Cited by 354Hepatocellular Carcinoma Treatment and PrognosisLiver Disease Diagnosis and TreatmentHepatitis C virus research

Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment

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Llovet, Josep M., Willoughby, Catherine E., Singal, Amit G., Greten, Tim F., Heikenwälder, Mathias, El-Serag, Hashem B., Finn, Richard S., Friedman, Scott L.·2023·Nature Reviews Gastroenterology & Hepatology

Abstract

Nonalcoholic fatty liver disease (NAFLD), including its more severe manifestation, nonalcoholic steatohepatitis (NASH), has a global prevalence of 20-25% and is a major public health problem. Its incidence is increasing in parallel to the rise in obesity, diabetes and metabolic syndrome. Progression from NASH to NASH-related hepatocellular carcinoma (HCC) (~2% of cases per year) is influenced by many factors, including the tissue and immune microenvironment, germline mutations in PNPLA3, and the microbiome. NASH-HCC has unique molecular and immune traits compared with other aetiologies of HCC and is equally prevalent in men and women. Comorbidities associated with NASH, such as obesity and diabetes mellitus, can prevent the implementation of potentially curative therapies in certain patients; nonetheless, outcomes are similar in patients who receive treatment. NASH-HCC at the early to intermediate stages is managed with surgery and locoregional therapies, whereas advanced HCC is treated with systemic therapies, including anti-angiogenic therapies and immune-checkpoint inhibitors. In this Review, we present the latest knowledge of the pathogenic mechanisms and clinical management of NASH-HCC. We discuss data highlighting the controversy over varying responses to immune-checkpoint inhibitors according to underlying aetiology and suggest that the future of NASH-HCC management lies in improved surveillance, targeted combination therapies to overcome immune evasion, and identifying biomarkers to recognize treatment responders.

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Crossref · 10.1038/s41575-023-00754-7

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Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Reprogramming of the liver microenvironment is a key feature of hepatocarcinogenesis, encompassing metabolic alterations of hepatocyte and immune cells, re-emergence of fetal-associated endothelial cells and altered inflammatory milieu.

    “Reprogramming of liver microenvironment is a key feature of hepatocarcinogenesis, which encompasses but not limited to metabolic alterations of hepatocyte and immune cells, re-emergence of fetal-associated endothelial cells and altered inflammatory milieu [10, 46, 65, 66].”

    From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [10]

    The Pathogenesis section (page unavailable) describes hepatocyte metabolic injury, metabolically activated immune cells shaping the liver microenvironment, and an altered inflammatory milieu during progression from NASH to HCC. It discusses endothelial-cell dysregulation but does not describe the re-emergence of fetal-associated endothelial cells. The claim also generalizes findings framed around NASH-related HCC to hepatocarcinogenesis broadly. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • There are no approved therapies for MASH.

    “Currently, there are no approved therapies for MASH [10]”

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Research works printed but not linked: 1

  1. [155]Lo ST, Gane E, Bartlett A & Orr D Clinical features and survival of non-alcoholic fatty liver disease-related hepatocellular carcinoma. Hepatol. Int. 10, S437 (2016).

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Authors
Llovet, J. M., Willoughby, C. E., Singal, A. G., Greten, T. F., Heikenwälder, M., El-Serag, H. B., Finn, R. S., & Friedman, S. L.
Affiliations
  • Institució Catalana de Recerca i Estudis Avançats (ES)
  • Hospital Clínic de Barcelona (ES)
  • The University of Texas Southwestern Medical Center (US)
  • National Institutes of Health (US)
  • German Cancer Research Center (DE)
  • University of California, Los Angeles (US)
  • Tisch Cancer Institute (US)
Corresponding author
Llovet, Josep M.
Venue
Nature Reviews Gastroenterology & Hepatology
Published
2023-03-17
Volume
20
Issue
8
Pages
487-503
ISSN
  • 1759-5045 (ISSN-L)
  • 1759-5053
OpenAlex
W4327744345
Cited by
354
References
224
Citations by year
2026: 70 · 2025: 127 · 2024: 120 · 2023: 37
FWCI
15.32
Type
journal article
Language
en
Open access
Locations
  • Nature Reviews Gastroenterology & Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by)
  • PubMed Central (acceptedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders
  • Fundació Institut de Recerca Hospital Universitari Vall d’Hebron
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK128289)
Topics
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Hepatitis C virus research
Keywords
nonalcoholic steatohepatitis, hepatocellular carcinoma, non-alcoholic fatty liver disease, tumor immune microenvironment, gut microbiota, obesity, diabetes mellitus, metabolic syndrome, immune checkpoint inhibitors, anti-angiogenic therapy, locoregional therapy, surgical resection, cancer surveillance, biomarkers, immune evasion
MeSH terms
Immune Checkpoint Inhibitors, Diabetes Mellitus, Female, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Obesity, Disease Progression, Tumor Microenvironment, Non-alcoholic Fatty Liver Disease

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