CDK4/6 inhibitor-induced liver injury: Clinical phenotypes and role of corticosteroid treatment.

Background & Aims: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are the cornerstone of systemic therapy for patients with hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer. In the various therapeutic studies with CDK4/6 inhibitors, elevations in liver tests were more frequent than in the control groups. The mechanism of CDK4/6 inhibitor-induced liver toxicity is not well understood; moreover, natural history and appropriate management are poorly described. Methods: We conducted a retrospective study, collecting cases of CDK4/6 hepatitis from the REFHEPS (Réseau Francophone pour l'étude de l'HEpatotoxicité des Produits de Santé) database. Results: In this study, we report on 22 cases of hepatitis induced by CDK4/6 inhibitors (ribociclib, n = 19 and abemaciclib, n = 3). According to the CTCAE classification, all hepatitis cases were grade 3 or 4. Twelve (54.6%) patients had a liver biopsy showing acute centrilobular hepatitis with foci of necrosis and lymphocytic infiltrate. Nine (40.9%) patients were treated with corticosteroids for resolution of hepatitis. In three cases, another CDK4/6 inhibitor could be resumed after resolution of the hepatitis without recurrence. Conclusions: CDK4/6 inhibitor-induced hepatitis is poorly described in the literature but there are several arguments pointing out that these drugs should be included in the DI-ALH (drug-induced autoimmune-like hepatitis) category. Impact and implications: This study highlights the clinical significance and hepatotoxic risks of CDK4/6 inhibitors, like ribociclib and abemaciclib, in HR+/HER2-metastatic breast cancer treatment. It underscores the necessity for enhanced hepatic monitoring and tailored management strategies, including corticosteroid intervention for unresolved hepatitis post-withdrawal. These findings are crucial for oncologists, hepatologists, and patients, guiding therapeutic decisions and indicating careful liver function monitoring during therapy. The utility of corticosteroids in managing drug-induced hepatitis and the feasibility of resuming CDK4/6 inhibitor therapy post-recovery are notable practical outcomes. Nonetheless, the study's retrospective nature and limited case numbers introduce constraints, underscoring the need for further research to refine our understanding of CDK4/6 inhibitor-associated hepatotoxicity.

Patients with chronic liver diseases are at risk for diabetes even before development of cirrhosis.

BACKGROUND AND AIMS: The prevalence of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) is higher in patients with cirrhosis, compared to control patients without liver disease. The exact mechanism for this is unknown but could include liver inflammation. In this study we investigate whether cirrhosis is the primum movens of IR or if impaired insulin sensitivity is already present in non-cirrhotic patients with chronic liver diseases. METHODS: Patients were recruited and divided into three groups: control (CTL), chronic liver disease without cirrhosis (CLD) and cirrhosis (CIR). In patients not taking pharmacological treatment for T2DM, IR was quantified using the homeostasis model assessment of insulin resistance (HOMA-IR). The proportion of patients with T2DM as well as HOMA-IR levels among different disease etiologies were recorded and compared. RESULTS: 532 patients were included in our study. Median glycemia and insulinemia and therefore HOMA-IR values were significantly different between the three cohorts (p-value <0.001): IR levels in CLD subjects lie between those seen in CTL and CIR subjects. The proportion of diabetic patients in the two case categories also differs (p-value = 0.027): one quarter of CLD subjects and one third of CIR patients suffer from T2DM. Finally, HOMA-IR levels vary according to disease etiology (p-value <0.001): metabolic steatosis and chronic viral hepatitis C are at greater risk than alcohol and other disease causes. CONCLUSION: CLD is already a predisposing factor to T2DM, regardless of the presence of CIR. CIR is a factor which elicits additional increase in insulin levels. Metabolic steatosis and hepatitis C are associated with more severe IR.