During the last decade, patients with steroid

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1 REVIEWS Immunoglobulin G4 Associated Cholangitis: Description of an Emerging Clinical Entity Based on Review of the Literature Einar Björnsson, 1 Suresh T. Chari, 2 Thomas C. Smyrk, 2 and Keith Lindor 2 During the last decade, patients with steroid responsive sclerosing cholangitis have been described in a number of case reports and a few cases series. These patients meet diagnostic criteria for primary sclerosing cholangitis (PSC) but seem to have a better prognosis and are often, but not always, associated with autoimmune pancreatitis (AIP). Unlike biliary strictures in PSC, most PSC-like biliary strictures seen in association with AIP respond well to steroids and some have been shown to resolve after immunosuppressive treatment during prolonged follow-up. In addition, steroid-responsive dominant bile duct lesions, sometimes mimicking infiltrating hilar cholangiocarcinoma, without pancreatic abnormalities have also been reported. Here we review the literature on this emerging clinical entity and suggest that this condition of steroid responsive biliary strictures be named Immunoglobulin G4 (IgG4) Associated Cholangitis (IAC). We performed an electronic database search of MEDLINE for case reports and case series of sclerosing cholangitis with pancreatitis and/or pancreatic mass (1960 July 2006). Articles were limited to English and these case reports and cases series were reviewed and all references on the combination of sclerosing cholangitis and pancreatitis as well as IgG4 positive cholangitis without pancreatic involvement not identified by our original search were obtained. Abbreviations: AIP, autoimmune pancreatitis; IAC, immunoglobulin G4 (IgG4) associated cholangitis; IgG4, immunoglobulin G4; PSC, primary sclerosing cholangitis. From the 1 Department of Internal Medicine, Division of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg Sweden; and 2 the Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN. Received November 26, 2006; accepted February 2, Address reprint requests to: Einar Bjornsson, Department of Internal Medicine, Section of Gastroenterology and Hepatology, Med pol II, Sahlgrenska University Hospital, SE Gothenburg, Sweden. einar.bjornsson@medic.gu.se; fax: (31) Copyright 2007 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience ( DOI /hep Potential conflict of interest: Nothing to report Terminology and Definition In 1963, two cases of PSC with pancreatic involvement 1 seen at the Mayo Clinic were reported in the New England Journal of Medicine; these might have been the first two cases of IASC reported. A total of 54 articles with cases of suspected IgG4 associated cholangitis were included in the final analysis From 1963 July 2006 a total of 215 cases of IAC have been reported For obvious reasons it is difficult to be certain that all these cases are really IAC as IgG4 has not been measured in all and corticosteroids have not always been tried. This entity has had many descriptive names in the literature including inflammatory pseudotumor from sclerosing cholangitis, 9 primary sclerosing cholangitis mimicking chronic pancreatitis 13 pancreatic pseudotumor with multifocal idiopathic fibrosclerosis 14 lymphoplasmacytic sclerosing pancreatitis with cholangitis, 19 sclerosing pancreato-cholangitis, 31,33,40,49 atypical primary sclerosing cholangitis associated with unusual pancreatitis, 34 lymphoplasmacytic sclerosing cholangitis without pancreatitis 44 immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis and autoimmune pancreatitis-associated sclerosing cholangitis. AIP is often associated with sclerosing cholangitis and this entity has therefore been called sclerosing pancreato-cholangitis 31,33,40,49,50 Strictures of the biliary tract, in the hilar region or intrahepatic strictures have been well documented. 31,33-36,40,45,48-50,54 Definition of IAC. Strict criteria for IAC are lacking at the present time but one of the aims of this review is to propose radiological, histological, and serological criteria which might be helpful for the diagnosis of IAC. Since steroid responsiveness is its most distinguishing clinical feature, IAC may be defined as a biliary stricture that responds to or improves with steroid therapy. However, it remains to be determined if all IAC-related strictures respond to steroid therapy. It is likely that burnt out IAC may not show steroid responsiveness. It is also possible that in some cases IAC may resolve spontaneously. IAC can be defined as a steroid responsive biliary disease, frequently involving the extrahepatic ducts, that is often associated with other fibrosing conditions, especially autoimmune pancreatitis. It is characterized by elevation 1547

2 1548 BJÖRNSSON ET AL. HEPATOLOGY, June 2007 Table 1. The Age and Gender Distribution in the Largest Published Series Erkelens 1999 Nakazawa 2001 Hirano 2003 Zen 2004 Nakazawa 2004 Takikawa 2004 Nakazawa 2005 Kamisawa 2006 van Buuren 2006 Cases Age (range) 48 (19-62) 63 (59-70) 66 (49-75) 71 (55-79) 62 (-) - 65 (-) 68 (-) 55 (19-80) Male/females 4/0 5/3 6/2 12/5 16/10 18/10 14/6-10/0 of IgG4 in serum and infiltration of IgG4 positive plasma cells in bile ducts. As opposed to PSC, IAC is not usually associated with colitis. The Concept of Autoimmune Pancreatitis Since steroid-responsive biliary strictures are often associated with AIP, we discuss first the concept of AIP as a part of a systemic disease and its relationship to IAC. Autoimmune pancreatitis is a recently recognized entity It is a form of chronic pancreatitis which is characterized by typical features on histology, imaging, and serology and associated frequently with extrapancreatic organ involvement. The manifestations, both pancreatic and extra-pancreatic, respond to steroid therapy. Pancreatic immunostaining is diagnostic of AIP when it shows abundant IgG4 positive cells and it can distinguish AIP from alcoholic pancreatitis and inflammatory infiltrate surrounding pancreatic cancer. 57 The most frequently reported clinical presentation is that of diffuse enlargement of the pancreas or a pancreatic mass that is very similar to pancreatic ductal adenocarcinoma Although dramatic response to corticosteroids has been widely reported, spontaneous resolution of AIP has also been reported. 57 The diagnosis of AIP is based on the current criteria of the Japan Pancreas Society which requires the presence of characteristic imaging findings showing a diffusely enlarged sausage-shaped pancreas and a diffusely irregular, attenuated pancreatic duct. 55 However, recently these criteria have been shown to lack sensitivity and new criteria for AIP based on histology and the response to steroids have been proposed. 57 In a recent series of prospectively collected cases of AIP at the Mayo Clinic from , other organ involvement was observed in 49% of patients. 57 The biliary tract (other than the distal bile duct) was involved in 17% of patients. 57 If only the intrapancreatic portion of the common bile duct is involved, the condition should not be called IAC but rather be considered a part of AIP. We have tried to include in our literature review only cases with more proximal common bile duct involvement in order to classify them as IAC cases. Clinical Features of IAC Prevalence Very limited epidemiological data exist on the prevalence of IAC and there are no data on its prevalence in the general population. Some studies have looked at its prevalence among subjects presenting as PSC. A study from a single center in Toronto Canada revealed that 5/72 (7%) PSC patients diagnosed between 1972 and 2003 had associated pancreatic problems 43 including pancreatic insufficiency, acute pancreatitis and 3 patients presented with a pancreatic mass. All three patients with a pancreatic mass were initially suspected on both clinical and radiological findings to have a pancreatic malignancy but were found to have a pancreatic pseudotumor associated with PSC, fulfilling some of the criteria for IAC. Interestingly, among a multicenter study of PSC patients in Japan, diagnosed between 1975 and 2004, altogether 28 of 388 (7%) patients were found to have PSC associated with AIP. 47 Recently, IgG4 levels were measured in a large cohort of PSC (n 128) from stored sera and elevated levels were found in 9% of PSC patients whereas this was only found in one of 87 (1.1%) PBC patients. 58 It is conceivable that they might represent a subset of PSC patients with IAC who potentially might be steroid responsive. Demographics IAC and PSC are diagnosed more commonly in male patients with two to one predominance over female patients. 43,45,50,54 This is somewhat paradoxical as autoimmune disorders are usually more common in females. The two largest series from Europe with 4 and 10 patients only included male patients. 31,54 Some of the patients in these two series are from one cohort of patients. 31,54 In the series from Japan the proportion of males has ranged from 62 to 70% 44,47,49 (Table 1). Age of presentation is highly variable but generally, IAC patients are older at diagnosis than patients with classic PSC. 59 No cases of IAC have been reported in children and although PSC can be steroid responsive in children this is probably due to a common overlap with AIH in children. 59 The age and gender distribution among patients in the largest published series is shown in Table 1.

3 HEPATOLOGY, Vol. 45, No. 6, 2007 BJÖRNSSON ET AL Clinical Presentation The clinical picture of IAC is very variable as is the case in classic PSC but obstructive jaundice is a common clinical presentation in IAC 4,5,19,20,29,31,34,40,43,45,47-50,54 which is rarely observed at diagnosis in PSC. 59 In a direct comparison of the clinical differences between classic PSC and patients with IAC the clinical presentation among IAC patients occurred more abruptly with obstructive jaundice in 15 of 20 patients (75%) whereas obstructive jaundice was only present in 1 of 27 (4%) patients with classic PSC. 49 The clinical diagnosis of patients presenting with hepatic hilar strictures without pancreatic involvement 7,44,45,49,50 has for obvious reasons been cholangiocarcinoma. 45 Among PSC patients presenting with a pancreatic mass, the clinical diagnosis has instead been pancreatic malignancy 43,45,54 and in a number of cases pancreatoduodenectomy has been performed in these patients. 9,19,23,24,27,35,45,46,48,49 Laboratory Data Levels of alkaline phosphatase 47 and serum bilirubin levels 49 were significantly higher in patients with IAC in comparison with classic PSC. Immunoserology Patients with IAC generally have increased gammaglobulin levels 19,37,40,49 indicating the presence of autoimmunity. However, no significant difference was found between IASC and PSC patients in gammaglobulin levels in general whereas IgG4 levels were significantly higher among the IAC patients. 49 Hamano et al. found normal levels of IgG4 in classic PSC patients whereas elevated IgG4 levels were found in patients with AIP. 56 It has been shown that some patients with IAC did not have increased levels of IgG4 initially but developed subsequently high levels during follow-up. 40 Thus, it seems that IAC patients do not necessarily present with definite biochemical and immunological abnormalities at the time of diagnosis. 40 Recently, the IgG4-positive plasma cell/mononuclear cell ratio was found to be significantly higher in IAC in comparison with classic PSC patients and this ratio was suggested to be a useful index to help distinguish IAC from PSC. 52 High serum IgG4 is only found in a very limited number of other conditions, such as pemphigus vulgaris and atopic dermatitis. 45,60 Among patients presenting with a hepatobiliary disease, high serum IgG4 levels have been reported to be highly specific for AIP. 56 However, at the present time the sensitivity and specificity of IgG4 levels for the diagnosis of IAC are not known. Tumor Markers Because an important differential diagnosis of IAC is cholangiocarcinoma, serum tumor markers are often measured in this context in order to help distinguish PSC, AIP, or IAC from cholangiocarcinoma. Interestingly, high levels of the tumor marker Ca 19-9 are common in patients with IAC. 19,28,29,40,51,54 Elevated levels of Ca 19-9 were found in 5 of 8 (63%) patients in one study and one patient had a value of 11470! (normal value 37 U/L). 40 However, CEA levels were normal or only slightly elevated in most patients. 40 Thus, Ca 19-9 levels do not seem to help to distinguish between IAC and cholangiocarcinoma and Ca 19-9 has generally been found to be unreliable for the diagnosis of CCA in PSC. 61 Cholangiography and Imaging Features Characteristic of the cholangiographic features in patients with IAC is stenosis of the lower common bile duct. Sclerosing changes in the intrahepatic and extrahepatic bile ducts were found in half of the IAC patients in one study. 49 Among patients with AIP, marked bile duct strictures were detected in 14 of 16 (88%) and the stricture were in the lower portion of the bile ducts in 9 patients, the middle portion in 2, and the lower middle, and intrahepatic portion in 2 patients. 48 In a follow-up study of 8 patients with AIP, extrapancreatic bile duct changes were observed such as stricture of the bile duct at the hepatic hilus or within the intrahepatic area in 6 patients. 40 Thus, imaging findings of the biliary tract can show abnormalities in all parts of the biliary tract in IAC. Although pancreatic involvement such as diffuse pancreatic enlargement or pancreatic mass is very common in patients with IAC, many cases have also been described with isolated biliary tract involvement without pancreatic disease. 44,45,50 These strictures may mimic those due to cholangiocarcinoma. Recently, Nakazawa et al. compared cholangiographic changes in 26 cases of IAC with a group of patients with classic PSC. 44 Segmental strictures, long strictures with prestenotic dilatation and strictures of the distal common bile duct were significantly more common in IAC patients whereas band-like strictures, beaded or pruned-tree appearance were significantly more common in classic PSC. 44 The spectrum of IAC is shown in Fig. 1 (from Zen et al ). Cholangiographic abnormalities in a patient with IAC are shown in Fig. 2. Histopathology As in the pancreas, biliary involvement by IgG4-related autoimmune disease can be diffuse or localized, producing either a generalized but irregular thickening or a tumefactive lesion. 45 The histological appearance is simi-

4 1550 BJÖRNSSON ET AL. HEPATOLOGY, June 2007 Fig. 1. A spectrum of IgG4 associated sclerosing cholangitis. In the paper by Zen et al. (2004 copyright by American Journal of Surgical Pathology, volume 28, pages , Zen Y, Harada K, Sasaki M, Sato Y, Tsuneyama K, Haratake J, et al, IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Reprinted with permission from Lippincott Williams & Wilkins). called sclerosing cholangitis. IgG4 related sclerosing lesions occur along the biliary tract and pancreatic duct, presenting with mass-forming or duct-stenosis. Black nodules and thick black wiggly lines are the site of the IgG4-related lesions. SP, sclerosing pancreatitis, SC, sclerosing cholangitis. Fig. 3. Dense periluminal infiltration by lymphocytes and plasma cells. The bile duct epithelium is intact. lar in both situations: lymphoplasmacytic inflammation, fibrosis (often with a swirling or storiform arrangement) and obliterative phlebitis. 40,45,49,52,54 Despite the dense periluminal inflammation, the biliary epithelium is usually intact (Fig. 3). This is in distinct contrast to PSC, which often produces mucosal erosion. In another contrast with PSC, the inflammatory process is often more dense at the periphery of the duct 45,49,53 (Fig. 4). This phenomenon is partly due to dense inflammation in the walls of periductal vein branches (Fig. 5), but lymphoplasmacytic inflammation around nerve twigs and forming nodular infiltrates in periductal soft tissue are also characteristic features of IAC. While lymphocytes and plasma cells predominate, eosinophils can be numerous 45,52 and are occasionally numerically dominant. Neutrophils, commonly seen in PSC, are not a feature of IAC. Fig. 2. Common hepatic duct and intra-hepatic biliary strictures of IgG4 associated sclerosing cholangitis: Patient had a diffusely irregular, narrow pancreatic duct characteristic of AIP. Serum IgG4 was elevated at 720 mg/dl (normal value mg/dl). Fig. 4. Cross-section of common bile duct in IAC. The wall is thickened and fibrotic. The inflammation is particularly dense at the periphery of the duct, and extends into periductal soft tissue.

5 HEPATOLOGY, Vol. 45, No. 6, 2007 BJÖRNSSON ET AL obstruction by IAC. Bile duct lesions (periductal fibrosis) and ductopenia have not been described in IAC, and their presence favors PSC. Portal infiltration by IgG4-positive plasma cells has been described in IAC, 53 but our experience suggests that it is less common than in the pancreas or extrahepatic bile ducts. Fig. 5. Periductal artery (upper right): the obliterated vein is in lower left, replaced by lymphoplasmacytic inflammation. Obliterative phlebitis is a nearly ubiquitous finding in both AIP and IAC. As the term implies, a dense infiltrate of lymphocytes and plasma cells surrounds and compresses the vein lumen, occasionally obliterating it entirely. The corresponding artery is not affected. Inflammation in vein walls is not specific to IgG4-related disease, but it is helpful in distinguishing IAC from PSC or cholangiocarcinoma, as it is not seen in those conditions. Immunohistochemical staining for IgG4 is a useful tool for confirming the diagnosis of IAC. (Fig. 6). 53 Scoring criteria have not been established for the biliary tract, but reported experience indicates that extrahepatic ducts affected by IAC usually have more than 30 IgG4-positive plasma cells per high-power microscopic field, corresponding to a score of 3 in the 0-3 system in use for the pancreas. 62 Is it possible to diagnose IAC in an endoscopically obtained bile duct biopsy? The fact that the most helpful features tend to be deep in the bile duct wall works against this idea, but a combination of lymphoplasmacytic inflammation and increased staining for IgG4 in a bile duct biopsy has been used to diagnose IAC. 52 The sensitivity and specifity of IgG4 immunostaining in bile duct biopsies have not been established. Hepatic pathology in IAC is variable. Tumefactive nodules have been described, 45 and it is likely that at least some inflammatory pseudotumors of the liver are manifestations of intrahepatic IAC. In the absence of a mass, liver biopsies from patients with IAC may not show specific changes. Mild to moderate lymphocytic portal inflammation, often accompanied by portal fibrosis and ductular proliferation, has been reported, 4,19,20,33,40,49 but these changes could be secondary to extrahepatic biliary Lack of Association with IBD and Cholangiocarcinoma In contrast to classic PSC, which in vast majority of cases is associated with IBD, 59 patients with IAC in almost all reported cases lack this association. Thus, based on the existing literature, the presence of IBD argues against the diagnosis of IAC. Cholangiocarcinoma is a complication of classic PSC that develops in up to 10%- 30% of patients. 59,61,63 However, development of CCA has not been reported to occur in patients with IAC. Although, follow-up has been rather short in many reported cases, a recent study of 388 cases with PSC in Japan found that none of the 28 IAC cases developed bile duct cancer. 47 Thus, the lack of association of IAC with IBD and potentially CCA, which are the most common associated conditions in classic PSC, suggests that these disorders have different underlying pathophysiologies. Diagnosis Many patients who have turned out to have IAC have only been diagnosed after a major surgical resection with pancreatoduodenectomy. 9,19,23,24,27,28,35,45,46,49 The accumulating literature of case reports and case series will hopefully minimize the need for major abdominal surgery in order to diagnose this condition. Obstructive jaundice is an uncommon presentation in classic PSC and this presentation should raise suspicion of IAC. However, Fig. 6. IgG4 stain showing many positive cells around duct.

6 1552 BJÖRNSSON ET AL. HEPATOLOGY, June 2007 PSC patients may present with cholangiocarcinoma which is therefore a very important differential diagnosis in this context. IAC should be clinically suspected when biliary strictures are associated with pancreatic duct irregularity or other pancreatic disease or other organ involvement (e.g., retroperitoneal fibrosis or salivary gland enlargement) and serum IgG4 levels are elevated. Diagnosis is confirmed if biliary or other organ histology shows marked infiltration with IgG4 positive cells ( 10 cells/ hpf) or the stricture responds/resolves with steroid treatment. Treatment Accumulating evidence suggests that the bile duct lesions and the concomitant pancreatitis in patients with IAC improve with corticosteroid treatment which distinguishes IAC from PSC. 5,14,20,22,30-38,42,48,50-52,54 Resolution of jaundice and improvement in liver tests associated with steroid treatment has been reported as well as resolution or improvement in biliary strictures seen on cholangiograms. 5,14,22,30-37,42,48,50-52,54 Most of the early literature of steroid responsiveness in patients with IAC consists of single case reports. 5,14,20-22,30 Erkelens et al. reported 4 cases with weight loss, jaundice, pancreatic enlargement, and multiple bile duct strictures, but without IBD, that were treated with cortiocosteroids. 31 In all cases a complete clinical remission was observed with normalization of liver tests and resolution of intrahepatic and extrahepatic strictures. 31 In some case series, the diagnosis of IAC has only become apparent after a surgical procedure and corticosteroids have not always been tried early on and evaluation of the efficacy of steroid therapy has not been available for all cases in some series. In 4 of 8 patients in whom corticosteroids were tried, steroids were effective in terms of clinical improvement and resolution of imaging abnormalities of the bile ducts and pancreas. 34 In another study of 7 IAC patients, liver tests improved after steroid therapy and improvement in pancreatic swelling, bile duct strictures and retroperitoneal fibrosis was noted. 40 In a retrospective study from Japan, obstructive jaundice resolved after steroids in all 5 patients with jaundice and the bile duct strictures improved to various degree in all 7 patients after steroid therapy. 48 The bile ducts improved to normal diameter in 60% of patients whereas the recovery was only slight to moderate in 40%. 48 However, pancreatic enlargement and irregular narrowing of the pancreatic duct had improved to almost normal size in all patients treated. 48 Apart from cases series of IAC patients in whom therapy results have been published in English, 31,34,40,48,49,54 Kojima et al. reviewed cases reported in the Japanese literature with steroid response in 13 of 14 patients. 42 Corticosteroids and other immunosuppressive agents have generally not been effective in classic PSC. 64 However, some patients with PSC had clinical and/or biochemical improvement while on corticosteroid therapy. 64 It is conceivable that in a subgroup of PSC patients, the disease process might be steroid responsive due to an important autoimmune etiology. The recent finding of elevated IgG4 levels in 9% of unselected PSC patients might identify such a subset of patients. 58 However, only prospectively evaluated trials will provide information about whether IgG4 might represent a marker for steroid sensitivity in these patients. Based on the literature it is difficult to give recommendations on the dose and duration of corticosteroid therapy. However, most researchers have used steroids for 2-3 months with a starting dose of 40 mg of prednisolone for 4 weeks with tapering by 5 mg per week thereafter. Prognosis Although most case series do not report long-term follow-up of patients with IAC it seems that the prognosis of these patients is more favorable than that of patients with classic PSC. Resolution of biliary strictures associated with corticosteroid therapy as experienced in patients with IAC is rare in classic PSC. Comparison between patients with classic PSC and IAC in Japan revealed that no patient with IAC underwent liver transplantation during a prolonged follow-up whereas liver transplantation was performed in substantial number of patients with classic PSC. 47 However, very limited data exists on the prognosis and the natural history of IAC and more longterm follow-up studies are needed to provide information on the prognosis. Only one case with liver failure necessitating liver transplantation has been reported in IAC. 23 Furthermore, cholangiocarcinoma in patients with IAC was not observed in the largest case series reported 47 whereas cholangiocarcinoma develops in up to 10%-30% of patients with classic PSC. 59,61,63 Conclusions We have reviewed the newly emerging clinical entity we choose to name IgG4 associated cholangitis. There seems to be important clinical, biochemical and histological differences between IAC and classic PSC. Patients with IAC more often have a rather abrupt clinical presentation with obstructive jaundice in comparison with patients with classic PSC. In the majority of cases pancreatic involvement is present and the diagnosis is supported by high levels of IgG4 in serum and lymphoplasmacytic infiltration on histology of the affected bile ducts, pancreas and other affected organs. A corticosteroid trial should be

7 HEPATOLOGY, Vol. 45, No. 6, 2007 BJÖRNSSON ET AL considered in cases with clinical, biochemical and imaging features of IAC. However, a steroid trial should only be given to patients with negative work-up for known etiologies for other pancreatic or biliary disease such as pancreatic and biliary carcinoma. Steroids should only be used in patients in whom response can be assessed with biliary and pancreatic abnormalities on imaging and liver biochemistries. Measurement of IgG4 should be performed in all newly diagnosed patients with PSC and steroids should be tried in those with elevated levels and clinical, biochemical and cholangiographic assessments should be performed in clinical studies. More studies on this very interesting newly recognized clinical entity are clearly warranted. References 1. Bartholomew LG, Cain JC, Woolner LB, Utz DC, Ferris DO. Sclerosing cholangitis: its possible association with Riedel s struma and fibrous retroperitonitis. Report of two cases. 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