Checkpoint inhibitor-induced hepatotoxicity: Role of liver biopsy and management approach

Abstract

Immunological checkpoint inhibitors (ICIs) have revolutionized therapy of many different malignanices. Concomitant immune-mediated adverse effects are common and can affect many organs such as the skin, lungs, gastrointestinal and endocrine organs as well as the liver. Liver injury has been reported in 3%-8% of patients with grade III-IV hepatitis in retrospective studies. The liver injury is characterized by hepatocellular injury resembling autoimmune hepatitis biochemically but not immunologically as patients with ICI induced hepatoxicity rarely have auto-antibodies or IgG elevation. The role for liver biopsy (LB) in patients with suspected liver injury due to ICIs is controversial and it is not clear whether results of a LB will change clinical management. LB can be helpful when there is diagnostic uncertainty and pre-existing liver disease is suspected. Although there are no distinctive histological features, the finding of granulomas and endothelitis may suggest a specific type of hepatitis induced by ICIs. The natural history of hepatotoxicity of ICI therapy is not well known. Recent studies have demonstrated that 33%-50% of patients improve spontaneously with discontinuation of ICIs. In patients with jaundice and/or coagulopathy corticosteroids are used. The high doses of corticosteroids with 1-2 mg/kg/d of methylprednisolone recommended by the oncological societies are controversial. Recently it has shown that initial treatment with 1 mg/kg/d provided similar liver tests improvement which was also associated with a reduced risk of steroid-induced adverse effects in comparison with higher-dose regimens. Secondary immunosuppression mostly with mycophenolate mofetil has been reported to be helpful.

Keywords: Biologics; Checkpoint inhibitors; Drug-induced liver injury; Hepatotoxicity; Liver biopsy; hepatitis.

Figure 1

Pathological changes of drug-induced liver injury -induced by atezolizumab used for treatment of hepatocellular carcinoma (H&E 40×). A: Portal inflammation and interfase hepatitis; B: Focal lobular necrosis; C: Frequent lobular acidophilic bodies; D: Ductal damage and migration of inflammatory cells into ductal epithelium; E: Hepatocyte rosettes as a result of liver regeneration; F: Hepatocanalicular cholestasis and biliary plugs.

Figure 2

Proposal algorithm on the role of liver biopsy in immunological checkpoint inhibitors –induced drug-induced liver injury. ICIs: Immunological checkpoint inhibitors.