4-related sclerosing cholan- gitis.16 intra- or extrahepatic bile ducts in areas without lated sclerosing cholangitis.19,20 Since, unlike PSC, stenosis on cholangiogram.8,17 On pancreatography, IgG4-related sclerosing cholangitis responds drama- patients with IgG4-related sclerosing cholangitis fre- tically to steroid therapy, rapid steroid responsive- quent show irregular narrowing of the main pan- ness reassures by confirming the diagnosis. If a creatic duct which is characteristic finding of AIP, diagnosis cannot be obtained using the procedures but pancreatograms of PSC patients are usually nor- described above, a steroid trial may be useful. Howe- mal. As the histological findings of IgG4-related scle- ver, to avoid delaying necessary surgery, a short- rosing cholangitis include transmural fibrosis and term (usually 2 weeks)21 trial should be performed dense lymphoplasmacytic infiltration of the bile duct carefully, and only by clinicians specializing in pan- wall as well as periportal areas of the liver, positive creatic and biliary disease. Routine steroid trials abundant IgG4 immunostaining of bile duct or liver conducted by general practitioners should be stron- biopsy specimens supports this diagnosis.18 Howe- gly discouraged. ver, the positive rate was not high due to the small In this issue, Clendenon, et al.22 report a 54-year- specimens.17 Positive IgG4 immunostaining of biop- old female who twice underwent orthotopic liver sy specimens taken from the major duodenal papilla transplant for recurrent sclerosing cholangitis after is useful to support the diagnosis of AIP or IgG4-re- pancreaticoduodenectomy performed for AIP on sus- 554 Kamisawa T, et al. , 2011; 10 (4): 552-555 picion of pancreatic cancer. Because the correct 6. Kamisawa T, Okamoto A. Autoimmune pancreatitis: propo- diagnosis was not made for 11 years, she did not sal of IgG4-related sclerosing disease. J Gastroenterol 2006; 41: 613-25. have steroid therapy until receiving the second liver 7. Nakazawa T, Ando T, Hayashi K, Naitoh I, Ohara H, Joh T. transplant. Surprisingly, her explanted liver allo- Diagnostic procedure for IgG4-related sclerosing cholan- graft revealed many IgG4 positive plasma cells simi- gitis. J Hepatobiliary Pancreat Sci 2011; 18: 127-36. lar to those seen in her native liver. We suggest that 8. Kamisawa T, Takuma K, Anjiki H, Egawa N, Kurata M, Honda G, et al. Sclerosing cholangitis associated with this case demonstrates the natural course of IgG4- autoimmune pancreatitis differs from primary sclero- related sclerosing cholangitis. Although the progno- sing cholangitis. World J Gastroenterol 2009; 15: sis of this disease is generally good due to good 2357-60. steroid responsiveness, its natural behavior may be 9. Hirano K, Tada M, Isayama H, Yamamoto K, Mizuno S, Ya- gioka H, et al. Endoscopic evaluation of factors contribu- aggressive, leading to progressive end-stage liver ting to intrapancreatic biliary stricture in autoimmune cirrhosis, if appropriate therapy is not administered. pancreatitis. Gastrointest Endosc 2010; 71: 85-90. In contrast, Koyabu, et al.,23 recently reported a 10. LaRusso NF, Wiesner RH, Ludwig J, MacCarty RL. Current series of PSC cases having elevated serum IgG4 le- consepts. Primary sclerosing cholangitis. N Engl J Med 1984; 310: 899-903. vels and infiltration of abundant IgG4-positive plas- 11. Wiesner RH, Grambsch PM, Dickson ER, Ludwig J, MacCar- ma cells in the hepatic portal area who did not ty RL, Hunter EB, et al. Primary sclerosing scholangitis: respond to steroid therapy. natural history, prognostic factors and survgival analysis. Recently, IgG4-associated autoimmune hepatitis Hepatology 1989; 10: 430-6. 12. Takikawa H, Takamori Y, Tanaka A, Kurihara H, Nakanuma 24 (AIH) has been reported. Umemura, et al. propo- Y. Analysis of 388 cases of primary sclerosing cholangitis sed provisional diagnostic criteria for this entity, as in Japan. Presence of a group without pancreatic involve- follows: ment in older patients. Hepatol Res 2004; 29: 153-9. 13. Nakazawa