INTRODUCTION

Immunoglobulin G4 (IgG4)-related sclerosing cholangitis (IgG4-SC) often presents with multiorgan involvement and non-specific serologic and imaging findings, making diagnosis challenging. Two diagnostic standards are widely accepted, the histology-imaging-serology-other organ involvement-response to therapy (HISORt) and Japanese Biliary Association criteria, and both are based on systemic involvement, pancreaticobiliary imaging, serologies, histology, and treatment response^1,2. Steroids are considered first-line treatment and prognosis is typically favorable; however, long-term outcomes are not well understood³. IgG4-SC and cholangiocarcinoma has been previously described; however, our case is distinct as it exemplifies the diagnostic uncertainty associated with such conditions, describes the challenges of treating such patients, and presents a unique course of rapid subsequent malignancy following initial IgG4 cholangitis diagnosis.

CASE REPORT

A 62-year-old male with past medical history notable for alcohol use initially presented with symptoms of abdominal pain, fatigue, jaundice, and weight loss. He was also incidentally found to be SARS-CoV-2 (COVID-19) positive. Liver enzymes on admission demonstrated a mixed pattern of liver injury and hyperbilirubinemia. Initial abdominal computed tomography (CT) and subsequent magnetic resonance cholangiopancreatography (MRCP) showed extrahepatic biliary wall thickening and hyperenhancement, suspicious for malignancy or infection, with upstream dilatation, and periportal and peripancreatic lymphadenopathy.

Endoscopic retrograde cholangiopancreatography (ERCP) was pursued, demonstrating a stricture of the upper third of the common bile duct (CBD) and common hepatic duct (CHD). Biliary sphincterotomy and stent placement was performed. CBD brushing cytology returned as non-specific atypical ductal cells (Fig. 1).

Repeat ERCP and stent removal several days later demonstrated beading and narrowing of the CBD and CHD without focal stricture, raising concerns for primary sclerosing cholangitis or COVID-19 cholangiopathy given recent infection. Cytology from CBD brushings was again non-specific.

Twelve days following discharge, the patient presented for outpatient hepatology evaluation with persistent fatigue and jaundice. Further autoimmune workup demonstrated elevated IgG (3,380 mg/dL) with high IgG1 (2,570 mg/dL) and IgG4 (362 mg/dL) levels. This presentation was thought to represent IgG4-SC, and the patient was initiated empirically on prednisone at 40 mg daily. Liver biopsy was performed in attempt to make a more precise diagnosis of IgG4 cholangiopathy, but only showed non-specific cholestasis.

The patient returned to clinic 3 months after initiating steroids and was found to have improvement in both subjective symptoms and liver enzymes. Following that visit, prednisone was tapered by 10 mg every 2 weeks with a plan to initiate azathioprine (AZA) at 75 mg for maintenance immunosuppression when prednisone dose of 20 mg was reached. Following initiation of AZA, prednisone was planned to be further tapered to 15 mg for 2 weeks followed by 10 mg daily (Fig. 2).

Follow-up liver magnetic resonance imaging (MRI), approximately 6 months after initial hospitalization, demonstrated increased central intrahepatic biliary dilation and irregular enhancement of intrahepatic ductal segments, CBD, and gallbladder. Given initial concerns of possible malignancy and such imaging findings, an image guided liver biopsy targeting this lesion was pursued. Core biopsies demonstrated mild portal inflammation with neutrophilic cholangitis but was negative for malignancy (Figs. 3, 4).

Ten days following biopsy, the patient presented with signs and symptoms of sepsis. Labs demonstrated significant leukocytosis and mild elevation in liver enzymes and bilirubin. CT abdomen demonstrated new multifocal cystic lesions concerning for hepatic abscesses with ascending cholangitis. The patient was eventually found to have Klebsiella bacteremia and was treated with intravenous antibiotics. ERCP demonstrated a single moderate biliary stricture of the right main hepatic duct and beading of the right intrahepatic bile duct. CBD brushing cytology again returned negative for malignancy. The patient was eventually discharged following clinical improvement with an outgoing antibiotic regimen.

One week after this hospitalization, the patient presented again with recurrent biliary sepsis. MRCP and liver MRI again showed progression of liver abscesses. Subsequent positron emission tomography (PET) CT showed multiple hypermetabolic foci with the largest measuring up to 2.5 cm, within the liver, described as non-specific. The patient was treated with ertapenem and percutaneous biliary drains were placed for source control of infection.

After review of this case by an interdisciplinary tumor board, right hepatic lobectomy and cholecystectomy were pursued with the primary goal of adequate infection control and secondarily, to definitively rule out malignancy. Gross examination of the hepatectomy specimen revealed a 3.2×2.4×2.2 cm well-circumscribed, tan-white, firm mass abutting the gallbladder bed surface. The hepatic parenchymal resection margin was negative for tumor. Post-surgery pathology demonstrated pT4N0 moderately-differentiated adenocarcinoma of the liver (small duct-type intrahepatic cholangiocarcinoma) with direct extension into the gallbladder with lymphovascular and perineural invasion. The tumor was predominantly mass-forming with areas of intraductal tumor growth, evidenced by cancerization of the intrahepatic bile ducts. Background liver parenchyma was notable for changes consistent with IgG4-SC. Surgical margins and lymph nodes were negative. Approximately 1 month after surgery (almost 1 year after initial presentation), the patient was started on adjuvant capecitabine chemotherapy and immunosuppressive therapy for IgG4-SC was eventually discontinued (Figs. 5-7).

DISCUSSION

The unique clinical course and rapid subsequent diagnosis of malignancy following initial IgG4-SC diagnosis differentiates this case from previously reported cases on IgG4-SC and cholangiocarcinoma. This case report distinctively highlights the particular challenges of diagnosis and management unique to this condition and furthermore, emphasizes the uncertainty of long-term outcomes and risk for malignancy – factors critical for clinicians involved in the management of IgG4-SC.

Steroids are the mainstay of treatment for IgG4-SC with reported treatment response rates of up to 95%^4,5. Disease recurrence however is not uncommon. Patients must be closely monitored for jaundice, elevation in liver enzymes and IgG/IgG4, and bile duct restenosis. Best practices for maintaining remission and treating recurrence are not well-established. Reinitiation of steroids at higher doses is often the approach for recurrence. Steroid-sparing agents, such as rituximab and azathioprine, have been reported to be effective; however, data remains limited and further research is necessary to best determine the role of these agents⁶. As in this case, steroids were utilized as the initial therapy of choice, followed by initiation of azathioprine; however, there is little established guidance in further management. Inebilizumab, a monoclonal antibody that targets the CD19 antigen of B cells, was recently approved by the Food and Drug Administration (FDA) as the first treatment specifically indicated for IgG4-related disease. A recent multicenter randomized controlled trial found inebilizumab to significantly reduce risk of IgG4-related disease flares and promote disease remission when compared to placebo⁷. This treatment shows promise as a potential intervention that may alter the clinical course of such patients; however, further research is warranted to determine outcomes specific to IgG4-SC.

When managing IgG4-SC, exclusion of malignancy is imperative. This case proved to be especially challenging given numerous negative biopsies were obtained prior to liver resection demonstrating cholangiocarcinoma, likely arising in the setting of IgG4-SC. This complicated course raises the question, whether IgG4-SC places patients at risk for malignancy. The association between chronic inflammation and malignancy is well established⁸. Prior small retrospective studies suggest increased cancer risk, particularly pancreatic and bile duct malignancy, in IgG4-SC⁴. In a cohort study of 121 Japanese patients, age ≥65, male sex, and pancreas involvement were found to be significantly associated with malignancy⁹.

This case exemplifies the challenges of diagnosis and management of IgG4-SC and the potential risk of malignancy. Patients with IgG4-SC should be closely followed for treatment response, relapse, and malignancy. Further research, with prospective trials and large-scale studies, is necessary to establish how to best manage these patients and the role of inebilizumab and to better understand long-term outcomes of IgG4-SC.

Article information

Conflicts of Interest

The authors have no conflicts of interest to declare.

Ethics Statement

The University Hospitals Institutional Review Board (IRB) has determined this study to not be considered human subjects research and does not require IRB review and approval.

Funding Statement

Not applicable.

Data Availability

Not applicable.

Author Contributions

Data curation: GH, AH, ETOC, AS

Supervision: SNS

Writing - original draft: AH, GH

Writing - review & editing: GH, AH, ETOC, AS, LKB, AM, LMO, SNS

Figure 1.

Timeline of patient course inclusive of several hospital admissions, with imaging labeled in green and procedures/interventions labeled in blue. ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography; CT, computed tomography; PET, positron emission tomography; MRI, magnetic resonance imaging.

Figure 2.

Coronal T2-weighted image demonstrates extrahepatic biliary wall thickening with contrast enhancement on post-contrast images (yellow arrows). MRCP image before treatment reveals marked stricture of the common bile duct and associated upstream biliary dilation. Images before treatment are representative of initial imaging obtained on presentation. Follow-up images post corticosteroid treatment show significant improvement of extrabiliary wall thickening (orange arrows) on both coronal T2-weighted and post-contrast images. Post-treatment MRCP demonstrates improved common bile duct stricture (orange arrows) but dilation of extrahepatic and intrahepatic biliary ducts. MRCP, magnetic resonance cholangiopancreatography.

Figure 3.

MRI-ultrasound fusion guided biopsy targeting the lesion of the liver identified on previous imaging, as indicated by the brown square. MRI, magnetic resonance imaging.

Figure 4.

MRI of the liver prior to biopsy with red arrows approximating the region that was targeted. This area targeted on biopsy roughly corresponds to the region of the surgically resected tumor that was eventually confirmed to be cholangiocarcinoma. MRI, magnetic resonance imaging.

Figure 5.

(A) Damaged large intrahepatic bile duct with prominent periductal inflammation (hematoxylin-eosin, original magnifications ×20). (B) A higher magnification of the inflammatory infiltrate shows a prominent plasma cell component (hematoxylin-eosin, original magnifications ×200).

Figure 6.

An IgG4 immunostain highlights numerous IgG4 positive plasma cells (original magnifications ×400). IgG4, immunoglobulin G4.

Figure 7.

Moderately-differentiated adenocarcinoma (intrahepatic cholangiocarcinoma) involving the hepatic parenchyma (hematoxylineosin, original magnifications ×40).

References

• 1. Ghazale A, Chari ST, Zhang L, Smyrk TC, Takahashi N, Levy MJ, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology 2008;134:706−715.ArticlePubMed
• 2. Nakazawa T, Kamisawa T, Okazaki K, Kawa S, Tazuma S, Nishino T, et al. Clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2020 (revision of the clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2012). J Hepatobiliary Pancreat Sci 2021;28:235−242.PubMed
• 3. Drazilova S, Veseliny E, Lenartova PD, Drazilova D, Gazda J, Grgurevic I, et al. IgG4-related sclerosing cholangitis: rarely diagnosed, but not a rare disease. Can J Gastroenterol Hepatol 2021;2021:1959832. ArticlePubMedPMCPDF
• 4. Ali AH, Bi Y, Machicado JD, Garg S, Lennon RJ, Zhang L, et al. The long-term outcomes of patients with immunoglobulin G4-related sclerosing cholangitis: the Mayo Clinic experience. J Gastroenterol 2020;55:1087−1097.ArticlePubMedPDF
• 5. Tanaka A, Tazuma S, Okazaki K, Nakazawa T, Inui K, Chiba T, et al. Clinical features, response to treatment, and outcomes of IgG4-related sclerosing cholangitis. Clin Gastroenterol Hepatol 2017;15:920−926.e3.ArticlePubMed
• 6. Kamisawa T, Nakazawa T, Tazuma S, Zen Y, Tanaka A, Ohara H, et al. Clinical practice guidelines for IgG4-related sclerosing cholangitis. J Hepatobiliary Pancreat Sci 2019;26:9−42.ArticlePubMedPMCPDF
• 7. Stone JH, Khosroshahi A, Zhang W, Della Torre E, Okazaki K, Tanaka Y, et al. Inebilizumab for treatment of IgG4-related disease. N Engl J Med 2025;392:1168−1177.ArticlePubMed
• 8. Chiba T, Marusawa H, Ushijima T. Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation. Gastroenterology 2012;143:550−563.ArticlePubMed
• 9. Kurita Y, Fujita Y, Sekino Y, Watanabe S, Iwasaki A, Kagawa K, et al. IgG4-related sclerosing cholangitis may be a risk factor for cancer. J Hepatobiliary Pancreat Sci 2021;28:524−532.ArticlePubMedPDF

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References

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