Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) improve clinical outcomes in patients suffering from different types of cancer. Liver toxicity is one of the immune-related adverse events associated with immunotherapy; although not common, its management is challenging as it is extremely heterogeneous in terms of presentation and severity. Differences in the development and evolution of ICI-related toxicity in healthy or cirrhotic livers have not yet been elucidated. Assessing causality is key to diagnosing ICI-induced liver toxicity; liver biopsies can assist not only in the differential diagnosis but also in assessing the severity of histological liver damage. The current classification of severity overestimates the grade of liver injury and needs to be revised to reflect the views of hepatologists. Spontaneous improvements in ICI-related liver toxicity have been reported, so corticosteroid therapy should probably be individualised not systematic. The reintroduction of ICIs in a patient with previous immune-mediated hepatitis may be possible, but the risk/benefit ratio should be considered, as the risk factors for hepatitis recurrence are currently unclear. The management of these patients, requiring a balance between efficacy, toxicity and specific treatments, necessitates multidisciplinary collaboration. The incidence of immune-related liver toxicity will continue to rise based on the increasing use of ICIs for most cancers, mandating improved understanding and management of this complication.

Keywords: AIH, autoimmune hepatitis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, anti-mitochondrial antibodies; ANA, anti-nuclear antibodies; ASMA, anti-smooth muscles antibodies; AST, aspartate aminotransferase; CTLA-4, cytotoxic T lymphocyte-associated protein 4; Corticosteroid therapy; DCR, disease control rate; DILI, drug-induced liver injury; GGT, gamma-glutamyltransferase; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; INR, international normalised ratio; Immune-mediated hepatitis; Immunotherapy; Liver biopsy; MMF, mycophenolate mofetil; ORR, objective response rate; OS, overall survival; PD-1, programmed cell death 1; PD-L1-2, programmed cell death ligands 1-2; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; UDCA, ursodeoxycholic acid; ULN, upper limit of normal; anti-LC1, anti-liver cytosol type-1 antibodies; anti-LKM, anti-liver-kidney microsomal antibodies; anti-SLA, anti-soluble liver antigen antibodies; irAE, immune-related adverse event; trAE, treatment-related adverse event.

Fig. 1

Distribution of irAEs for organ categories according to treatment in the main clinical trials of ICIs. Patients were treated with anti-PD-1 + anti-CTLA-4,^,, anti-CTLA-4^,,, and anti-PD-1.^,, The values quoted are mean irAE rates of clinical trials as a whole. CTLA-4, cytotoxic T lymphocyte-associated protein 4; Endoc, endocrine (hypo/hyper-thyroidism); GI, gastrointestinal (diarrhoea); ICI, immune checkpoint inhibitors; irAEs, immune-related adverse events; Liver (increased alanine aminotransferase); PD-1, programmed cell death 1; PD-L1, programmed cell death 1 ligand 1; Skin (rash).

Fig. 2

Distribution of ALT increase in patients treated for non-HCC malignancies and HCC according to treatment in the main clinical trials of ICIs. Patients with non-HCC malignancies were treated with anti-CTLA-4 anti-PD-1, anti-PD-1 + TKI, anti-PD-1 + anti-CTLA-4, while patients with HCC were treated with anti-PD-L1 + anti-VEGF, anti-PD-1, anti-PD-1 + anti-CTLA-4, anti-CTLA-4. (A) Distribution of ALT increase of all grades in non-HCC patients; (B) Distribution of ALT increase of grade ≥3 in non-HCC patients; (C) Distribution of ALT increase of all grade in HCC patients; (D) Distribution of ALT increase of grade ≥3 in HCC patients. ALT, alanine aminotransferase; CTLA-4, cytotoxic T lymphocyte-associated protein 4; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; PD-1, programmed cell death 1; PD-L1, programmed cell death 1 ligand 1; TKI, tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor.

Fig. 3

Liver biopsies of patients treated with anti-CTLA-4 or anti-PD-1 alone or in combination. (A) Microgranulomatous hepatitis (HES ×120); (B) Hepatitis with fibrin-ring granulomas (HES ×370); (C) Non-granulomatous lobular hepatitis (HES ×190); (D) Lobular and portal hepatitis with endotheliatis (HES ×190). CTLA-4, cytotoxic T lymphocyte-associated protein 4; PD-1, programmed cell death 1.

Fig. 4

Liver biopsies of patients treated with anti-PD-L1 and with combination of anti-PD-1 and anti-CTLA-4. (A) Destructing cholangitis (HES ×400); (B) Granulomatous cholangitis HES ×300. CTLA-4, cytotoxic T lymphocyte-associated protein 4; PD-1, programmed cell death 1; PD-L1, programmed cell death 1 ligand 1.

Fig. 5

Proposal for the management of patients who experience ICI-related grade ≥3 hepatitis. ∗Steroid tapering proposal see Table S2. ∗∗Wait until MMF and steroid discontinuation. Resume anti-PD-1 or anti-PD-L1 alone; permanently discontinue anti-CTLA-4; if UDCA administered resume ICI under UDCA. CTLA-4, cytotoxic T lymphocyte-associated protein 4; ICI, immune checkpoint inhibitor; LFTs, liver function tests; MMF, mycophenolate mofetil; PD-1, programmed cell death 1; PD-L1, programmed cell death 1 ligand 1; UDCA, ursodeoxycholic acid.