Background
Pembrolizumab is a monoclonal antibody, a second-generation immune checkpoint inhibitor, that inhibits the PD-1 surface receptor. PD-1 receptor is expressed mainly on T lymphocytes, recognises and binds the endogenous ligand PD-L1, and its activation has an inhibitory effect on the T cell response, inducing immune tolerance and preventing autoimmunity. However, immune checkpoints can also be hijacked by cancer cells if they express this ligand, developing a tolerant microenvironment for tumour growth [1]. So, these drugs can restore antitumour immunity, prevent immune escape, and promote tumour cell death [1,2]. Pembrolizumab is used to treat cancers that express the PD-L1 protein, such as non-small cell lung cancer, melanoma and Hodgkin lymphoma [3,4].
On the other hand, immune checkpoint inhibitors can cause excessive activation of the immune system, and this can lead to immune-related adverse events (irAE) [1], which have been reported to occur in 70% of patients treated with anti-PD-1/PD-L1 [5]. Nevertheless, immune-mediated cholangitis is an uncommon form of irAEs for any type of immune checkpoint inhibitor. As for pembrolizumab, immune-related hepatotoxicity is reported in 2%–10% of patients with case reports of vanishing bile duct syndrome, subacute biliary injury, and immune cholangitis [6].
Clinical Perspective
The median duration to the onset is 11–22 weeks. Abdominal pain is the most common symptom, followed by fever and jaundice [2], accompanied by a significant elevation of biliary enzymes relative to hepatic enzymes [7].
Imaging Perspective
Both contrast-enhanced MRI and computed tomography (CT) scans are useful in the evaluation of the bile tract [7]. Common findings are non-obstructive intrahepatic and extrahepatic bile duct dilatation, or stenosis of bile duct lumen, which could be segmental or diffuse; enhancement, hypertrophy, and irregularity of bile duct wall [6–8]; and changes of the adjacent structure, such as gallbladder oedema, gallbladder wall thickening and Glisson’s sheath oedema [7]. Contrast-enhanced MRI with MR cholangiopancreatography offers the most comprehensive evaluation of biliary stricture [7].
In our case, the new findings in CT were compatible with cholangitis, probably immune-mediated secondary to treatment with pembrolizumab.
Regarding the role of pathological anatomy, liver biopsy is considered in selected cases [4], in which it is necessary to exclude other causes such as immune-mediated hepatitis, autoimmune cholangitis (PBC, PSC, IgG4 cholangiopathy) or malignant disorders [7], or when the classification of inflammatory activity is needed [4].
Outcome
Corticosteroids are the mainstay of treatment, but the response rate is low at about 11.5% [2]. The application in the early stage is to control the inflammation induced by immune checkpoint inhibitors [7]. On the other hand, ursodeoxycholic acid (UDCA) may be a potential additional treatment, for its cytoprotective, antiapoptotic and immunomodulatory effects [3,7].
In our patient, pembrolizumab was discontinued, and prednisone 80 mg was prescribed, with a subsequent descending regimen of 10 mg less every week. Although immune-mediated cholangitis is relatively steroid-resistant, in our case, after a few days taking prednisone, the radiating pain in the RUQ disappeared, and liver enzyme values decreased in a few weeks.
Three months after the initial scan, another CT scan was performed, showing a normalization of the intrahepatic bile duct (Figure 3a) and a decrease in the enhancement of the intra- and extrahepatic bile duct (Figures 3b and 3c) compared to the previous study.
As the use of immune checkpoint inhibitors and, consequently, irAEs increases, awareness of this condition is required to successfully diagnose and treat them [1].
Teaching Points
It is important to be aware of the irAE when evaluating an imaging study of a patient in treatment with immune checkpoint inhibitors. In the case of immune-mediated cholangitis, common findings are non-obstructive intrahepatic and extrahepatic bile duct dilatation, or stenosis of bile duct lumen, and enhancement, hypertrophy, and irregularity of bile duct wall.
All patient data have been completely anonymised throughout the entire manuscript and related files.
