Irinotecan-Induced Steatohepatitis: Current Insights

Abstract

The hepatotoxicity of irinotecan is drawing wide concern nowadays due to the widespread use of this chemotherapeutic against various solid tumors, particularly metastatic colorectal cancer. Irinotecan-induced hepatotoxicity mainly manifests as transaminase increase and steatosis with or without transaminase increase, and is accompanied by vacuolization, and lobular inflammation. Irinotecan-induced steatohepatitis (IIS) increases the risk of morbidity and mortality in patients with colorectal cancer liver metastasis (CRCLM). The major risks and predisposing factors for IIS include high body mass index (BMI) or obesity, diabetes, and high-fat diet. Mitochondrial dysfunction and autophagy impairment may be involved in the pathogenesis of IIS. However, there is currently no effective preventive or therapeutic treatment for this condition. Thus, the precise mechanisms underlying the pathogenesis of IIS should be deciphered for the development of therapeutic drugs. This review summarizes the current knowledge and research progress on IIS.

Drug‐Drug Interactions and Disease Status Are Associated With Irinotecan‐Induced Hepatotoxicity: A Cross‐Sectional Study in Shanghai

“…This may be related to the different judgment criteria of irinotecan‐induced hepatotoxicity. The irinotecan‐induced steatohepatitis has been known to be a clinicopathological symptom of irinotecan, and includes inflammation and hepatocyte damage with or without transaminase increase 31,43,44 . However, in our study, given the clinical significance, irinotecan‐induced hepatotoxicity was defined as grade ≥I hepatotoxicity according to National Cancer Institute CTCAE 4.0, like the studies of Han et al 45 and Jung et al 46 …”

“…The irinotecan-induced steatohepatitis has been known to be a clinicopathological symptom of irinotecan, and includes inflammation and hepatocyte damage with or without transaminase increase. 31,43,44 However, in our study, given the clinical significance, irinotecan-induced hepatotoxicity was defined as grade ≥I hepatotoxicity according to National Cancer Institute CTCAE 4.0, like the studies of Han et al 45 and Jung et al 46 The active metabolite of irinotecan, SN-38, is known to be a substrate of organic anion-transporting polypeptide and ABC drug transporters. 1 Several ABC transporters (ie, ABCC1, ABCC2, ABCB1, and ABCG2) regulate the hepatic and biliary efflux of irinotecan metabolites.…”

“…On the premise of the same cumulative dose, the 8‐day irinotecan regimen had a higher incidence of hepatotoxicity than the 4‐day regimen in a phase I trial; nevertheless, the study did not elaborate on the association between the cumulative cycle and adverse reactions 30 . Long‐term or high‐dose administration of irinotecan may damage the liver parenchyma, thus resulting in hepatotoxicity 3,30–33 . This finding indicated that the cumulative dose of irinotecan (5‐9 cycles) as a risk factor for irinotecan‐induced hepatotoxicity was an actual effect rather than a coincident finding.…”

“…30 Long-term or high-dose administration of irinotecan may damage the liver parenchyma, thus resulting in hepatotoxicity. 3,[30][31][32][33] This finding indicated that the cumulative dose of irinotecan (5-9 cycles) as a risk factor for irinotecan-induced hepatotoxicity was an actual effect rather than a coincident finding. In this study, we demonstrated that the cumulative dose of irinotecan (5-9 cycles) significantly increased the risk of hepatotoxicity, whereas the longer treatment duration (≥10 cycles) of irinotecan decreased the hazard of time to hepatotoxicity.…”

“…Multiple studies have demonstrated that the use of irinotecan was linked to the development of hepatotoxicity and in particular nonalcoholic steatohepatitis. 3,31 Nonalcoholic steatohepatitis is thought to be the hepatic manifestation of insulin resistance and the metabolic syndrome. 3 Han 31 reported that the development of irinotecan-induced steatohepatitis could be affected by many confounding factors, including high body mass index or obesity, diabetes, and highfat diet.…”