CDK4/6 inhibitor liver injury: zone 3 necrosis, cholangitis, and recovery on withdrawal

Design

Retrospective single-centre case series

Population

7 women with metastatic breast cancer on CDK4/6 inhibitors with biopsied liver injury

Primary outcome

Histological pattern and resolution

Effect

Severe acute hepatitis in 5 of 7; zone 3 necrosis in all acute cases; all normalised after withdrawal

A single-centre series described seven women with metastatic breast cancer who had liver biopsies for raised enzymes while on a CDK4/6 inhibitor (ribociclib in six, palbociclib in one) between 2020 and 2024. All had a RUCAM causality score of at least 6 and other causes excluded.

Enzymes rose a mean of 60 days after starting (range 20 to 114). Five biopsies showed severe acute hepatitis, one mild lobular hepatitis and one subacute hepatitis with early fibrosis. Every acute biopsy had perivenular (zone 3) confluent necrosis, three with bridging necrosis; all had portal inflammation and five had lymphocytic cholangitis. Three patients were ANA-positive, but none had the histology of autoimmune hepatitis.

All seven normalised after the drug was stopped, a mean of 63 days from peak, and six were switched successfully to another agent.

For the pathologist, the value is a recognisable pattern: in a woman on a CDK4/6 inhibitor, zone 3 necrosis with lymphocytic cholangitis should prompt a drug-induced injury comment, and a positive ANA should not by itself push the report towards autoimmune hepatitis.

• Ask for the drug history in any liver biopsy from a patient with metastatic breast cancer.
• Zone 3 confluent necrosis with lymphocytic cholangitis fits CDK4/6 inhibitor injury.
• A positive ANA did not mean autoimmune hepatitis in this series; weigh the histology.
• Note in the report that the pattern is compatible with drug-induced injury, so the oncologist considers withdrawal.
• Injury appeared about two months after starting, within a range of 3 to 16 weeks.

Why it matters

A pathologist who recognises the pattern can save a patient from steroids for a mistaken autoimmune hepatitis.

Don't overread it

This is a seven-patient series from one centre; it describes the pattern, not its frequency.

The statistics, in plain English

Seven cases describe a pattern; they cannot say how often it occurs or whether every case looks like this.

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