Analysis of Risk Factors for Hepatotoxicity Induced by Immune Checkpoint Inhibitors

Abstract

Although hepatotoxicity induced by immune checkpoint inhibitors (ICPIs) can cause severe clinical complications, the risk factors associated with hepatotoxicity have rarely been investigated. The purpose of this study was to determine the potential risk factors for the incidence of hepatotoxicity and for time to ICPI-induced hepatotoxicity. Patients who received ICPIs (atezolizumab, nivolumab, pembrolizumab, and ipilimumab) were included in this retrospective 2-center study. Collected data included sex, age, body weight, body surface area, Eastern Cooperative Oncology Group performance status, underlying disease, liver metastasis, programmed cell death ligand-1 expression, interval from previous chemotherapy, and concomitant drug use. Among the 194 patients, patients who experienced hepatotoxicity after ICPI administration was 64.4% (n=125) in all grade and 10.8% (n=21) in grade III or higher. Multivariate analysis showed that patients aged 30–50 and 50–70 years had increased risks of hepatotoxicity by 4.9-fold (95% confidence interval, 1.3–18.0) and 2.7-fold (95% confidence interval, 1.3–5.5), respectively, compared with those older than 70 years. The use of acetaminophen increased the occurrence of hepatotoxicity by 2.1 times; the attributable risk was 53.2%. Male patients and patients younger than 65 years had around 1.5-fold increased hazard of time to reach hepatotoxicity. Patients treated with 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors had a 4.7-fold higher risk of grade III–IV hepatotoxicity compared with those without HMG-CoA reductase inhibitors; the attributable risk was 78.8%. In conclusion, close monitoring of liver function is recommended, especially in male patients, patients younger than 65 years old, and when there is concomitant use of hepatotoxic drugs including acetaminophen and HMG-CoA reductase inhibitors.

Hepatotoxicity Induced by Biological Agents: Clinical Features and Current Controversies

“…Although hepatotoxicity may manifest as early as 7 days, it usually occurs between 4 and 12 weeks after drug administration. 32 , 33 Diagnosis of ICI-induced liver injury requires excluding other causes of DILI and underlying liver diseases that may occur with any type of hepatotoxicity. 34 An asymptomatic increase of liver tests is a widespread event linked to these agents and usually represents an incidental finding.…”

Drug-Induced Liver Injury: Highlights and Controversies in the Recent Literature

“…Tyrosine kinase inhibitors are another class of chemotherapeutic agents well known to cause hepatotoxicity. In a large literature review of all articles published in English from 2000 to 2018, Houron et al evaluated 29 FDA-approved Cho et al [116] Korean study excluding HCC and elevated AST at baseline Liver metastases? Li et al [117] Overall, metastatic disease not a risk factor Rechallenge with combination therapy of anti-CTLA-4 and anti-PD1…”

Mechanisms of immune checkpoint inhibitor-mediated liver injury

“…ILICI differs from direct and idiosyncratic DILI (IDILI) based on the underlying mechanism, clinical signs, symptoms, and management 1 , 64 . The incidence of ILICI varies depending on multiple risk factors such as type and dosage of ICI, monotherapy, or combination therapy (with other ICIs or small molecule inhibitors), genetic predisposition, pharmacotherapy, exposure to acetaminophen, and statins 65 . Younger age, male sex, and pre-existing co-morbidities such as autoimmune diseases have been shown to influence the incidence, time of onset and grade of hepatotoxicity 65 , 66 , 67 , 68 .…”