The advent of checkpoint inhibitor immunotherapy has rapidly changed the landscape of the management of cancers. However, its use has also been associated with the rise of immunotherapy-related adverse effects (irAEs). There has been an emergence in recent years of sclerosing cholangitis as a mimic of the classical autoimmune hepatitis irAE. We present a case of a 59-year-old female who received pembrolizumab for stage IV lung adenocarcinoma and developed an immune checkpoint inhibitor (ICI) related sclerosing cholangitis diagnosed on radiological and histopathological grounds. This patient was successfully treated with prednisone, azathioprine, and ursodeoxycholic acid. Clinicians should be aware that ICI sclerosing cholangitis is a rare hepatic complication of ICIs. The workup for ICI-associated mixed liver function test derangement that is steroid resistant should include a magnetic resonance cholangiopancreatography to investigate for changes of sclerosing cholangitis and a liver biopsy if the magnetic resonance cholangiopancreatography is nondiagnostic.

© 2023 The Author(s). Published by S. Karger AG, Basel

Immune checkpoint inhibitors (ICIs) have been used in the management of various cancers including the lung, skin, bowel, kidney, bladder, and leukemias among various other cancers. Common adverse reactions of ICIs include rash, thyroid dysfunction, and diarrhea [1]. Biliary system complications are rare, with an incidence of 1–3%, and their clinicopathologic features and ideal management are yet to be established [2]. Much more common is a transaminitis with a rate of up to 7% with single-agent ICI [3]. Here, we report a patient with stage IV lung adenocarcinoma treated with pembrolizumab, who developed ICI sclerosing cholangitis. High-dose prednisone, azathioprine, and ursodeoxycholic acid were employed which resulted in improvement of cholestatic liver function test (LFT) derangement.

A 59-year-old Caucasian female with no background of liver disease presented with stage IV lung adenocarcinoma with extensive bilateral lung, cerebellar, and lymph node metastases. She had a past medical history of COPD secondary to heavy smoking and poorly controlled hypertension. The patient’s adenocarcinoma had a PD-L1 score of 60–70%, a Ki67 index of 40–50%, a KRAS G12V mutation and was positive for TTF1 on immunohistochemical staining. The patient received pembrolizumab 3 weekly which resulted in a reduction in tumor size after 2 cycles. However, after 6 cycles of pembrolizumab, the patient had developed asymptomatic grade 4 (National Cancer Institute Common Toxicity Criteria) LFT derangement (GGT 1690 U/L, ALP 2696 U/L) with an associated grade 3 hepatitis (ALT 235 U/L, AST 252 U/L). CT abdomen and pelvis were arranged to exclude hepatic metastatic disease but instead demonstrated diffuse wall thickening of the biliary tree suggesting chronic cholangitis with the common bile duct dilated up to 10 mm. Significantly, there was no evidence of intrahepatic biliary dilatation. Pembrolizumab was withheld, and the patient was commenced on oral prednisone 50 mg which resulted in an improvement of the transaminitis within 4 weeks (ALT 35 U/L, AST 33 U/L), however, with persisting cholestatic dysfunction (GGT 1195 U/L, ALP 938 U/L). Pembrolizumab was restarted and the patient redeveloped asymptomatic cholestatic derangement (ALP 988 U/L, GGT 1363 U/L) 10 days later. A magnetic resonance cholangiopancreatography (MRCP) (Fig. 1) demonstrated no choledocholithiasis but revealed subtle changes involving the intrahepatic ducts, dilated common bile duct to 9 mm with associated wall thickening, and heterogeneous arterial enhancement of the liver, in keeping with cholangitis. Given her asymptomatic state and presence of cerebral metastases, the decisions at this stage were to continue monitoring the patient’s progress and continue with the next cycle of pembrolizumab as the initial impression was cholestatic variant ICI hepatitis. Four days later, there was worsening of the cholestatic LFT derangement (GGT 2563 U/L, ALP 1783 U/L) and reemergence of a mild transaminitis (ALT 159 U/L, AST 105 U/L) and mild hyperbilirubinemia to 25 μmol/L. The patient was recommenced on oral prednisone (50 mg daily), and pembrolizumab was ceased. An infective (HBV, HCV, EBV, HPV, CMV) and autoimmune panel including serum immunoglobulin, IgG4, and autoantibodies (antinuclear antibodies, anti-mitochondrial antibody, smooth muscle antibody, anti-liver-kidney microsomal antibody) to investigate causes of LFT dysfunction were unremarkable. A liver biopsy (Fig. 2, 3) was performed given the intercurrent transaminitis. This demonstrated mixed portal inflammation, prominent ductular reaction with focal neutrophils, ductopenia, occasional small bile infarcts with absence of hepatic fibrosis. The portal tracts were expanded with edema and moderate inflammatory infiltrates of mainly lymphocytes with focal collections of neutrophils and eosinophils. These findings were consistent with the diagnosis of ICI sclerosing cholangitis. The cholestatic LFTs improved initially (GGT 2029 U/L, ALP 1438 U/L) but deteriorated at the end of 4 weeks of corticosteroid therapy (GGT 2357 U/L, ALP 1492 U/L), and the patient was commenced on azathioprine 50 mg and ursodeoxycholic acid 15 mg/kg daily which resulted in a significant improvement of cholestatic LFTs by 6 weeks (GGT 191 U/L, ALP 121 U/L). Upon restaging with MRI Brain and CT, the patient’s cerebellar metastases had resolved, and the lung lesions had reduced by 50%. Prednisone was successfully weaned, and azathioprine and ursodeoxycholic acid were continued indefinitely. There is no further intent to reintroduce pembrolizumab given the autoimmune episode and the excellent response. No side effects of corticosteroid therapy, azathioprine, or ursodeoxycholic acid were encountered in this patient. The CARE checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000530009).

MRCP. Dilated common bile duct to 9 mm with associated wall thickening and heterogeneous arterial enhancement of the liver.

Liver biopsy. CK7 – bile ductular proliferation, inflammation.

Liver biopsy. Inflammation, bile ductular proliferation, ductopenia, bile infarct, no fibrosis.

ICI sclerosing cholangitis can be considered as an immune-related hepatotoxicity. This condition was first reported to be an adverse effect of nivolumab in 2017 [4]. Since this discovery, various case reports have demonstrated that this complication can be featured with other ICIs including avelumab, pembrolizumab, and durvalumab [5]. The clinical manifestations of ICI sclerosing cholangitis include bile duct dilatation and wall thickness that develops after the commencement of immunotherapy [6]. The diagnostic criterion of this rare condition remains yet to be established [5]. Although not present in our case, various risk factors predispose the development of ICI hepatotoxicity including young age, ICIs combination therapy, and high AST level [7].

Kawakami et al. [6] noted in a case series that this condition was characterized by (1) localized extrahepatic bile duct dilation without obstruction, (2) diffuse hypertrophy of the extrahepatic bile duct wall, (3) a dominant increase in the biliary tract enzyme alkaline phosphatase and alanine aminotransferase, (4) normal or reduced levels of the serum immunological markers antinuclear antibody, anti-mitochondrial antibody, smooth muscle antibody, and immunoglobulin G4, (5) the pathological finding of biliary tract cluster of differentiation 8-positive (CD8) T cell infiltration from liver biopsy, and (6) a moderate to poor response to steroid therapy. These clinical manifestations were found in our patient after diagnostic investigations with an MRCP and liver biopsy. Our patient did not have any history of the biliary, hepatic, or pancreatic disease and there was no previous abdominal surgery that could explain alternative causes of the cholestatic derangement. Unfortunately, as this was an unfamiliar condition our initial impression was that the patient had cholestatic variant ICI hepatitis hence the patient was commenced on a rapid tapering dose of corticosteroids with resumption of pembrolizumab thereafter. This had resulted in worsening of the cholestatic LFTs. At this stage, the differential diagnoses considered included ICI autoimmune hepatitis (cholestatic variant), ICI sclerosing cholangitis, ICI overlap syndrome (autoimmune hepatitis and sclerosing cholangitis), granulomatous hepatitis, and viral infection. We believe liver biopsies should be performed where there is a significant cholestatic injury alongside the transaminitis to differentiate these pathologies. The biopsy resulted in a change of management and a longer period of immunosuppression.

The management of ICI sclerosing cholangitis is unclear. As with all severe immunotherapy-related adverse effects, cessation of immunotherapy is important. In contrast to ICI hepatitis, which can also cause derangement of LFTs in a cholestatic picture, ICI sclerosing cholangitis is typically steroid resistant, with a systematic review demonstrating that only 11.5% cases achieved normalization of LFTs and up to 30% appeared to show no response [6]. The predictors associated with a good response to corticosteroids are unclear. A case report also noted that cholestatic liver injury can also improve and later deteriorate despite not having re-exposure to the immunotherapy [8]. Studies have also used other immunosuppressive medications such as mycophenolate, tacrolimus, and azathioprine [5], although outcomes also remain poor. Ursodeoxycholic acid has also demonstrated efficacy in the management of this condition [9]. In our case, the patient demonstrated complete improvement in the cholestatic injury with a combination of prednisone, azathioprine, and ursodeoxycholic acid.

1. ICI sclerosing cholangitis is a rare hepatic complication of ICIs.

2. The workup for ICI-associated mixed LFT derangement that is steroid resistant should include an MRCP to investigate for changes of sclerosing cholangitis and a liver biopsy if the MRCP is nondiagnostic.

Dr. Harry Luske, Pathologist, Orange Base Hospital.

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

On behalf of all authors, the corresponding author states that there is no conflict of interest.

The author(s) received no financial support for the research, authorship, and/or publication of this article.

All authors have contributed significantly to this work, and all authors agree regarding the content of the manuscript. Ian Liang: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing. Geoffrey Chu: data analysis and interpretation and manuscript writing. Robert Zielinski: conception and design, provision of patient, manuscript writing, and final approval of manuscript contributed to collection.

The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary material. Further inquiries can be directed to the corresponding author.

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