Grade 3 immune-mediated hepatitis on pembrolizumab in MSI-high colorectal cancer
A 44-year-old woman with Lynch syndrome and metastatic colorectal cancer (MSI-high, RAS/BRAF wild-type) began second-line pembrolizumab after progression on FOLFOX plus bevacizumab. At the 12-week scan she had a partial response, with her largest liver metastasis shrinking from 42 mm to 19 mm, and CEA falling from 210 to 34 µg/L. She now presents two weeks after cycle 4 with fatigue and mild right upper quadrant discomfort but no fever. She drinks no alcohol and has started no new medicines, supplements or herbal products. Examination is unremarkable apart from mild jaundice. Bloods: ALT 412 U/L (ULN 40), AST 388 U/L, ALP 180 U/L, bilirubin 28 µmol/L, INR 1.1, albumin 38 g/L. Viral serology: HBsAg negative, anti-HBc negative, HCV RNA negative, HEV IgM negative; CMV and EBV PCR negative. CT shows stable liver metastases with no biliary dilatation. ECOG performance status is 0.
1. How do you grade and investigate this, and what treatment do you start today?
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Working diagnosis: grade 3 immune-mediated hepatitis. ALT 412 U/L is roughly 10× ULN, which is grade 3 (grade 3 is >5–20× ULN); bilirubin 28 µmol/L is about 1.7× ULN. The pattern is hepatocellular (ALT > ALP), the INR and albumin are preserved, and there is no biliary dilatation on CT. This fits checkpoint-inhibitor hepatitis, but the diagnosis remains one of exclusion.
Exclusions to complete now:
- Viral: hepatitis A, B, C and E, CMV, EBV, HIV. The serology already sent covers most of this.
- Drug-induced: specifically ask about paracetamol, over-the-counter remedies and herbal products again, since patients often do not count these as medicines.
- Vascular: portal vein thrombosis - ask the radiologist to review the portal phase specifically.
- Tumour: progression or new liver lesions; the CT shows stable metastases.
- Autoimmune: ANA, anti-smooth muscle antibody and IgG, although these do not exclude immune hepatitis.
- Liver biopsy is not needed to start treatment, but should be considered if the diagnosis is uncertain or there is no improvement within 72 hours.
Management today: hold pembrolizumab. Start prednisolone 1 mg/kg/day (or intravenous methylprednisolone 1 mg/kg if absorption is a concern). Monitor LFTs, glucose, blood pressure and infection screen every 24–48 hours. Do not use infliximab - it is hepatotoxic and has been associated with fatal outcomes in immune hepatitis.
2. Seventy-two hours later she is more jaundiced: ALT 620 U/L, bilirubin 45 µmol/L, despite prednisolone 1 mg/kg. What now?
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This is steroid-refractory hepatitis and needs escalation, not simply more of the same.
Before escalating, re-check the basics:
- Confirm the steroid has actually been taken and absorbed; if there is vomiting or poor absorption, switch to intravenous methylprednisolone.
- Re-run the differential: sepsis, new drugs, biliary obstruction, portal vein thrombosis, and CMV/EBV reactivation with repeat PCR.
- Review the trend rather than a single value; a doubling over 72 hours despite adequate steroids is significant.
Escalation:
- Add mycophenolate mofetil 500 mg twice daily, increasing to 1 g twice daily as tolerated. It is preferred over infliximab in hepatitis because infliximab itself can cause drug-induced liver injury.
- If there is no response after a further 1–2 weeks, consider tacrolimus or anti-thymocyte globulin in consultation with hepatology and an immune-toxicity expert. Azathioprine is an alternative but has a slower onset.
- Arrange a liver biopsy at this point: it helps distinguish immune hepatitis from drug injury, infiltration or infection, and guides the intensity of immunosuppression.
- Supportive care: avoid all hepatotoxic drugs, monitor for encephalopathy and coagulopathy, check IgG and consider prophylaxis against Pneumocystis jirovecii if immunosuppression is prolonged.
- Taper steroids only once ALT is falling and below 3× ULN, over at least 4–6 weeks. Abrupt withdrawal causes rebound hepatitis.
3. She recovers to grade 1 hepatitis after 8 weeks. She asks whether she can restart pembrolizumab, given how well the cancer responded. How do you decide?
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Guideline position: grade 3 hepatitis is a relative contraindication to rechallenge and grade 4 is a permanent contraindication. The decision must be individualised rather than rule-driven.
Factors in favour of cautious rechallenge here:
- MSI-high colorectal cancer with an objective partial response and a large CEA fall - checkpoint inhibition is her most active option, and chemotherapy has already failed.
- No evidence of liver failure: normal INR, albumin 38 g/L.
Factors against:
- Toxicity severe enough to require second-line immunosuppression, which raises both the risk of recurrence and the risk of opportunistic infection.
- Rechallenge carries a substantial risk (roughly 25–50%) of the same immune-related adverse event recurring.
Practical approach:
- Wait until hepatitis has resolved to grade ≤1 and prednisolone has been tapered to ≤10 mg/day.
- Hold a shared decision-making conversation that names the risk of fulminant hepatitis and the need for close monitoring, and document it.
- If she chooses rechallenge, monitor LFTs every 2 weeks initially and restart steroids at the first sign of a rise.
- If she declines or rechallenge fails, discuss regorafenib or TAS-102, acknowledging their modest activity in MSI-high disease, and involve hepatology.
- Do not rechallenge while she is still on high-dose steroids.