요약Immunoglobulin G4 (IgG4) 관련 경화성 담관염과 원발성 담즙성 담관염의 중복은 매우 드문 임상 양상으로, 이로 인한 비대상성 간경변증으로의 진행은 극히 예외적인 것으로 알려져 있다. 본 증례는 두 질환이 병존하며 스테로이드 포함한 치료에도 불구하고 반복적인 담관염과 담도 협착, 지속적인 IgG4 상승이 관찰되었고, 결국 간섬유화와 복수를 동반한 비대상성 간경변증으로 진행한 사례이다. 기존 문헌에서도 IgG4 관련 질환과 원발성 담즙성 담관염의 중복 또는 다른 장기 침범 사례가 보고된 바 있으나 ursodeoxycholic acid와 면역 치료 병합에 반응하였고 일부에서만 불완전한 치료 반응과 진행성 경과를 보였다. 이러한 중복 사례에서는 간경변 진행 가능성을 신중히 고려해야 하며, 재발성 IgG4 관련 경화성 담관염의 경우 rituximab이 치료 대안이 될 수 있으나, 중복 질환에서의 유효성은 아직 확립되지 않아 최종적으로 간이식까지 고려해야함을 증례로서 보고하는 바이다.
AbstractWe report a rare case of overlapping immunoglobulin G4-sclerosing cholangitis (IgG4-SC) and primary biliary cholangitis (PBC) in a 78-year-old woman presenting with sudden-onset jaundice, cholestatic liver enzyme elevation, and biliary strictures. Elevated alkaline phosphatase levels, positive antimitochondrial antibodies, increased serum IgG4 levels, and a high IgG4/IgG ratio, combined with endobiliary biopsy via endoscopic retrograde cholangiopancreatography biopsy showing lymphoplasmacytic infiltration and IgG4-positive cells, confirmed the diagnosis. Initial treatment with biliary drainage, ursodeoxycholic acid (UDCA), and corticosteroids provided temporary relief; however, the patient experienced recurrent episodes of cholangitis and biliary obstruction, eventually progressing to decompensated cirrhosis over 2 years. This case highlights the importance of considering IgG4-SC in patients with PBC who fail to respond adequately to UDCA and underscores the significant challenges in diagnosing and managing such overlapping syndromes. Further research is crucial to better understand the underlying pathophysiology, refine therapeutic strategies, and improve clinical outcomes of these rare, complex autoimmune conditions.
INTRODUCTIONImmunoglobulin G4-related disease (IgG4-RD) is characterized by elevated serum levels of immunoglobulin G4 (IgG4) and significant infiltration of IgG4-positive plasma cells within the affected tissues [1]. Among the conditions associated with IgG4-RD, IgG4-sclerosing cholangitis (IgG4-SC) is characterized by dense infiltration of IgG4-positive plasma cells and accompanying fibrosis in the bile duct wall, along with a stronger response to corticosteroid therapy than other biliary diseases [2]. Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic disease characterized by the presence of serum anti-mitochondrial antibodies and histological findings of non-suppurative destructive cholangitis [3]. IgG4-SC and PBC are distinct diseases, with IgG4-SC showing a favorable response to steroid therapy, while the standard treatment for PBC generally involves the use of ursodeoxycholic acid (UDCA) [2,3]. However, the association between IgG4-SC and PBC remains unclear. To date, a total of seven cases were identified in which IgG4-SC and PBC coexisted, as well as cases where a specific IgG4 subtype was associated with PBC: two cases have indicated an association between autoimmune pancreatitis and PBC and two additional cases of IgG4-SC associated with PBC have been reported in Japan [4-6]. The remaining three cases involved IgG4-SC with the involvement of other organs, including retroperitoneal fibrosis [7-9]. One case of IgG4-SC progressing to decompensated liver cirrhosis after prolonged inadequate treatment with steroid resistance has been previously reported [10]. However, no cases of decompensated liver cirrhosis have been reported in patients with overlapping IgG4-SC and PBC. Here, we report such a case and provide a comprehensive review of the relevant literature.
CASEA 78-year-old female patient presented with sudden-onset jaundice, on December 18, 2019. Laboratory findings were as follows: aspartate aminotransferase (AST) 93 U/L (reference, 0-35 U/L), alanine aminotransferase (ALT) 102 U/L (reference, 0-35 U/L), alkaline phosphatase (ALP) 331 U/L (reference, 30-120 U/L), total bilirubin 16.1 mg/dL (reference, 0.2-1.2 mg/dL), direct bilirubin 9 mg/dL (reference, 0-0.4 mg/dL), gamma-glutamyl transferase (GGT) 1,008 U/L (reference, 9-64 U/L), and lactate dehydrogenase 521 U/L (reference, 140-480 U/L). Hemoglobin was 9.7 g/dL (reference, 11-15 g/dL) and C-reactive protein was 0.27 mg/dL (reference, 0-0.5 mg/dL). Tests for hepatitis viruses revealed no abnormalities. The patient had no significant medical or medication history. Abdominal computed tomography (CT) revealed dilatation of the intrahepatic bile ducts and the common hepatic duct with abrupt narrowing at the intrapancreatic portion of the common bile duct (CBD) but no overt thickening of the bile duct wall (Fig. 1A). Magnetic resonance imaging (MRI) revealed a segmental stricture extending from the mid to the distal CBD with low signal intensity on T2-weighted images, resulting in diffuse upstream biliary dilatation (Fig. 1B). Further laboratory tests revealed alpha-fetoprotein 3.39 ng/mL (reference, 0-7 ng/mL), carbohydrate antigen 19-9 (CA19-9) 267 U/mL (reference, 0-27 U/mL), and carcinoembryonic antigen 4.75 ng/mL (reference, 0-5 ng/mL), confirming an elevated CA19-9 level. Autoimmune screening showed positivity for antinuclear antibody (ANA) at 1:160 and antimitochondrial antibody (AMA) at 1:100 dilution with M2 specificity. Serum IgG was 1,384.3 mg/dL (reference, 700-1,600 mg/dL), and IgG4 was 81.35 mg/dL (reference, 3.92-86.40). Additional autoimmune antibody tests were performed due to ANA positivity, but no significant findings were observed. Differential diagnoses included malignant strictures, such as CBD cancer, and inflammatory strictures, such as IgG4-RD. Based on MRI findings and laboratory results, PBC was also considered, given the elevated ALP and GGT levels, along with ANA and AMA positivity. Additionally, mild diffuse dilation of the main pancreatic duct and pancreatic swelling with a peripancreatic low-signal halo raised suspicion of autoimmune pancreatitis. Multifocal linear and wedge-shaped lesions in both kidneys suggested the possibility of IgG4-related kidney disease. Emergency percutaneous transhepatic biliary drainage (PTBD) was performed the following day, which resulted in significant improvement in bilirubin levels. Cholangiography performed through the PTBD revealed irregular luminal narrowing in the mid to distal CBD (Fig. 2). At the initial visit, a tissue biopsy could not be performed due to the patient’s advanced age, procedural risks, and poor overall condition, and both the patient and caregivers declined the procedure. Two weeks later, a biliary metal stent was placed because of suspicion of cancer after consultation with the radiology department. Three months later, the patient experienced recurrence of jaundice with elevated bilirubin levels. Unlike previous findings, laboratory tests revealed an IgG level of 1,352 mg/dL and an IgG4 level of 266.73 mg/dL, confirming an elevated IgG4/IgG ratio. Consequently, a tissue biopsy was performed via endoscopic retrograde cholangiopancreatography to differentiate between CBD cancer and IgG4-SC. Biopsy revealed IgG4-positive plasma cell infiltration into the lamina propria of the bile duct mucosa. However, storiform fibrosis and obliterative phlebitis were absent (Fig. 3). Based on the histological findings, imaging data, serological results, and involvement of other organs, the patient was diagnosed with IgG4-SC. Steroid therapy was initiated on November 15, 2021 and continued until February 1, 2023. Over the subsequent 2 years, improvements in bilirubin levels and symptom relief were observed during steroid therapy. However, elevated IgG4 levels were detected 6 months after treatment completion. One year and 7 months after completing steroid therapy, laboratory findings showed IgG at 3,721 mg/dL, IgG4 at 1,199 mg/dL, and total bilirubin at 3.4 mg/dL. Additionally, AST was 103 U/L, ALT was 115 U/L, and CT and ultrasonography confirmed liver cirrhosis, mild splenomegaly, biliary cirrhosis, and significant ascites. The patient was diagnosed as having decom-pensated cirrhosis caused by overlapping PBC and IgG4-SC. Diuretics were prescribed for ascites management and the patient remained under outpatient care. Steroid therapy was restarted in conjunction with ongoing UDCA treatment. A decrease in IgG4 levels was observed during steroid therapy, declining sequentially from 1,199.48 mg/dL to 474.76 mg/dL and then to 208.08 mg/dL. However, the decompensated cirrhosis did not improve, with an increase in ascites, worsening cirrhotic changes on follow-up ultrasound, and the development of hepatorenal syndrome (Fig. 4). Although rituximab therapy was considered for recurrent disease, a high IgG4-RD responder index score of 4 or higher combined with a Mayo risk score for PBC of 10.583, and refusal by the patient and caregivers precluded its use. Supportive care and steroid tapering remain the current management approaches.
DISCUSSIONAfter excluding drug-induced cholestasis, infiltrative disease, and extrahepatic bile duct obstruction, PBC was diagnosed based on cholestatic biochemical abnormalities and positive AMA. MRI revealed mild diffuse main pancreatic duct dilatation and pancreatic swelling with a peripancreatic low-signal halo, indicating the presence of autoimmune pancreatitis. Based on Japan’s 2012 clinical criteria, IgG4-SC was diagnosed using a combination of imaging, serology, histology, involvement of other organs, and treatment response [11]. Most patients with PBC are diagnosed while still asymptomatic. Without treatment, liver disease progression is inevitable in most cases, with fibrosis and cirrhosis developing as a result of ongoing inflammatory and cholestatic processes. A recent retrospective study on PBC reported a 10-year incidence of major non-neoplastic hepatic complications at 9% and a 15-year incidence at 15%, which dropped to 5.8% after 2000 with the introduction of UDCA treatment. Although regional differences exist, the progression of IgG4-SC to cirrhosis is not as common as that of PBC. Cirrhosis occurs in approximately 7% of Western IgG4-related sclerosing cholangitis cohorts [2]. In Asian cohorts, decompensated liver failure is rare (<1%) in Japanese data. Liver transplantation for liver failure has been reported in only one United States case, with no cases reported in the United Kingdom, Japan, or Korea [12]. This case suggests two key considerations: first, in patients with PBC and poor UDCA response, overlapping IgG4-SC should be considered, warranting IgG/IgG4 testing; second, overlap of these diseases may lead to decompensated cirrhosis. Liver transplantation is the only effective treatment for patients with advanced PBC and decompensated cirrhosis or liver failure. However, aside from a single liver transplant for advanced cirrhosis in a United Kingdom cohort, treatment data for disease progression are limited. Therefore, the early recognition of cases of overlapping PBC and IgG4-SC is crucial, as it can significantly impact treatment decisions and improve patient outcomes. In addition to the two reported cases of direct overlap between PBC and IgG4-SC, there are five reported cases of retroperitoneal fibrosis and autoimmune pancreatitis overlapping with PBC as examples of involvement of other organs in IgG4-SC. Seven cases were reviewed from the literature (Table 1) [4-9,13]. Patients with PBC and retroperitoneal fibrosis showed improvement after UDCA monotherapy or surgical treatment. Those overlapping with autoimmune pancreatitis or directly with IgG4-SC generally responded well to combined steroid and UDCA therapies. In another case, similar to our patient, IgG4-SC was diagnosed 5 years after the initial diagnosis of PBC. Steroid therapy led to a reduction in IgG4 levels and radiologic improvement of biliary tract strictures; however, no improvement in liver enzyme levels was observed. As in our case, the response to treatment was limited after a prolonged period following recurrence. In our case, steroid treatment was effective at the time of diagnosis in 2021; however, after 1 year and 7 months, the patient was confirmed to be unres-ponsive to treatment. Considering that approximately 60% of IgG4-related patients show a complete response to steroids, the disease may have transitioned from an inflammatory state to a less inflammatory and fibrotic state, resulting in a lack of response to steroid therapy [2,11]. Understanding the pathogenic overlap between PBC and IgG4-SC provides important insights into the mechanisms underlying steroid resistance and the progression to cirrhosis. Both diseases share key characteristics, including genetic susceptibility linked to human leukocyte antigen-DQB1, dysregulation of cytotoxic T-lymphocyte-associated protein 4, and the critical involvement of T and B lymphocytes in driving inflammation and fibrosis [14]. Chronic, low-grade microbial stimulation through toll-like receptor 3 and toll-like receptor 4 pathways plays a central role, with T-lymphocytes contributing to tissue damage, B lymphocytes producing autoantibodies and promoting plasma cell infiltration, and molecular mimicry by bacterial proteins, such as those from escherichia coli, initiating autoimmune responses [15]. Evidence of pathogenic overlap between PBC and IgG4-SC highlights the possibility of their co-occurrence. Additionally, in overlapping cases, the potential for cirrhotic changes, as observed in this case, must be carefully considered. Although rituximab may be a therapeutic option for the recurrence or progression of IgG4-SC, its efficacy in overlapping cases remains unclear. Ultimately, it is important to recognize that liver transplantation may be the only definitive treatment for such cases. This case highlights the need for further research into the mechanisms of overlapping syndromes, their progression, and the role of immunomodulatory therapies in optimizing patient outcomes.
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![]() ![]() ![]() ![]() Fig. 1.(A) Computed tomography image shows the intrahepatic bile ducts and the common hepatic duct dilatation with narrowing (arrows). (b) Magnetic resonance image shows a segmental ductal stricture of the common bile duct (arrow). ![]() Fig. 2.Cholangiography performed via percutaneous transhepatic biliary drainage shows irregular luminal narrowing at the mid to distal common bile duct (arrow). ![]() Fig. 3.(A) Lymphoplasmacytic infiltration in the lamina propria of the bile duct mucosa (hematoxylin and eosin stain, ×400), (b) chronic superficial inflammation with IgG4(+) plasma cell infiltration (23/HPF, ×400). IgG4, immunoglobulin G4; HPF, high-power field. ![]() Fig. 4.Time-sequential changes in IgG4, total bilirubin, and creatinine levels in a patient with overlapping IgG4-SC and PbC. Key interventions (PTbD, ERCP with biopsy, and steroid therapy) are indicated, showing the clinical course and treatment response. IgG4, immunoglobulin G4; PTbD, percutaneous transhepatic biliary drainage; ERCP & bx., endoscopic retrograde cholangiopancreatography and biopsy; IgG4-SC, immunoglobulin G4 sclerosing cholangitis; PbC, primary biliary cholangitis. ![]() Table 1.Summary of previously reported cases of IgG4-related sclerosing cholangitis with treatment and prognosis
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