Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that can block inhibitors of T-cell activation and function and have shown remarkable effects in treating many cancers. Drugs targeting programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) have been approved as first- or second-line treatments for multiple malignancies, including melanoma, non-small cell lung cancer and hepatocellular cancer (HCC) [[1], [2], [3]]. However, ICIs can disrupt the self-tolerance of the immune system, which leads to adverse events (AEs), including immune-mediated hepatitis (IMH) [4]. The incidence of IMH is estimated to be between 1 % and 8 % depending on the type and dosage of drug [5]. It has been reported that CTLA-4 inhibitors have a higher risk of hepatotoxicity than PD-1 inhibitors and that ipilimumab use is a predictive risk factor for IMH [6]. Furthermore, combination ICI application is likely to increase the rates of hepatotoxicity. The presentation of IMH is heterogeneous, ranging from asymptomatic with only liver function test (LFT) abnormalities to severe or even fatal liver dysfunction. In most scenarios, the diagnosis of IMH can be made according to an abnormal LFT. However, liver biopsy is helpful in some complex clinical situations. It can estimate the possible cause of liver injury and classify the pattern of injury, providing information for tailored therapy. Previous studies have depicted different histological portraits of IMH [[7], [8], [9], [10], [11]]. We sought to further address the clinicopathological features of IMH in a large Chinese cohort.

Anti-angiogenic drugs, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, have been widely used in various tumors. They inhibit angiogenesis and tumor growth by targeting the vascular endothelial growth factor (VEGF) signaling pathway [12]. Currently, the combination of ICIs together with anti-angiogenic agents has been shown to be effective in multiple malignancies [3,[13], [14], [15]]. It has been reported that atezolizumab plus bevacizumab showed a better survival impact than sorafenib in patients with unresectable HCC [3]; thus, the combination of ICI and anti-angiogenic therapy has been approved as a first-line regimen for advanced HCC [16]. However, such a combination of ICI plus anti-angiogenic drugs might raise safety concerns, and it has been reported that nivolumab combined with sunitinib or pazopanib resulted in a high incidence of high-grade AE in patients with renal cell carcinoma [17]. The frequency of grade ≥ 3 hepatotoxicity in combined therapy with ICIs and anti-angiogenic agents ranges from 8 % to 60 % according to the specific type of regimen [18]. We wondered whether such combined medication might increase the risk of liver injury. The present research aimed to explore the clinicopathological characteristics of IMH caused by ICI therapy with or without anti-angiogenic drugs to better understand immune-related hepatotoxicity, which may be increasingly more frequently encountered in clinical scenarios.