Severe everolimus-induced steatohepatis: a case report

Abstract

The mammalian target of rapamycin inhibitors are normally favored as immunosuppressant agents for solid organ transplantation such as kidney, liver or heart. Only in recent years have they been increasingly administered for the treatment of neuroendocrine tumors. Even though mammalian target of rapamycin inhibitors are known to exhibit specific side effects, everolimus-related severe hepatic steatosis has not as yet been described in the literature. We report the case of a 76-year-old man who developed severe hepatic steatosis within four weeks of treatment with everolimus as concomitant tumor therapy for a progressively growing neuroendocrine carcinoma of the ileum. A diagnosis of hepatic steatosis was established using computer tomography and fibroscan©. Other underlying causes for steatosis hepatis could be excluded. Further studies are warranted to explain the underlying mechanisms.

Dysfunction of estrogen-related receptor alpha-dependent hepatic VLDL secretion contributes to sex disparity in NAFLD/NASH development

“…Anti-estrogen such as tamoxifen and tormifene can reduce ERRα expression through suppressing ERα; whereas, rapamycin has been demonstrated to suppress hepatic ERRα activity in a post-translation manner by destabilizing the ERRα protein 43 . These three drugs are known clinically to increase NAFLD incidences 20 , 22 , 57 . While these three drugs act indirectly to reduce ERRα expression level, we proved that bona fide inverse agonist C29 exacerbates hepatosteatosis in HFD mice in consistence with a previous study 33 .…”

Livers with Constitutive mTORC1 Activity Resist Steatosis Independent of Feedback Suppression of Akt

“…These findings predict that the manipulation of Akt and mTORC1 can be exploited to develop novel strategies in the treatment of fatty liver disease. Clinical evidence in support of this concept comes from reports of treatment-related steatosis in patients exposed to rapamycin analogs prescribed for cancer therapy [ 34 ]. In contrast, leucine and other branched-chain amino acids are potent activators of mTORC1 [ 35 ], and dietary supplements with these amino acids have been reported to alleviate NAFLD and its associated metabolic syndrome [ 36 ].…”

Hepatotoxicity of targeted therapy for cancer

“…[80] Fatal hepatotoxicity has occurred after pazopanib treatment with acute cholestatic hepatitis with mild bile duct injury on biopsy, and after everolimus with features of severe steatosis. [81,82] Steatosis after everolimus was not associated with elevations in blood glucose or lipid levels, supporting that it was direct drug-induced liver injury. [82] varices, ascites and thrombocytopenia along with elevations in liver enzymes.…”

“…[81,82] Steatosis after everolimus was not associated with elevations in blood glucose or lipid levels, supporting that it was direct drug-induced liver injury. [82] varices, ascites and thrombocytopenia along with elevations in liver enzymes. Discontinuation of the ado-trastuzumab emtansine lead to complete and sustained resolution of these complications.…”