Nodular Regenerative Hyperplasia Associated With Immune Checkpoint Blockade

LoPiccolo, Jaclyn; Brener, Michael I.; Oshima, Kiyoko; Lipson, Evan J.; Hamilton, James P.

doi:10.1002/hep.30157

Cited by 21 publications

(15 citation statements)

References 5 publications

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“…Although pan‐lobular hepatitis was the most common pattern of liver injury, 50% of cases showed features of cholangiopathy, granulomatous hepatitis or bland cholestasis. In addition, two cases of pembrolizumab‐induced liver injury reported in the literature exhibited nodular regenerative hyperplasia or lobular hepatitis with microgranulomas and confluent necrosis . To our knowledge, no reports, including detailed liver biopsy findings, are available for atezolizumab‐related irAEs.…”

Section: Discussionmentioning

confidence: 99%

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Immune‐related adverse reactions in the hepatobiliary system: second‐generation check‐point inhibitors highlight diverse histological changes

et al. 2019

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Aims Immune check‐point inhibitors are known to cause immune‐mediated adverse liver injury, but our knowledge is mainly based on cases treated with ipilimumab or nivolumab. Methods and results Clinicopathological features of 10 patients with hepatobiliary adverse reactions caused by second‐generation drugs, pembrolizumab (n = 6) and atezolizumab (n = 4), were reviewed. Liver dysfunction developed during a median period of 3.5 weeks after administration of the check‐point inhibitor (3 days–1 year). Antinuclear antibodies were detected in two patients at a low titre (1/80), and serum IgG concentrations were also only mildly elevated in two patients. Liver biopsies showed panlobular hepatitis (n = 5), cholangiopathic changes (n = 2), granulomatous injury (n = 2) and bland cholestasis (n = 1). Two cases of cholangiopathy (both pembrolizumab‐treated) showed diffuse sclerosing cholangitis on imaging, and one also presented lymphocytic cholangitis resembling primary biliary cholangitis on biopsy. In two atezolizumab‐treated cases, Küpffer cells were hyperplastic and aggregated, forming microgranulomas. Confluent necrosis and eosinophilic or plasma cell infiltration were rare. On immunostaining, the ratio of CD8+/CD4+ cells was 12.2 ± 5.1, which was significantly higher than that in autoimmune hepatitis (2.7 ± 1.1; P < 0.001) or idiosyncratic drug‐induced liver injury (5.0 ± 1.1; P = 0.014). All patients responded to steroid therapy, but it was less effective in patients with sclerosing cholangitis. Conclusions Pembrolizumab and atezolizumab manifested not only lobular hepatitis but also sclerosing cholangitis, lymphocytic duct injury and granulomatous hepatitis, probably representing various impaired cellular functions in CD8+ lymphocytes and macrophages due to blockage of PD‐1–PD‐L1 interaction.

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Section: Discussionmentioning

confidence: 99%

“…However, those observations are based on irAEs caused by nivolumab and ipilimumab. A limited number of single‐case reports are available for hepatobiliary irAEs of second‐generation check‐point inhibitors …”

Section: Introductionmentioning

confidence: 99%

Immune‐related adverse reactions in the hepatobiliary system: second‐generation check‐point inhibitors highlight diverse histological changes

et al. 2019

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“…LoPiccolo et al (1) describe the very effective clinical management of severe portal hypertension associated with nodular regenerative hyperplasia (NRH), developing acutely during melanoma treatment with pembrolizumab. Pembrolizumab is a novel immunoglobulin G4 antibody targeting the antiprogrammed death-1 receptor on lymphocytes, and therefore physiologically serving as an immune check-point blocker.…”

Section: To the Editormentioning

confidence: 99%

Letter to the Editor: Is Nodular Regenerative Hyperplasia an Immune‐Mediated Phenomenon?

Hadžić

2019

Hepatology

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“…Expression of programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2), the major ligands for PD-1, is induced by IFN-γ, which appears to play a role in tumor immune evasion. (1) Blockade of the immunoregulatory pathway comprised of PD-1 and its ligands may break immune tolerance, thereby activating T cells against tumor and sinusoidal endothelial cells. Thus, we agree that so-called "idiosyncratic" cases of NRH that arise in association with certain drugs are likely to have substrate-specific genetic underpinnings.…”

Section: Replymentioning

confidence: 99%

“…(3) Finally, one report described NRH in adult sibling pairs from three unrelated families with no triggering factors in history and severe clinical phenotypes. (5) Although LoPiccolo et al (1) suggest the idiosyncratic nature of this rare complication in background of immune check blockade, we wonder whether patients with NRH should be subjected to formal immunological studies and the emerging large-scale genetic sequencing studies involving subtler immunological aberrations. Although NRH is likely a heterogeneous condition, it is conceivable that a proportion could have a verifiable underlying immune dysregulation.…”

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confidence: 99%