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Ulcerative colitis associated with IgG4 cholangitis: Similar features in two HLA identical siblings
Journal of Hepatology 51 (2009) 601–605 www.elsevier.com/locate/jhep
Case report
Ulcerative colitis associated with IgG4 cholangitis: Similar features in two HLA identical siblingsq Sergio Negrin Dastis1, Dominique Latinne2, Christine Sempoux3, Andre´ P. Geubel1,* 1
Department of Gastroenterology and Hepatology, St. Luc University Hospital, Universite´ Catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium 2 Department of Immunology, St. Luc University Hospital, Universite´ Catholique de Louvain, Brussels, Belgium 3 Department of Pathology, St. Luc University Hospital, Universite´ Catholique de Louvain, Brussels, Belgium
Background: IgG4-associated cholangitis (IAC) can mimic primary sclerosing cholangitis although, in contrast to the latter, it is highly responsive to steroid therapy. IAC is known to be associated with autoimmune pancreatitis and has also been shown to be part of a more complex autoimmune IgG4 syndrome. However, an association with inflammatory bowel disease (IBD), a condition in which its identification may have therapeutic and prognostic importance, has not yet been described. Case reports: We report the cases of two HLA identical siblings both DRB*1501 positive exhibiting features of IAC together with ulcerative colitis. Subsequent high resolution HLA typing performed by sequence-based-typing showed similar alleles in both siblings: A*0301 A*3201 B*07 (0702/ 62) B*1401 C*0702 C*0802 DRB1*1501. There is indirect evidence that this hitherto undescribed association, likely to be strongly linked to a genetic background, might account for a proportion of the cases of cholangitis associated with IBD. Conclusion: Appropriate investigation for IBD-associated cholangitis is mandatory to identify IAC, the recognition of which has particular therapeutic and prognostic implications. Ó 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Autoimmune cholangitis; Ulcerative colitis; IgG4; HLA-identical siblings
1. Introduction IAC is known to be often associated with autoimmune pancreatitis (AP), although it can occasionally be a single facet of a more complex autoimmune systemic IgG4 syndrome [1,2]. It is likely that this autoimmune entity has been under-recognized due to few distinguishable features from the more common picture
Received 17 March 2009; received in revised form 26 May 2009; accepted 30 May 2009 Associate Editor: V. Barnaba q The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. * Corresponding author. Fax: +32 27648927. E-mail address: [email protected] (A.P. Geubel).
of primary sclerosing cholangitis (PSC). On one hand, there are reports of patients having both PSC and AP, a context in which the disease has been shown to be responsive to corticotherapy, an uncommon observation in PSC. On the other hand, increased IgG4 serum levels have been found in 9% of unselected patients with PSC [3], the significance of which remains uncertain because of the retrospective documentation of the association. Whether this biochemical feature may be used to identify a subtype of cholangitis related to different pathophysiological mechanisms remains to be determined. It is now recognized that IAC is a manifestation of a wider autoimmune syndrome with increased IgG4 commonly known as IgG4 related systemic disease (ISD) and typically responsive to steroids. Pancreatitis is the most frequent manifestation, but other associations have been described, involving other organs such as
0168-8278/$36.00 Ó 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2009.05.032
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S.N. Dastis et al. / Journal of Hepatology 51 (2009) 601–605
salivary glands, retroperitoneum, kidneys and lymph nodes [4–6]. An algorithm for the diagnosis and management of this syndrome has been constructed in the light of occasional lack of elevated IgG4 [1]. It is widely accepted that approximately 5% of UC patients exhibit associated PSC, a proportion which varies from one study to another [7–9]. By contrast, the majority of patients with PSC have underlying IBD (from 23% to 72%) [10,11]. The wide variation in prevalence is probably related to the absence of universal endoscopic examination and also, to variable geographical distribution. The association has important therapeutic and prognostic implications especially in the context of liver transplantation, The mechanisms involved in the pathogenesis of this common association often characterized by serological ANCA positivity, found in up to 80% of cases [12] remains largely unknown. So far, and to the best of our knowledge, no association has been reported between IAC and definite HLA haplotypes or between IgG4-related cholangitis and UC. In this paper we report two cases of HLA-identical siblings both with UC and IgG4-related cholangitis highly responsive to low-dose steroids. This leads us to postulate that in the spectrum of immune cholangiopathy associated with inflammatory bowel diseases, the identification of such an entity has important implications for therapy and prognosis.
2. Case reports 2.1. Case 1 A 17-year-old male was seen by a gastroenterologist of another center in May 2007 because of diarrhea. A biochemical work-up performed at the end of a short course of ciprofloxacin (500 mg per day for 7 days) showed biochemical cholestasis. Serology was negative for hepatitis viruses, cytomegalovirus (CMV) and Epstein–Barr virus (EBV), but high levels of anti-actine and antinuclear antibodies were reported and a liver biopsy was performed. Histological examination showed features suggestive of mild chronic hepatitis with bile duct injury. At colonoscopy, the picture was that of a diffuse form of ulcerative colitis, a diagnosis confirmed by the histological examination of mucosal biopsies. Magnetic resonance imaging (MRI) of the liver and biliary tree showed diffuse irregularities of the intrahepatic biliary tract. Corticotherapy (methylprednisolone, 32 mg per day at decreasing doses during four months) combined with azathioprine was initiated, azathioprine being rapidly withdrawn due to the occurrence of an episode of acute pancreatitis. This was followed by a rapid improvement of both clinical symptoms and biological tests such as liver function tests and hyper-gam-
maglobulinemia. At the time of initial work-up no serum IgG4 levels had been obtained. Therapy with steroids (tapered doses) was given until November 2007 when methylprednisolone was shifted to budesonide. The patient was then referred to our center for a second opinion. Upon arrival, he was asymptomatic and was kept on budesonide 6 mg per day. The liver biopsy obtained previously was reviewed by one of the authors (CS) who emphasized the presence of features of interlobular cholangitis superimposed on those suggestive of mild chronic hepatitis with a dense lymphocytic infiltrate of the portal triads (Fig. 1A). Immunostaining of liver biopsy for IgG4 plasmocytic cells was positive in a few cells. Serum IgG4 levels were normal with no hypergammaglobulinemia, probably due to the high doses of corticosteroids given during the previous four months. HLA testing showed a class II DRB1*15. Repeat MRI performed six months after the first examination showed a complete disappearance of biliary tract abnormalities. Moreover, there was a spectacular improvement in the liver function tests, which had almost returned to normal by July 2008. 2.2. Case 2 The sister of the patient was also referred to our center on March 2007 due to liver function test abnormalities and diarrhea. In October 2006, she had been treated for urinary tract infection manifested by urinary symptoms and fever. She was first prescribed amoxycillin-clavulanate (500 mg, 3 times per day). However, because of the persistence of fever she was hospitalized and treated by ciprofloxacin and amikacin. Biochemical work-up performed at the time of hospitalization showed increased ALT at 225 IU/l, and biochemical cholestasis (alkaline phosphatase: 848 UI/l, N < 94; gamma-GT: 880 IU/l, N < 40). Total serum bilirubin level was 2.9 mg/dl. Hepatitis, EBV and CMV serology was negative. There was a hypergammaglobulinemia with increased total IgG levels (2800 mg/dl, N < 1600) and an elevated IgG4 level at 323 mg/dl (N < 186). Antinuclear antibodies were positive (1/1280, N < 1/40) as were the ANCA (1/2560, N < 1/40) and anti-smooth muscle antibodies (1/320, positive for actine specificity). Tests for anti-mitochondrial antibodies and LKM1 were negative. Abdominal tomodensitometry was normal. An MRI of the liver was performed which was interpreted as showing irregularities of the common bile duct. A liver biopsy was then performed which showed a preserved architecture with enlarged portal tracts infiltrated by lymphocytes, polynuclear neutrophils, eosinophils and plasmocytes. Inflammation was often located around interlobular ducts with pictures of bile duct destruction and concentric periductular fibrosis (Fig. 1B and C). There was cholangiolar proliferation but no interface hepatitis.
S.N. Dastis et al. / Journal of Hepatology 51 (2009) 601–605
603
Fig. 1. (A) Part of an enlarged portal tract showing a dense lymphocytic infiltration and an interlobular bile duct also infiltrated with inflammatory cells (hematoxylin-eosin, 40 original magnification). (B) Picture of an enlarged portal tract infiltrated with inflammatory cells (lymphocytes, polynuclear neutrophils, eosinophils and plasmocytes) containing a severely damaged bile duct with concentric periductular fibrosis (Masson’s trichrome, 10 original magnification). (C) Higher magnification showing cholangiolitis, cholangiolar proliferation and a dense plasmocytic infiltration (hematoxylin-eosin, 40 original magnification). (D) IgG4 immunostaining of a portal space showing an infiltration with numerous IgG4 positive plasmocytic cells (arrows: immunoperoxydase, 40 original magnification).
Treatment with methylprednisolone (32 mg per day) was initiated in mid-November and doses were rapidly tapered down. Liver function tests showed a slow improvement. However, in February 2007 the patient’s tests worsened repeatedly. At that time, the patient complained of diarrhea and fever. Due to these new clinical features and relapsing liver tests abnormalities, the patient was referred to our center. At clinical examination, the patient looked chroni-
cally ill with pallor and acne. Colonoscopy showed a picture of moderately active ulcerative colitis extending to the entire colonic mucosa. Biopsies taken during this examination showed an inflamed mucosa infiltrated by polynuclear neutrophils and plasmocytes together with microabcesses, a picture compatible with ulcerative colitis. Repeated MRI showed diffuse irregularities of the biliary tract. The recent liver biopsy was reviewed and an immunostaining for IgG4 was obtained which
604
S.N. Dastis et al. / Journal of Hepatology 51 (2009) 601–605
showed numerous IgG4 positive plasmocytic cells infiltrating portal tracts (Fig. 1D). Treatment with ursodeoxycholic acid (750 mg per day) and mesalazin was first initiated. Due to only minimal improvement, budesonide (3 mg, 3 times per day) was added, then tapered down after three months at 3 mg, 2 times per day. One year after the initiation of treatment with budesonide the clinical condition of this patient dramatically improved, with a weight increase of 5 kg. Liver biochemistry showed a regressive isolated increase in cGT. IgG4 blood determination was reduced to 269 mg/dl and HLA determination showed, as in her brother, a class II DRB1*15. Subsequent high resolution HLA typing performed by sequence-based-typing showed in both siblings similar alleles: A*0301 A*3201 B*07 (0702/62) B*1401 Cw*0702 Cw*0802 DRB1*1501. After a further six months follow-up, both patients were asymptomatic. The brother had normal hepatic and pancreatic tests as well as normal IgG4 levels. Repeated MRI with cholangio-pancreatography performed one year after the initiation of treatment showed a complete disappearance of bile duct abnormalities in both cases. After a three year follow-up period and under small doses of budesonide (3–6 mg per day) both patients remains asymptomatic with a normal liver serobiochemistry.
3. Discussion We report two cases of two identical siblings presenting with cholangitis associated with ulcerative colitis. Both expressed IgG4 plasmocytic positivity in liver biopsy specimens, the expression being, however, much stronger in the sister. This was probably due to the shorter history of the disease and its greater activity. Serum levels of IgG4 were also higher in the sister who had been treated with a much lower dose of steroids. Both patients responded promptly to treatment with prednisolone, the therapeutic benefit being maintained under budesonide, ursodeoxycholic acid and mesalazin. Clinical and biochemical response to treatment was complete in both cases and MRI biliary tract abnormalities had completely disappeared after one year of therapy. HLA testing showed that both siblings were class II DRB1-15 positive with high resolution typing indicating DRB*1501, an allele more often shown in association with PSC, but not with IgG4 cholangitis. Cholangitis described in association with inflammatory bowel disease includes mainly PSC, its IgG4 positive form being less frequently observed in this context [3]. By contrast, IgG4 cholangitis appears more often associated with autoimmune pancreatitis, and may be a component of a rather more diffuse, systemic autoimmune IgG4 disease highly responsive to steroid therapy [1].
HLA studies performed in PSC have led to rather inconsistent associations, DRB*1501 being more consistently associated as in our two siblings [13,14]. Tests performed in autoimmune pancreatitis in Japan have suggested that the two critical regions for disease susceptibility are limited to the HLA–DRB1*0405DQB1*0401 in class II and the ABCF1 proximal to C3-2-11, telomeric of HLA-E, in the class I regions [15–17]. The disease has also been suspected to be associated with cytotoxic T-lymphocyte antigen four gene polymorphism, also in Japanese patients [18]. An association with DRB*1501 as in our siblings has not yet been reported. Another remaining possibility is that the DRB*1501 allele represents a predisposing factor for bile duct involvement in patients with ISD. From a diagnostic point of view, the diagnosis of PSC in our two case reports was unlikely, not so much because of atypical serological features as more importantly, based on the early and sustained disappearance of clinical, biochemical and morphological features of bile duct involvement. As exemplified in our cases, the clinical and biological pictures occurring in IgG4-associated cholangitis may mimic those of autoimmune hepatitis (AIH) or those of the AIH/PSC overlap syndrome. Considering co-existing AIH, confusion may exist and scoring our cases for this condition would give a score of 12 using the 1999 scoring system and a score of 6 (probable AIH) using the simplified 2008 criteria. However, segmental and/or large extra-hepatic bile duct involvement is not known to occur in AIH, an observation which can also be done for the AIH/PSC overlap syndrome. In addition to the absence of positive IgG4 staining on the liver biopsy, both conditions are also far less responsive to small doses of steroids than IAC. Search for the identification of IgG4 cholangitis and/ or disease through increased IgG4 serum levels and/or increased tissular IgG4 plasmocytic expression thus appears important both for diagnostic and therapeutic purposes. Indeed immunosuppression is effective and may lead to long-term remission, improved prognosis and/or transplantation-free survival. Our observations also reinforce the concept of the existence of ISD, a disease in which the existence of a genetic predisposition remains to be determined.
4. Conclusions Our case reports document the fact that IBD-associated autoimmune cholangitis may in some cases be part of ISD different from PSC and highly responsive to steroid therapy. Moreover, the occurrence of identical features in two HLA-identical siblings reinforces arguments in favor of a strong genetic predisposition.
S.N. Dastis et al. / Journal of Hepatology 51 (2009) 601–605
References [1] de Suray N, Van Beers B, Sempoux C, Borschette C, Lonneux M, Deprez P, et al. Autoimmune pancreatitis, sclerosing cholangitis, liver inflammatory pseudotumors, retroperitoneal fibrosis, lymphadenopathy, and sialoadenitis in a single patient: a multifaced expression of a hitherto unrecognized systemic autoimmune syndrome? Pancreas 2009;38:476–478. [2] Bjo¨rnsson E, Chari ST, Smyrk TC, Lindor K. Immunoglobulin G4 associated cholangitis: description of an emerging clinical entity based on review of the literature. Hepatology 2007:1547–1554. [3] Mendes FD, Jorgensen R, Keach J, Katzmann JA, Smyrk T, Donlinger J, et al. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol 2006;101: 2070–2075. [4] Kamisawa T. IgG4-positive plasma cells specifically infiltrate various organs in autoimmune pancreatitis. Pancreas 2004;29: 167–168. [5] Takahashi N, Kawashima A, Fletcher JG, Chari ST. Renal involvement in patients with autoimmune pancreatitis: CT and MR imaging findings. Radiology 2007;242:791–801. [6] Deshpande V, Chicano S, Finkelberg D, Selig MK, Mino-Kenudson M, Brugge WR, et al. Autoimmune pancreatitis: a systemic immune complex mediated disease. Am J Surg Pathol 2006;30:1537–1545. [7] Perret AD, Higgins G, Johnston HH, Massarella GR, Truelove SC, Wright R. The liver in ulcerative colitis. Q J Med 1971;40:187–209. [8] Olsson R, Danielsson A, Jarnerot G, Lindstrom E, Loof L, Rolny P, et al. Prevalence of primary sclerosing cholangitis in ulcerative colitis. Gastroenterology 1991;100:1319–1323. [9] Schrumpf E, Elgjo K, Fausa O, Gjone E, Kolmannskog F, Ritland S. Sclerosing cholangitis in ulcerative colitis. Scand J Gastroenterol 1980;15:689–697.
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[10] Broome U, Glaumann H, Hultcrantz R. Liver histology and follow up of 68 patients with ulcerative colitis and normal liver tests. Gut 1990;31:468–472. [11] Okada H, Mizuno M, Yamamoto K, Tsuji T. Primary sclerosing cholangitis in Japanese patients: association with inflammatory bowel disease. Acta Med Okayama 1996;50:227–235. [12] Van Milligen de Wit AW, van Deventer SJ, Tytgat GN. Immunogenetic aspects of primary sclerosing cholangitis: implications for therapeutic strategies. Am J Gastroenterol 1995;90: 893–900. [13] Bambha K, Kim WR, Talwalkar J, Torgerson H, Benson JT, Therneau TM, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology 2003;125:1364–1369. [14] Escorsell A, Pare´s A, Rode´s J, Solı´s-Herruzo JA, Miras M, de la Morena E. Epidemiology of primary sclerosing cholangitis in Spain. J Hepatol 1994;21:787–791. [15] Karlsen TH, Schrumpf E, Boberg KM. Genetic epidemiology of primary sclerosing cholangitis. World J Gastroenterol 2007;13: 5421–5431. [16] Neri TM, Cavestro GM, Seghini P, Zanelli PF, Zanetti A, Savi M, et al. Novel association of HLA haplotypes with primary sclerosing cholangitis (PSC) in a southern European population. Dig Liver Dis 2003;35:571–576. [17] Ota M, Katsuyama Y, Hamano H, Umemura T, Kimura A, Yoshizawa K, et al. Two critical genes (HLA-DRB1 and ABCF1) in the HLA region are associated with the susceptibility to autoimmune pancreatitis. Immunogenetics 2007;59:45–52. [18] Umemura T, Ota M, Hamano H, Katsuyama Y, Muraki T, Arakura N, et al. Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients. Am J Gastroenterol 2008;103:588–594.
Case report
Ulcerative colitis associated with IgG4 cholangitis: Similar features in two HLA identical siblingsq Sergio Negrin Dastis1, Dominique Latinne2, Christine Sempoux3, Andre´ P. Geubel1,* 1
Department of Gastroenterology and Hepatology, St. Luc University Hospital, Universite´ Catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium 2 Department of Immunology, St. Luc University Hospital, Universite´ Catholique de Louvain, Brussels, Belgium 3 Department of Pathology, St. Luc University Hospital, Universite´ Catholique de Louvain, Brussels, Belgium
Background: IgG4-associated cholangitis (IAC) can mimic primary sclerosing cholangitis although, in contrast to the latter, it is highly responsive to steroid therapy. IAC is known to be associated with autoimmune pancreatitis and has also been shown to be part of a more complex autoimmune IgG4 syndrome. However, an association with inflammatory bowel disease (IBD), a condition in which its identification may have therapeutic and prognostic importance, has not yet been described. Case reports: We report the cases of two HLA identical siblings both DRB*1501 positive exhibiting features of IAC together with ulcerative colitis. Subsequent high resolution HLA typing performed by sequence-based-typing showed similar alleles in both siblings: A*0301 A*3201 B*07 (0702/ 62) B*1401 C*0702 C*0802 DRB1*1501. There is indirect evidence that this hitherto undescribed association, likely to be strongly linked to a genetic background, might account for a proportion of the cases of cholangitis associated with IBD. Conclusion: Appropriate investigation for IBD-associated cholangitis is mandatory to identify IAC, the recognition of which has particular therapeutic and prognostic implications. Ó 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Autoimmune cholangitis; Ulcerative colitis; IgG4; HLA-identical siblings
1. Introduction IAC is known to be often associated with autoimmune pancreatitis (AP), although it can occasionally be a single facet of a more complex autoimmune systemic IgG4 syndrome [1,2]. It is likely that this autoimmune entity has been under-recognized due to few distinguishable features from the more common picture
Received 17 March 2009; received in revised form 26 May 2009; accepted 30 May 2009 Associate Editor: V. Barnaba q The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. * Corresponding author. Fax: +32 27648927. E-mail address: [email protected] (A.P. Geubel).
of primary sclerosing cholangitis (PSC). On one hand, there are reports of patients having both PSC and AP, a context in which the disease has been shown to be responsive to corticotherapy, an uncommon observation in PSC. On the other hand, increased IgG4 serum levels have been found in 9% of unselected patients with PSC [3], the significance of which remains uncertain because of the retrospective documentation of the association. Whether this biochemical feature may be used to identify a subtype of cholangitis related to different pathophysiological mechanisms remains to be determined. It is now recognized that IAC is a manifestation of a wider autoimmune syndrome with increased IgG4 commonly known as IgG4 related systemic disease (ISD) and typically responsive to steroids. Pancreatitis is the most frequent manifestation, but other associations have been described, involving other organs such as
0168-8278/$36.00 Ó 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2009.05.032
602
S.N. Dastis et al. / Journal of Hepatology 51 (2009) 601–605
salivary glands, retroperitoneum, kidneys and lymph nodes [4–6]. An algorithm for the diagnosis and management of this syndrome has been constructed in the light of occasional lack of elevated IgG4 [1]. It is widely accepted that approximately 5% of UC patients exhibit associated PSC, a proportion which varies from one study to another [7–9]. By contrast, the majority of patients with PSC have underlying IBD (from 23% to 72%) [10,11]. The wide variation in prevalence is probably related to the absence of universal endoscopic examination and also, to variable geographical distribution. The association has important therapeutic and prognostic implications especially in the context of liver transplantation, The mechanisms involved in the pathogenesis of this common association often characterized by serological ANCA positivity, found in up to 80% of cases [12] remains largely unknown. So far, and to the best of our knowledge, no association has been reported between IAC and definite HLA haplotypes or between IgG4-related cholangitis and UC. In this paper we report two cases of HLA-identical siblings both with UC and IgG4-related cholangitis highly responsive to low-dose steroids. This leads us to postulate that in the spectrum of immune cholangiopathy associated with inflammatory bowel diseases, the identification of such an entity has important implications for therapy and prognosis.
2. Case reports 2.1. Case 1 A 17-year-old male was seen by a gastroenterologist of another center in May 2007 because of diarrhea. A biochemical work-up performed at the end of a short course of ciprofloxacin (500 mg per day for 7 days) showed biochemical cholestasis. Serology was negative for hepatitis viruses, cytomegalovirus (CMV) and Epstein–Barr virus (EBV), but high levels of anti-actine and antinuclear antibodies were reported and a liver biopsy was performed. Histological examination showed features suggestive of mild chronic hepatitis with bile duct injury. At colonoscopy, the picture was that of a diffuse form of ulcerative colitis, a diagnosis confirmed by the histological examination of mucosal biopsies. Magnetic resonance imaging (MRI) of the liver and biliary tree showed diffuse irregularities of the intrahepatic biliary tract. Corticotherapy (methylprednisolone, 32 mg per day at decreasing doses during four months) combined with azathioprine was initiated, azathioprine being rapidly withdrawn due to the occurrence of an episode of acute pancreatitis. This was followed by a rapid improvement of both clinical symptoms and biological tests such as liver function tests and hyper-gam-
maglobulinemia. At the time of initial work-up no serum IgG4 levels had been obtained. Therapy with steroids (tapered doses) was given until November 2007 when methylprednisolone was shifted to budesonide. The patient was then referred to our center for a second opinion. Upon arrival, he was asymptomatic and was kept on budesonide 6 mg per day. The liver biopsy obtained previously was reviewed by one of the authors (CS) who emphasized the presence of features of interlobular cholangitis superimposed on those suggestive of mild chronic hepatitis with a dense lymphocytic infiltrate of the portal triads (Fig. 1A). Immunostaining of liver biopsy for IgG4 plasmocytic cells was positive in a few cells. Serum IgG4 levels were normal with no hypergammaglobulinemia, probably due to the high doses of corticosteroids given during the previous four months. HLA testing showed a class II DRB1*15. Repeat MRI performed six months after the first examination showed a complete disappearance of biliary tract abnormalities. Moreover, there was a spectacular improvement in the liver function tests, which had almost returned to normal by July 2008. 2.2. Case 2 The sister of the patient was also referred to our center on March 2007 due to liver function test abnormalities and diarrhea. In October 2006, she had been treated for urinary tract infection manifested by urinary symptoms and fever. She was first prescribed amoxycillin-clavulanate (500 mg, 3 times per day). However, because of the persistence of fever she was hospitalized and treated by ciprofloxacin and amikacin. Biochemical work-up performed at the time of hospitalization showed increased ALT at 225 IU/l, and biochemical cholestasis (alkaline phosphatase: 848 UI/l, N < 94; gamma-GT: 880 IU/l, N < 40). Total serum bilirubin level was 2.9 mg/dl. Hepatitis, EBV and CMV serology was negative. There was a hypergammaglobulinemia with increased total IgG levels (2800 mg/dl, N < 1600) and an elevated IgG4 level at 323 mg/dl (N < 186). Antinuclear antibodies were positive (1/1280, N < 1/40) as were the ANCA (1/2560, N < 1/40) and anti-smooth muscle antibodies (1/320, positive for actine specificity). Tests for anti-mitochondrial antibodies and LKM1 were negative. Abdominal tomodensitometry was normal. An MRI of the liver was performed which was interpreted as showing irregularities of the common bile duct. A liver biopsy was then performed which showed a preserved architecture with enlarged portal tracts infiltrated by lymphocytes, polynuclear neutrophils, eosinophils and plasmocytes. Inflammation was often located around interlobular ducts with pictures of bile duct destruction and concentric periductular fibrosis (Fig. 1B and C). There was cholangiolar proliferation but no interface hepatitis.
S.N. Dastis et al. / Journal of Hepatology 51 (2009) 601–605
603
Fig. 1. (A) Part of an enlarged portal tract showing a dense lymphocytic infiltration and an interlobular bile duct also infiltrated with inflammatory cells (hematoxylin-eosin, 40 original magnification). (B) Picture of an enlarged portal tract infiltrated with inflammatory cells (lymphocytes, polynuclear neutrophils, eosinophils and plasmocytes) containing a severely damaged bile duct with concentric periductular fibrosis (Masson’s trichrome, 10 original magnification). (C) Higher magnification showing cholangiolitis, cholangiolar proliferation and a dense plasmocytic infiltration (hematoxylin-eosin, 40 original magnification). (D) IgG4 immunostaining of a portal space showing an infiltration with numerous IgG4 positive plasmocytic cells (arrows: immunoperoxydase, 40 original magnification).
Treatment with methylprednisolone (32 mg per day) was initiated in mid-November and doses were rapidly tapered down. Liver function tests showed a slow improvement. However, in February 2007 the patient’s tests worsened repeatedly. At that time, the patient complained of diarrhea and fever. Due to these new clinical features and relapsing liver tests abnormalities, the patient was referred to our center. At clinical examination, the patient looked chroni-
cally ill with pallor and acne. Colonoscopy showed a picture of moderately active ulcerative colitis extending to the entire colonic mucosa. Biopsies taken during this examination showed an inflamed mucosa infiltrated by polynuclear neutrophils and plasmocytes together with microabcesses, a picture compatible with ulcerative colitis. Repeated MRI showed diffuse irregularities of the biliary tract. The recent liver biopsy was reviewed and an immunostaining for IgG4 was obtained which
604
S.N. Dastis et al. / Journal of Hepatology 51 (2009) 601–605
showed numerous IgG4 positive plasmocytic cells infiltrating portal tracts (Fig. 1D). Treatment with ursodeoxycholic acid (750 mg per day) and mesalazin was first initiated. Due to only minimal improvement, budesonide (3 mg, 3 times per day) was added, then tapered down after three months at 3 mg, 2 times per day. One year after the initiation of treatment with budesonide the clinical condition of this patient dramatically improved, with a weight increase of 5 kg. Liver biochemistry showed a regressive isolated increase in cGT. IgG4 blood determination was reduced to 269 mg/dl and HLA determination showed, as in her brother, a class II DRB1*15. Subsequent high resolution HLA typing performed by sequence-based-typing showed in both siblings similar alleles: A*0301 A*3201 B*07 (0702/62) B*1401 Cw*0702 Cw*0802 DRB1*1501. After a further six months follow-up, both patients were asymptomatic. The brother had normal hepatic and pancreatic tests as well as normal IgG4 levels. Repeated MRI with cholangio-pancreatography performed one year after the initiation of treatment showed a complete disappearance of bile duct abnormalities in both cases. After a three year follow-up period and under small doses of budesonide (3–6 mg per day) both patients remains asymptomatic with a normal liver serobiochemistry.
3. Discussion We report two cases of two identical siblings presenting with cholangitis associated with ulcerative colitis. Both expressed IgG4 plasmocytic positivity in liver biopsy specimens, the expression being, however, much stronger in the sister. This was probably due to the shorter history of the disease and its greater activity. Serum levels of IgG4 were also higher in the sister who had been treated with a much lower dose of steroids. Both patients responded promptly to treatment with prednisolone, the therapeutic benefit being maintained under budesonide, ursodeoxycholic acid and mesalazin. Clinical and biochemical response to treatment was complete in both cases and MRI biliary tract abnormalities had completely disappeared after one year of therapy. HLA testing showed that both siblings were class II DRB1-15 positive with high resolution typing indicating DRB*1501, an allele more often shown in association with PSC, but not with IgG4 cholangitis. Cholangitis described in association with inflammatory bowel disease includes mainly PSC, its IgG4 positive form being less frequently observed in this context [3]. By contrast, IgG4 cholangitis appears more often associated with autoimmune pancreatitis, and may be a component of a rather more diffuse, systemic autoimmune IgG4 disease highly responsive to steroid therapy [1].
HLA studies performed in PSC have led to rather inconsistent associations, DRB*1501 being more consistently associated as in our two siblings [13,14]. Tests performed in autoimmune pancreatitis in Japan have suggested that the two critical regions for disease susceptibility are limited to the HLA–DRB1*0405DQB1*0401 in class II and the ABCF1 proximal to C3-2-11, telomeric of HLA-E, in the class I regions [15–17]. The disease has also been suspected to be associated with cytotoxic T-lymphocyte antigen four gene polymorphism, also in Japanese patients [18]. An association with DRB*1501 as in our siblings has not yet been reported. Another remaining possibility is that the DRB*1501 allele represents a predisposing factor for bile duct involvement in patients with ISD. From a diagnostic point of view, the diagnosis of PSC in our two case reports was unlikely, not so much because of atypical serological features as more importantly, based on the early and sustained disappearance of clinical, biochemical and morphological features of bile duct involvement. As exemplified in our cases, the clinical and biological pictures occurring in IgG4-associated cholangitis may mimic those of autoimmune hepatitis (AIH) or those of the AIH/PSC overlap syndrome. Considering co-existing AIH, confusion may exist and scoring our cases for this condition would give a score of 12 using the 1999 scoring system and a score of 6 (probable AIH) using the simplified 2008 criteria. However, segmental and/or large extra-hepatic bile duct involvement is not known to occur in AIH, an observation which can also be done for the AIH/PSC overlap syndrome. In addition to the absence of positive IgG4 staining on the liver biopsy, both conditions are also far less responsive to small doses of steroids than IAC. Search for the identification of IgG4 cholangitis and/ or disease through increased IgG4 serum levels and/or increased tissular IgG4 plasmocytic expression thus appears important both for diagnostic and therapeutic purposes. Indeed immunosuppression is effective and may lead to long-term remission, improved prognosis and/or transplantation-free survival. Our observations also reinforce the concept of the existence of ISD, a disease in which the existence of a genetic predisposition remains to be determined.
4. Conclusions Our case reports document the fact that IBD-associated autoimmune cholangitis may in some cases be part of ISD different from PSC and highly responsive to steroid therapy. Moreover, the occurrence of identical features in two HLA-identical siblings reinforces arguments in favor of a strong genetic predisposition.
S.N. Dastis et al. / Journal of Hepatology 51 (2009) 601–605
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