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IgG4-related sclerosing cholangitis overlapping with autoimmune hepatitis: Report of a case
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Case report
IgG4-related sclerosing cholangitis overlapping with autoimmune hepatitis: Report of a case Hongyan Li a , Li Sun a , David R. Brigstock b,c , Lina Qi a , Runping Gao a,∗ a b c
Department of Hepatic-Biliary-Pancreatic Medicine, First Hospital, Jilin University, Changchun 130021, Jilin Province, China The Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States Division of Pediatric Surgery, Department of Surgery, The Ohio State University, Columbus, OH 43205, United States
a r t i c l e
i n f o
Article history: Received 27 August 2016 Keywords: IgG4-related disease IgG4-related sclerosing cholangitis IgG4-related autoimmune hepatitis Hilar cholangiocarcinoma
a b s t r a c t Background: IgG4-related sclerosing cholangitis (IgG4-SC) is the biliary manifestation of IgG4-related disease (IgG4-RD) but the presence of IgG4-SC in the porta hepatis is difficult to differentiate from hilar cholangiocarcinoma (HCCA). IgG4-related autoimmune hepatitis (IgG4-related AIH) is extremely rare and it is not fully clear whether IgG4-related AIH is a hepatic manifestation of IgG4-RD or a subtype of AIH. Case presentation: We present a rare case of a 52-year-old male who was admitted with obstructive jaundice and itchy skin. He primarily presented a severe bile duct stricture in the porta hepatis and an elevated serum level of carbohydrate antigen 19-9 (CA19-9) mimicking HCCA. The patient underwent a surgical resection of the left hepatic lobular and cholecyst as well as common bile duct with a right hepatico-jejunostomy. He was finally diagnosed as IgG4-SC accompanied with IgG4-related AIH by immunohistochemistry, but he lacked conventional autoantibodies. The patient responded well to steroid therapy and remains healthy with no signs of recurrence at six-month follow-up. Conclusion: This is the first case report that hepatic portal IgG4-SC overlapping with IgG4-related AIH without the presence of conventional autoantibodies. Additionally, we suggest that IgG4-RD should be always considered in case of a bile duct stricture in the porta hepatis to avoid unnecessary surgical operation. © 2017 Elsevier GmbH. All rights reserved.
1. Introduction IgG4-related disease (IgG4-RD) is a multi-organ system disease characterized by unique histopathologic features including a dense lymphoplasmacytic infiltrate, obliterative phlebitis, and storiform fibrosis, with prominent IgG4-positive plasma cell infiltration in affected organs [1]. IgG4-related sclerosing cholangitis (IgG4-SC) is an uncommon disorder that has recently been confirmed as a biliary manifestation of IgG4-RD [2]. The manifestation of hepatic portal
Abbreviations: IgG4-RD, IgG4-related disease; IgG4-SC, IgG4-related sclerosing cholangitis; HCCA, hilar cholangiocarcinoma; AIH, autoimmune hepatitis; IgG4related AIH, IgG4-related autoimmune hepatitis; CA19-9, carbohydrate antigen 19-9; ANA, anti-nuclear antibody; Anti-SMA, anti-smooth muscle actin antibody; MRCP, magnetic resonance cholangiopancreatography; CT, computed tomography; IAIHG, International Autoimmune Hepatitis Group. ∗ Corresponding author at: Department of Hepatic-Biliary-Pancreatic Medicine, First Hospital, Jilin University, 71 Xinmin Avenue, Changchun 130021, Jilin Province, China. E-mail address: gao [email protected] (R. Gao).
IgG4-SC is extremely similar to that of hilar cholangiocarcinoma (HCCA) [3], but the treatment and prognosis are entirely different between these two diseases. Therefore, a definite diagnosis of IgG4SC is very important. Autoimmune hepatitis (AIH) is characterized by increased transaminase levels, presence of autoantibodies and elevated serum immunoglobulin G (IgG) level. Typical histological features of AIH include interface hepatitis, numerous lymphoplasmocyte infiltration and rosette formation [4]. According to the pattern of autoantibodies detected, AIH is currently classified into three subtypes. AIH-1 is characterized by the presence of antinuclear antibody (ANA) and/or anti-smooth muscle actin (SMA) antibody. AIH-2 is identified by the presence of specific antiliver/kidney microsomal antibody type 1 (anti-LKM1) and/or antibodies against liver cytosol type 1 antigen (anti-LC1). AIH3 is correlated with the presence of anti-soluble liver antigens (anti-SLA)/anti-liver pancreas antibodies (anti-LP) [4]. In 1990 the concept of autoantibody-negative AIH was first proposed by Czajia [5]. Recently, this phenotype of AIH was reported to account for 10.2% of AIH in China [6].
http://dx.doi.org/10.1016/j.prp.2017.01.024 0344-0338/© 2017 Elsevier GmbH. All rights reserved.
Please cite this article in press as: H. Li, et al., IgG4-related sclerosing cholangitis overlapping with autoimmune hepatitis: Report of a case, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.01.024
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Fig. 1. Imaging of IgG4-related sclerosing cholangitis. Magnetic Resonance Cholangiopancreatography(MRCP) scan showing intrahepatic bile duct dilation and a severe bile duct stricture in the porta hepatis (A); Computed tomography (CT) scan showing intrahepatic bile duct dilation (B) (C), the obstruction in the upper portion of the common bile duct with nodular diutinum wall (B), and the thickening of adjacent common bile duct wall (C). An image of the right hepatico-jejunostomy with an almost normal intrahepatic bile duct after steroid therapy is shown (D).
IgG4-related AIH is a new disease entity characterized by elevated levels of serum IgG4 and marked IgG4-positive plasma cell infiltration in the liver in the presence of classical features of AIH [7]. However, it currently remains unclear as to whether IgG4-related AIH is a hepatic manifestation of IgG4-RD or a subtype of AIH. In this report, we present a rare case of IgG4-SC in the porta hepatis which overlapped with IgG4-related AIH, the latter of which occurred without the presence of conventional autoantibodies. This rare clinical condition has not yet been reported in literature. 2. Case presentation A 52-year-old male from Northeast China was admitted for a 7-day history of jaundice and itchy skin. He did not have right upper quadrant pain and weight loss. He had a two-year history of rheumatoid arthritis, but he denied any history of alcohol, tobacco, or illicit drug use. On admission, the patient had yellow staining of the skin and sclera. Serum biochemical data on admission were as follows: total bilirubin 344.5 mol/L, alkaline phosphatase 300.5 U/L, aspartate aminotransferase 658.7 U/L, alanine aminotransferase 646.3 U/L. Serum immunological testing displayed negative reactions for ANA, anti-SMA, anti-LKM-1, anti-LC1, or anti-SLA/anti-LP, RF 202 IU/ml (normal range <15 IU/mL). Tumor marker carbohydrate antigen 199 (CA19-9) was 671.92 U/mL (normal range <37 U/mL). Infections with hepatitis A–C, and E viruses as well as cytomegalovirus were excluded. Magnetic resonance cholangiopancreatography (MRCP) scan revealed intrahepatic bile duct dilation and severe bililary stricture in the porta hepatis (Fig. 1A). Computed tomography (CT) scan of the abdomen revealed intrahepatic bile duct dilation (Fig. 1B and C), an obstruction in the upper portion of the common bile duct with nodular diutinum wall (Fig. 1B), and thickening of adjacent common bile duct wall (Fig. 1C), suggesting the possibility of HCCA. On the 13th day after admission, the patient underwent a surgical resection of the left hepatic lobular and cholecyst as well
Table 1 Autoimmune hepatitis score using IAIHG scoring system. Variable/feature
Score
ALP:AST ratio: 0.46 (<1.5) Serum IgG:ULN:1.7 (1.5–2.0) Hepatitis viral markers: negative Drug history: negative Average alcohol intake: 0 (<25 g/day) Other autoimmune disease: rheumatoid arthritis Liver histology: Interface hepatitis Predominantly lymphoplasmacytic infiltrate Rosetting of liver cells Total
+2 +2 +3 +1 +2 +2 +3 +1 +1 +17
as common bile duct with a right hepatico-jejunostomy. To verify whether the patient suffered from HCCA or other diseases, the resected bile duct specimen was sectioned and stained with hematoxylin and eosin (HE) which showed phlebitis and storiform fibrosis (Fig. 2A), extensive lymphoplasmacyte infiltration, and phlebitis (Fig. 2B). Immunohistochemical staining revealed numerous IgG4-positive plasmacytes (>50/HPF) (Fig. 2C) and IgGpositive plasmacytes (Fig. 2D) in the bile duct tissue, with a ratio of IgG4/IgG-positive plasmacytes of more than 40%. HE staining of the resected left hepatic lobectomy specimen revealed phlebitis, numerous lymphoplasmacytes, interface inflammation (Fig. 3A and B), and rosette formation (Fig. 3B), meeting typical histological features of AIH. To investigate whether the potential involvement of the IgG4 pathway, liver sections were analyzed by immunohistochemistry revealing IgG4-positive plasmacytes (>50/HPF) (Fig. 3C) and IgG-positive plasmacytes (Fig. 3D), with a ratio of IgG4/IgGpositive plasmacytes of more than 40%. On the 15th postoperative day, serological testing for autoimmune function displayed a high level of IgG4 (13.40 g/L, normal range 0.03–2.01 g/L) and IgG (27.2 g/L). Since the patient had an international AIH group (IAIHG) score of 17 (Table 1) he was diagnosed with hilar IgG4-SC and IgG4- related AIH. He then received
Please cite this article in press as: H. Li, et al., IgG4-related sclerosing cholangitis overlapping with autoimmune hepatitis: Report of a case, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.01.024
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Fig. 2. Histological findings of the resected bile duct specimen. HE stain showing phlebitis (A, ×100) and the inset showing storiform fibrosis (×200); numerous lymphoplasmacyte infiltration and phlebitis (B, ×200); immunohistochemical stain showing IgG4-positive plasma cells (C, ×100); and IgG-positive plasma cells (D, ×100).
Fig. 3. Histological findings of the resected hepatic left lobe specimen. HE stain showing phlebitis (white arrow), numerous lymphoplasmacyte infiltration and interface inflammation (black arrow) (A and B), and rosette formation (white arrow) (B); immunohistochemical stain showing IgG4-positive plasma cells (C); and IgG-positive plasma cells (D) in the resected liver sections of the patient. Original magnification × 100(A), ×400 (B–D).
40 mg/d prednisone for 4 wk. At 4-wk follow-up, the patient exhibited no signs of jaundice and body itching. Liver function test results and elevated serum levels of CA19-9 returned to normal levels. A CT scan showed right hepatico-jejunostomy with an almost normal intrahepatic bile duct (Fig. 1D). The patient then received a long-term maintenance dose of 10 mg/d of prednisone after steroid tapering. At 6-mo follow-up, his illness had not recurred.
3. Discussion IgG4-RD is a recently recognized multi-organ fibroinflammatory condition characterized by the presence of abundant IgG4-positive plasma cells, elevation of serum IgG4 levels, and a dramatic steroid responsiveness [1]. New histological diagnostic criteria for IgG4-RD require the presence of at least two of three characteristic histological features, namely, dense lymphoplasma-
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cyte infiltration, fibrosis arranged at least focally in a storiform pattern, and obliterative phlebitis [8]. Thus the patient in this study fully met the diagnostic criteria for IgG4-SC. This patient, however, originally presented with a severe biliary stricture in the porta hepatis and a marked elevation of serum CA19-9 level, which was extremely similar to HCCA. Over the last decade, the association of IgG4-SC with cholangiocarcinoma has received much attention. Since IgG4-SC was recognized as fibroinflammatory disorder with chronic cholestasis, it was proposed as a precursor lesion of biliary intraepithelial neoplasia [9]. Recently, a case of cholangiocarcinoma was reported that developed from IgG4-SC after 4 years of steroid therapy [10]. CA19-9 is expressed by normal biliary ductal epithelial cells and secreted into bile juice. The elevated levels of CA19-9 can be caused by bile duct obstruction or biliary epithelial injury or high biliary pressure. CA19-9 is a widely used tumor marker in that it is increased in benign and malignant biliary tract diseases. There has not been a definite cutoff value of elevated CA19-9 levels in differential diagnosis between IgG4-SC and cholangiocarcinoma but a strong indication of a malignant cause of obstruction is suggested when serum levels of CA19-9 remain unchanged or are greater than 90 U/mL after successful drainage of obstructive jaundice [11]. Over the last decade, although clinicians have paid great attention to the differentiation of hepatic portal IgG4-SC from HCCA, there still remains no good practical strategy to distinguish between them. However, clinicians must differentiate between the two disorders to prevent unnecessary surgery or delayed initiation of steroid therapy. Recently Nakazawa et al. reported four intraductal ultrasonographic features that may be helpful for diagnosing IgG4-SC: (1) circular and symmetric wall thickness; (2) a smooth outer margin and a smooth inner margin; (3) a homogeneous internal echo in the stricture; and (4) a bile duct wall thickness exceeding 0.8 mm in regions of non-stricture [12]. However, differentiating such cases of IgG4-SC in the porta hepatis from HCCA is rather difficult using CT or MRCP alone. Although a mild elevation of serum IgG4 level was also observed in 13.5% of patients with cholangiocarcinoma, the serum IgG4 level was valuable for the diagnosis of IgG4-SC [13]. In the last several years, it has been reported that a cut-off value of serum IgG4 (4-fold ULN) is 100% specific for distinguishing IgG4-SC from cholangiocarcinoma and primary sclerosing cholangitis [13,14]. Additionally, other organ involvement (diffuse swelling pancreas with loss of lobulation, salivary gland swelling and retroperitoneal fibrosis) were also highly specific for IgG4-SC. Recently, SpyGlassTM choledochoscopy was successfully used for evaluation of indeterminate biliary stricture because of its high success rates for adequate tissue sampling and an acceptable safety profile [15]. More recently, a novel qPCR technique analyzing the IgG4/IgG RNA-ratio in blood has been shown to achieve excellent diagnostic accuracy in the differentiation of IgG4-SC from cholangiocarcinoma and primary sclerosing cholangitis [16]. Therefore, comprehensive data including clinical, imaging, serological, histological differences and other organ involvement should be analyzed to differentiate IgG4-SC in the porta hepatis from HCCA. IgG4-associated AIH was first described in 2007, for an elderly woman who showed changes of AIH-1 accompanied with elevated levels of serum IgG4 and abundant IgG4-positive plasma cell infiltration in the liver as well as good response to steroid therapy [17]. In 2011, it was further reported that 2 of 60 Japanese patients with AIH-1 were recognized as IgG4-associated AIH [7]. Provisional diagnostic criteria for IgG4-associated AIH were subsequently proposed as follows: (1) having definite AIH according to the IAIHG score system; and (2) a serum IgG4 concentration of ≥135 mg/dL; and (3) IgG4-positive plasma cell infiltration in the portal tract (≥10/HPF). The authors proposed that IgG4-associated AIH should be differentiated from classical AIH [7]. On the contrary, it was reported that AIH could be divided into IgG4-associated or
IgG4 non-associated types based on the number of IgG4-positive plasma cell infiltration in the portal tract (≥5/HPF or <5/HPF). The authors suggested that IgG4-associated AIH was a novel subtype of classical AIH rather than hepatic manifestation of IgG4-RD [18]. IgG4-related AIH has been proposed instead of IgG4-associated AIH since 2012 [19]. So far two types of hepatic parenchymal involvement of IgG4-RD have been reported, namely IgG4-related AIH and IgG4-related hepatopathy. IgG4-related hepatopathy is currently considered as a collective term covering hepatic lesions primarily or secondly related to IgG4-SC and type I autoimmune pancreatitis [20]. Although the case in this study fully met the diagnostic criteria of IgG4-realted AIH, the infiltration of IgG4-positive cells in the liver tissues might be an adjacent inflammatory reaction of IgG4-SC. Therefore, it remains to be further investigated whether IgG4-related AIH is the hepatic manifestation of IgG4-RD or a subtype of classical AIH. The patient in this study exhibited typical histological features of classical AIH, a high level of serum aminotransferase and an elevation of serum IgG, but an absence of conventional serum autoantibodies. He not only met diagnostic criteria for autoantibody-negative AIH based on IAIHG disease score of 17 before steroid therapy but also met diagnostic criteria for IgG4related AIH because he had elevated level of serum IgG4 and abundant IgG4-positive plasma cell infiltration in the portal tract [6,7,21]. Since IgG4 hardly forms immune complexes and has low affinity for both Fc receptors and complements, its ability to initiate immune responses is limited [22,23]. The pathogenesis of IgG4related AIH without the presence of conventional autoantibodies may be associated with a signature autoantibody outside the conventional repertoire that is still undiscovered, or with undetectable levels of conventional autoantibodies that may have been suppressed or have a delayed expression [21]. Clarification of the actual underlying mechanism will require more detailed investigation. 4. Conclussion We report a rare case of IgG4-SC in the porta hepatis overlapping with IgG4-related AIH without the presence of conventional autoantibodies and which primarily mimicked HCCA. Since the differentiation of hepatic portal IgG4-SC from HCCA is extremely difficult and their treatment and prognosis are very different, we suggest that IgG4-SC should always be considered in case of a bile duct stricture in the porta hepatis. Funding National Natural Scientific Foundation, No. 81270544, 81070370 (to Gao RP) and NIH5R01AA016003 to (Brigstock D). Consent Informed consent was obtained from the patient for publication of this case report and any accompanying images. Author contributions Hongyan Li, Sun Li, Lina Qi contributed the study design, data collection; Runping Gao designed the study and wrote the manuscript; David R. Brigstock co-ordinated the study and edited the manuscript. References [1] W.L. Smit, E.L. Culver, R.W. Chapman, New thoughts on immunoglobulin G4–related sclerosing cholangitis, Clin. Liver Dis. 20 (1) (2016) 47–65.
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Case report
IgG4-related sclerosing cholangitis overlapping with autoimmune hepatitis: Report of a case Hongyan Li a , Li Sun a , David R. Brigstock b,c , Lina Qi a , Runping Gao a,∗ a b c
Department of Hepatic-Biliary-Pancreatic Medicine, First Hospital, Jilin University, Changchun 130021, Jilin Province, China The Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States Division of Pediatric Surgery, Department of Surgery, The Ohio State University, Columbus, OH 43205, United States
a r t i c l e
i n f o
Article history: Received 27 August 2016 Keywords: IgG4-related disease IgG4-related sclerosing cholangitis IgG4-related autoimmune hepatitis Hilar cholangiocarcinoma
a b s t r a c t Background: IgG4-related sclerosing cholangitis (IgG4-SC) is the biliary manifestation of IgG4-related disease (IgG4-RD) but the presence of IgG4-SC in the porta hepatis is difficult to differentiate from hilar cholangiocarcinoma (HCCA). IgG4-related autoimmune hepatitis (IgG4-related AIH) is extremely rare and it is not fully clear whether IgG4-related AIH is a hepatic manifestation of IgG4-RD or a subtype of AIH. Case presentation: We present a rare case of a 52-year-old male who was admitted with obstructive jaundice and itchy skin. He primarily presented a severe bile duct stricture in the porta hepatis and an elevated serum level of carbohydrate antigen 19-9 (CA19-9) mimicking HCCA. The patient underwent a surgical resection of the left hepatic lobular and cholecyst as well as common bile duct with a right hepatico-jejunostomy. He was finally diagnosed as IgG4-SC accompanied with IgG4-related AIH by immunohistochemistry, but he lacked conventional autoantibodies. The patient responded well to steroid therapy and remains healthy with no signs of recurrence at six-month follow-up. Conclusion: This is the first case report that hepatic portal IgG4-SC overlapping with IgG4-related AIH without the presence of conventional autoantibodies. Additionally, we suggest that IgG4-RD should be always considered in case of a bile duct stricture in the porta hepatis to avoid unnecessary surgical operation. © 2017 Elsevier GmbH. All rights reserved.
1. Introduction IgG4-related disease (IgG4-RD) is a multi-organ system disease characterized by unique histopathologic features including a dense lymphoplasmacytic infiltrate, obliterative phlebitis, and storiform fibrosis, with prominent IgG4-positive plasma cell infiltration in affected organs [1]. IgG4-related sclerosing cholangitis (IgG4-SC) is an uncommon disorder that has recently been confirmed as a biliary manifestation of IgG4-RD [2]. The manifestation of hepatic portal
Abbreviations: IgG4-RD, IgG4-related disease; IgG4-SC, IgG4-related sclerosing cholangitis; HCCA, hilar cholangiocarcinoma; AIH, autoimmune hepatitis; IgG4related AIH, IgG4-related autoimmune hepatitis; CA19-9, carbohydrate antigen 19-9; ANA, anti-nuclear antibody; Anti-SMA, anti-smooth muscle actin antibody; MRCP, magnetic resonance cholangiopancreatography; CT, computed tomography; IAIHG, International Autoimmune Hepatitis Group. ∗ Corresponding author at: Department of Hepatic-Biliary-Pancreatic Medicine, First Hospital, Jilin University, 71 Xinmin Avenue, Changchun 130021, Jilin Province, China. E-mail address: gao [email protected] (R. Gao).
IgG4-SC is extremely similar to that of hilar cholangiocarcinoma (HCCA) [3], but the treatment and prognosis are entirely different between these two diseases. Therefore, a definite diagnosis of IgG4SC is very important. Autoimmune hepatitis (AIH) is characterized by increased transaminase levels, presence of autoantibodies and elevated serum immunoglobulin G (IgG) level. Typical histological features of AIH include interface hepatitis, numerous lymphoplasmocyte infiltration and rosette formation [4]. According to the pattern of autoantibodies detected, AIH is currently classified into three subtypes. AIH-1 is characterized by the presence of antinuclear antibody (ANA) and/or anti-smooth muscle actin (SMA) antibody. AIH-2 is identified by the presence of specific antiliver/kidney microsomal antibody type 1 (anti-LKM1) and/or antibodies against liver cytosol type 1 antigen (anti-LC1). AIH3 is correlated with the presence of anti-soluble liver antigens (anti-SLA)/anti-liver pancreas antibodies (anti-LP) [4]. In 1990 the concept of autoantibody-negative AIH was first proposed by Czajia [5]. Recently, this phenotype of AIH was reported to account for 10.2% of AIH in China [6].
http://dx.doi.org/10.1016/j.prp.2017.01.024 0344-0338/© 2017 Elsevier GmbH. All rights reserved.
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Fig. 1. Imaging of IgG4-related sclerosing cholangitis. Magnetic Resonance Cholangiopancreatography(MRCP) scan showing intrahepatic bile duct dilation and a severe bile duct stricture in the porta hepatis (A); Computed tomography (CT) scan showing intrahepatic bile duct dilation (B) (C), the obstruction in the upper portion of the common bile duct with nodular diutinum wall (B), and the thickening of adjacent common bile duct wall (C). An image of the right hepatico-jejunostomy with an almost normal intrahepatic bile duct after steroid therapy is shown (D).
IgG4-related AIH is a new disease entity characterized by elevated levels of serum IgG4 and marked IgG4-positive plasma cell infiltration in the liver in the presence of classical features of AIH [7]. However, it currently remains unclear as to whether IgG4-related AIH is a hepatic manifestation of IgG4-RD or a subtype of AIH. In this report, we present a rare case of IgG4-SC in the porta hepatis which overlapped with IgG4-related AIH, the latter of which occurred without the presence of conventional autoantibodies. This rare clinical condition has not yet been reported in literature. 2. Case presentation A 52-year-old male from Northeast China was admitted for a 7-day history of jaundice and itchy skin. He did not have right upper quadrant pain and weight loss. He had a two-year history of rheumatoid arthritis, but he denied any history of alcohol, tobacco, or illicit drug use. On admission, the patient had yellow staining of the skin and sclera. Serum biochemical data on admission were as follows: total bilirubin 344.5 mol/L, alkaline phosphatase 300.5 U/L, aspartate aminotransferase 658.7 U/L, alanine aminotransferase 646.3 U/L. Serum immunological testing displayed negative reactions for ANA, anti-SMA, anti-LKM-1, anti-LC1, or anti-SLA/anti-LP, RF 202 IU/ml (normal range <15 IU/mL). Tumor marker carbohydrate antigen 199 (CA19-9) was 671.92 U/mL (normal range <37 U/mL). Infections with hepatitis A–C, and E viruses as well as cytomegalovirus were excluded. Magnetic resonance cholangiopancreatography (MRCP) scan revealed intrahepatic bile duct dilation and severe bililary stricture in the porta hepatis (Fig. 1A). Computed tomography (CT) scan of the abdomen revealed intrahepatic bile duct dilation (Fig. 1B and C), an obstruction in the upper portion of the common bile duct with nodular diutinum wall (Fig. 1B), and thickening of adjacent common bile duct wall (Fig. 1C), suggesting the possibility of HCCA. On the 13th day after admission, the patient underwent a surgical resection of the left hepatic lobular and cholecyst as well
Table 1 Autoimmune hepatitis score using IAIHG scoring system. Variable/feature
Score
ALP:AST ratio: 0.46 (<1.5) Serum IgG:ULN:1.7 (1.5–2.0) Hepatitis viral markers: negative Drug history: negative Average alcohol intake: 0 (<25 g/day) Other autoimmune disease: rheumatoid arthritis Liver histology: Interface hepatitis Predominantly lymphoplasmacytic infiltrate Rosetting of liver cells Total
+2 +2 +3 +1 +2 +2 +3 +1 +1 +17
as common bile duct with a right hepatico-jejunostomy. To verify whether the patient suffered from HCCA or other diseases, the resected bile duct specimen was sectioned and stained with hematoxylin and eosin (HE) which showed phlebitis and storiform fibrosis (Fig. 2A), extensive lymphoplasmacyte infiltration, and phlebitis (Fig. 2B). Immunohistochemical staining revealed numerous IgG4-positive plasmacytes (>50/HPF) (Fig. 2C) and IgGpositive plasmacytes (Fig. 2D) in the bile duct tissue, with a ratio of IgG4/IgG-positive plasmacytes of more than 40%. HE staining of the resected left hepatic lobectomy specimen revealed phlebitis, numerous lymphoplasmacytes, interface inflammation (Fig. 3A and B), and rosette formation (Fig. 3B), meeting typical histological features of AIH. To investigate whether the potential involvement of the IgG4 pathway, liver sections were analyzed by immunohistochemistry revealing IgG4-positive plasmacytes (>50/HPF) (Fig. 3C) and IgG-positive plasmacytes (Fig. 3D), with a ratio of IgG4/IgGpositive plasmacytes of more than 40%. On the 15th postoperative day, serological testing for autoimmune function displayed a high level of IgG4 (13.40 g/L, normal range 0.03–2.01 g/L) and IgG (27.2 g/L). Since the patient had an international AIH group (IAIHG) score of 17 (Table 1) he was diagnosed with hilar IgG4-SC and IgG4- related AIH. He then received
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Fig. 2. Histological findings of the resected bile duct specimen. HE stain showing phlebitis (A, ×100) and the inset showing storiform fibrosis (×200); numerous lymphoplasmacyte infiltration and phlebitis (B, ×200); immunohistochemical stain showing IgG4-positive plasma cells (C, ×100); and IgG-positive plasma cells (D, ×100).
Fig. 3. Histological findings of the resected hepatic left lobe specimen. HE stain showing phlebitis (white arrow), numerous lymphoplasmacyte infiltration and interface inflammation (black arrow) (A and B), and rosette formation (white arrow) (B); immunohistochemical stain showing IgG4-positive plasma cells (C); and IgG-positive plasma cells (D) in the resected liver sections of the patient. Original magnification × 100(A), ×400 (B–D).
40 mg/d prednisone for 4 wk. At 4-wk follow-up, the patient exhibited no signs of jaundice and body itching. Liver function test results and elevated serum levels of CA19-9 returned to normal levels. A CT scan showed right hepatico-jejunostomy with an almost normal intrahepatic bile duct (Fig. 1D). The patient then received a long-term maintenance dose of 10 mg/d of prednisone after steroid tapering. At 6-mo follow-up, his illness had not recurred.
3. Discussion IgG4-RD is a recently recognized multi-organ fibroinflammatory condition characterized by the presence of abundant IgG4-positive plasma cells, elevation of serum IgG4 levels, and a dramatic steroid responsiveness [1]. New histological diagnostic criteria for IgG4-RD require the presence of at least two of three characteristic histological features, namely, dense lymphoplasma-
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cyte infiltration, fibrosis arranged at least focally in a storiform pattern, and obliterative phlebitis [8]. Thus the patient in this study fully met the diagnostic criteria for IgG4-SC. This patient, however, originally presented with a severe biliary stricture in the porta hepatis and a marked elevation of serum CA19-9 level, which was extremely similar to HCCA. Over the last decade, the association of IgG4-SC with cholangiocarcinoma has received much attention. Since IgG4-SC was recognized as fibroinflammatory disorder with chronic cholestasis, it was proposed as a precursor lesion of biliary intraepithelial neoplasia [9]. Recently, a case of cholangiocarcinoma was reported that developed from IgG4-SC after 4 years of steroid therapy [10]. CA19-9 is expressed by normal biliary ductal epithelial cells and secreted into bile juice. The elevated levels of CA19-9 can be caused by bile duct obstruction or biliary epithelial injury or high biliary pressure. CA19-9 is a widely used tumor marker in that it is increased in benign and malignant biliary tract diseases. There has not been a definite cutoff value of elevated CA19-9 levels in differential diagnosis between IgG4-SC and cholangiocarcinoma but a strong indication of a malignant cause of obstruction is suggested when serum levels of CA19-9 remain unchanged or are greater than 90 U/mL after successful drainage of obstructive jaundice [11]. Over the last decade, although clinicians have paid great attention to the differentiation of hepatic portal IgG4-SC from HCCA, there still remains no good practical strategy to distinguish between them. However, clinicians must differentiate between the two disorders to prevent unnecessary surgery or delayed initiation of steroid therapy. Recently Nakazawa et al. reported four intraductal ultrasonographic features that may be helpful for diagnosing IgG4-SC: (1) circular and symmetric wall thickness; (2) a smooth outer margin and a smooth inner margin; (3) a homogeneous internal echo in the stricture; and (4) a bile duct wall thickness exceeding 0.8 mm in regions of non-stricture [12]. However, differentiating such cases of IgG4-SC in the porta hepatis from HCCA is rather difficult using CT or MRCP alone. Although a mild elevation of serum IgG4 level was also observed in 13.5% of patients with cholangiocarcinoma, the serum IgG4 level was valuable for the diagnosis of IgG4-SC [13]. In the last several years, it has been reported that a cut-off value of serum IgG4 (4-fold ULN) is 100% specific for distinguishing IgG4-SC from cholangiocarcinoma and primary sclerosing cholangitis [13,14]. Additionally, other organ involvement (diffuse swelling pancreas with loss of lobulation, salivary gland swelling and retroperitoneal fibrosis) were also highly specific for IgG4-SC. Recently, SpyGlassTM choledochoscopy was successfully used for evaluation of indeterminate biliary stricture because of its high success rates for adequate tissue sampling and an acceptable safety profile [15]. More recently, a novel qPCR technique analyzing the IgG4/IgG RNA-ratio in blood has been shown to achieve excellent diagnostic accuracy in the differentiation of IgG4-SC from cholangiocarcinoma and primary sclerosing cholangitis [16]. Therefore, comprehensive data including clinical, imaging, serological, histological differences and other organ involvement should be analyzed to differentiate IgG4-SC in the porta hepatis from HCCA. IgG4-associated AIH was first described in 2007, for an elderly woman who showed changes of AIH-1 accompanied with elevated levels of serum IgG4 and abundant IgG4-positive plasma cell infiltration in the liver as well as good response to steroid therapy [17]. In 2011, it was further reported that 2 of 60 Japanese patients with AIH-1 were recognized as IgG4-associated AIH [7]. Provisional diagnostic criteria for IgG4-associated AIH were subsequently proposed as follows: (1) having definite AIH according to the IAIHG score system; and (2) a serum IgG4 concentration of ≥135 mg/dL; and (3) IgG4-positive plasma cell infiltration in the portal tract (≥10/HPF). The authors proposed that IgG4-associated AIH should be differentiated from classical AIH [7]. On the contrary, it was reported that AIH could be divided into IgG4-associated or
IgG4 non-associated types based on the number of IgG4-positive plasma cell infiltration in the portal tract (≥5/HPF or <5/HPF). The authors suggested that IgG4-associated AIH was a novel subtype of classical AIH rather than hepatic manifestation of IgG4-RD [18]. IgG4-related AIH has been proposed instead of IgG4-associated AIH since 2012 [19]. So far two types of hepatic parenchymal involvement of IgG4-RD have been reported, namely IgG4-related AIH and IgG4-related hepatopathy. IgG4-related hepatopathy is currently considered as a collective term covering hepatic lesions primarily or secondly related to IgG4-SC and type I autoimmune pancreatitis [20]. Although the case in this study fully met the diagnostic criteria of IgG4-realted AIH, the infiltration of IgG4-positive cells in the liver tissues might be an adjacent inflammatory reaction of IgG4-SC. Therefore, it remains to be further investigated whether IgG4-related AIH is the hepatic manifestation of IgG4-RD or a subtype of classical AIH. The patient in this study exhibited typical histological features of classical AIH, a high level of serum aminotransferase and an elevation of serum IgG, but an absence of conventional serum autoantibodies. He not only met diagnostic criteria for autoantibody-negative AIH based on IAIHG disease score of 17 before steroid therapy but also met diagnostic criteria for IgG4related AIH because he had elevated level of serum IgG4 and abundant IgG4-positive plasma cell infiltration in the portal tract [6,7,21]. Since IgG4 hardly forms immune complexes and has low affinity for both Fc receptors and complements, its ability to initiate immune responses is limited [22,23]. The pathogenesis of IgG4related AIH without the presence of conventional autoantibodies may be associated with a signature autoantibody outside the conventional repertoire that is still undiscovered, or with undetectable levels of conventional autoantibodies that may have been suppressed or have a delayed expression [21]. Clarification of the actual underlying mechanism will require more detailed investigation. 4. Conclussion We report a rare case of IgG4-SC in the porta hepatis overlapping with IgG4-related AIH without the presence of conventional autoantibodies and which primarily mimicked HCCA. Since the differentiation of hepatic portal IgG4-SC from HCCA is extremely difficult and their treatment and prognosis are very different, we suggest that IgG4-SC should always be considered in case of a bile duct stricture in the porta hepatis. Funding National Natural Scientific Foundation, No. 81270544, 81070370 (to Gao RP) and NIH5R01AA016003 to (Brigstock D). Consent Informed consent was obtained from the patient for publication of this case report and any accompanying images. Author contributions Hongyan Li, Sun Li, Lina Qi contributed the study design, data collection; Runping Gao designed the study and wrote the manuscript; David R. Brigstock co-ordinated the study and edited the manuscript. References [1] W.L. Smit, E.L. Culver, R.W. Chapman, New thoughts on immunoglobulin G4–related sclerosing cholangitis, Clin. Liver Dis. 20 (1) (2016) 47–65.
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Please cite this article in press as: H. Li, et al., IgG4-related sclerosing cholangitis overlapping with autoimmune hepatitis: Report of a case, Pathol. – Res. Pract (2017), http://dx.doi.org/10.1016/j.prp.2017.01.024