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.

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma and Their Hepatic-Related Side Effects: A Review

“…Depending on the clinical presentation, hepatic ultrasound with Dopplers or cross-sectional imaging can be helpful to rule out pathologies, such as malignancy progression or portal vein thrombosis [ 64 , 65 , 66 , 67 , 68 ]. There is no general consensus regarding the necessity of a liver biopsy, but it tends to have more utility as the grade of ICH increases [ 69 ]. However, these patients also tend to be at a higher risk for procedures, so this decision should be tailored to the overall clinical picture.…”

“…For those that do undergo a liver biopsy, there is no pathognomonic finding for ICH. The most common histologic findings show that panlobular inflammation is consistent with acute hepatitis along with the foci of centrilobular necrosis, periportal inflammation, and perivenular infiltrate with endothelialitis [ 69 , 71 ].…”

Immune Checkpoint Inhibitor-Induced Liver Injury

“…50 The risk of biopsy should be balanced with the potential benefit of diagnostic and staging information it would yield in an individualized approach guided by multidisciplinary discussion. 59,61 Guideline-Based Management…”

Checkpoint inhibitor-induced gastritis followed by delayed severe hepatitis in a patient with lung metastases of head and neck squamous cell carcinoma: a case report

“…The patient was negative for the antinuclear antibody and antimitochondrial antibody. Although we did not conduct liver biopsy whose role in patients with suspected liver injury due to ICIs is controversial (7), the immunological origin of delayed severe hepatitis was strongly suspected based on the abovementioned test results and the development of delayed severe hepatitis during the treatment of pembrolizumab-induced gastritis. Hence, pulse corticosteroid therapy with intravenous methylprednisolone (1,000 mg/day) was administered for 3 days, followed by cotreatment with oral prednisolone (2 mg/kg/day) and oral mycophenolate mofetil (MMF) (2,000 mg/day) due to…”