Recompensation in cirrhosis: unravelling the evolving natural history of nonalcoholic fatty liver disease

Feng, Gong; Valenti, Luca; Wong, Vincent Wai-Sun; Fouad, Yasser Mahrous; Yilmaz, Yusuf; Kim, Won; Sebastiani, Giada; Younossi, Zobair M.; Hernandez-Gea, Virginia; Zheng, Ming-Hua

doi:10.1038/s41575-023-00846-4

Cited by 76 publications

(28 citation statements)

References 102 publications

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“…remains debated [22]. It is well known that SLD is a heterogeneous disease, thus identifying a specific cause of hepatic steatosis is a great challenge.…”

Section: Key Pointsmentioning

confidence: 99%

Lipid droplets in steatotic liver disease

Bilson,

Scorletti

2023

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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Purpose of review This review aims to discuss the most recent evidence exploring the role of lipid droplets in steatotic liver disease (SLD). We highlight the breadth of mechanisms by which lipid droplets may contribute to the progression of SLD with a particular focus on the role of lipid droplets as inducers of mechanical stress within hepatocytes and genetic mutations in lipid droplet associated proteins. Finally, this review provides an update on clinical trials exploring the therapeutic potential and strategies targeting lipid droplets. Recent findings The size, composition and location of hepatic lipid droplets strongly influence the pathological role of these organelles in SLD. Emerging studies are beginning to elucidate the importance of lipid droplet induced hepatocyte mechanical stress. Novel strategies targeting lipid droplets, including the effects of lipid droplet associated protein mutations, show promising therapeutic potential. Summary Much more than a histological feature, lipid droplets are complex heterogenous organelles crucial to cellular metabolism with important causative roles in the development and progression of SLD. Lipid droplet induced mechanical stress may exacerbate hepatic inflammation and fibrogenesis and potentially contribute to the development of a pro-carcinogenic hepatic environment. The integration of advancements in genetics and molecular biology in upcoming treatments aspires to transcend symptomatic alleviation and address the fundamental causes and pathological development of SLD.

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“…remains debated [22]. It is well known that SLD is a heterogeneous disease, thus identifying a specific cause of hepatic steatosis is a great challenge.…”

Section: Key Pointsmentioning

confidence: 99%

Lipid droplets in steatotic liver disease

Bilson,

Scorletti

2023

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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“…Non-alcoholic fatty liver disease (NAFLD), now recognised as metabolic dysfunction-associated steatotic liver disease (MASLD), 1,2 is one of the most prevalent liver diseases globally, with its morbidity escalating at an alarming rate, positioning it among the primary causes of liver-related morbidity and mortality. [3][4][5][6][7] Additionally, non-alcoholic steatohepatitis (NASH), characterised by persistent inflammation and subsequent NASH-related fibrosis, represents an inflammatory subtype of NAFLD, globally affecting approximately 2%-5% of the population. 8,9 Over time, fibrosis may progress in patients with NASH, with over 20% developing cirrhosis.…”

Section: Introductionmentioning

confidence: 99%

Meta‐analysis: Efficacy and safety of fibroblast growth factor 21 analogues for the treatment of non‐alcoholic steatohepatitis and non‐alcoholic steatohepatitis‐related fibrosis

Lin,

Zhou,

Sun

et al. 2024

Aliment Pharmacol Ther

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SummaryBackgroundFibroblast growth factor 21 (FGF21) analogues have emerged as promising therapeutic targets for non‐alcoholic steatohepatitis (NASH). However, the effects and safety of these analogues on NASH and NASH‐related fibrosis remain unexplored.AimsTo estimate the efficacy and safety of FGF21 analogues for treating NASH and NASH‐related fibrosis.MethodsPubMed, Embase, and the Cochrane Library were searched for relevant studies up to 11 October 2023. Primary outcomes were defined as the fibrosis improvement ≥1 stage without worsening of NASH and NASH resolution without worsening fibrosis. Secondary outcomes included biomarkers of fibrosis, liver injury, and metabolism. Treatment‐related adverse events were also analysed.ResultsNine studies, including 1054 patients with biopsy‐proven NASH and stage F1–F4 fibrosis, were identified. Seven studies reported histological outcomes. The relative risk (RR) for obtaining fibrosis improvement ≥1 stage efficacy was 1.79 (95% CI 1.29–2.48, I2 = 37%, p < 0.001) with FGF21 analogues relative to placebo. Although no statistically significant difference was observed between FGF21 analogues in NASH resolution, sensitivity analyses and fragility index suggest that this result is unstable. The drugs improved hepatic fat fraction (HFF), along with other biomarkers of fibrosis, liver injury, and metabolism (MRE, LSM, Pro‐C3, ELF, ALT, AST, TG, HDL‐C, and LDL‐C). Additionally, no significant difference in serious adverse event incidence rate was observed (RR = 1.26, 95% CI 0.82–1.94, I2 = 24%, p = 0.3).ConclusionsFGF21 analogues appear as promising agents for the treatment of NASH and NASH‐related fibrosis, and they generally seem to be safe and well tolerated.

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“…1,2 MAFLD includes a range of adverse hepatic outcomes ranging from isolated hepatic steatosis to steatohepatitis, 3,4 cirrhosis and hepatocellular carcinoma. [5][6][7] The pathogenic feature of MAFLD is systemic metabolic dysregulation closely related to obesity and type 2 diabetes mellitus, which also predicts the development of MAFLD-related extrahepatic diseases, such as cardiovascular disease and chronic kidney disease (CKD). [8][9][10] Many cohort studies have confirmed that MAFLD is an independent risk factor for CKD, and the severity of MAFLD may further increase the risk of incident CKD.…”

Section: Introductionmentioning

confidence: 99%

Serum PRO‐C3 is useful for risk prediction and fibrosis assessment in MAFLD with chronic kidney disease in an Asian cohort

Tang,

Sun,

Song

et al. 2024

Liver International

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BackgroundMetabolic dysfunction‐associated fatty liver disease (MAFLD) is an emerging risk factor for chronic kidney disease (CKD). N‐terminal propeptide of collagen type 3 (PRO‐C3) is a biomarker of advanced fibrosis in MAFLD and PRO‐C3 may be involved in renal fibrosis. We aimed to use PRO‐C3 measurements to generate a new algorithmic score to test the prediction of MAFLD with chronic kidney disease (MAFLD–CKD).MethodsA derivation and independent validation cohort of 750 and 129 Asian patients with biopsy‐confirmed MAFLD were included. Serum PRO‐C3 concentration was measured and regression analyses were performed to examine associations with MAFLD–CKD. A derivative algorithm for MAFLD–CKD risk prediction was evaluated with receiver operator characteristic (ROC) curve analysis.ResultsThe study included two Asian cohorts (n = 180 with MAFLD–CKD; mean‐eGFR: 94.93 mL/min/1.73 m2; median‐urinary albumin‐to‐creatinine ratio: 6.58 mg/mmol). PRO‐C3 was associated with the severity of MAFLD‐CKD and independently associated with MAFLD–CKD (adjusted odds ratio = 1.16, 95% confidence interval [CI]: 1.08–1.23, p < .001). A new non‐invasive score (termed PERIOD) including PRO‐C3 efficiently predicted MAFLD‐CKD (AUROC = .842, 95% CI: .805–.875). Accuracy, specificity and negative predictive values were 80.2%, 85.1% and 88.4%, respectively. In the validation cohort, the PERIOD score had good diagnostic performance (AUROC = .807, 95% CI: .691–.893) with similar results in all patient subgroups. In the MAFLD–CKD subgroup, the accuracy for identifying advanced fibrosis was further improved by combining the PRO‐C3‐based ADAPT with the Agile 3+ scores (AUROC = .90, 95% CI: .836–.964).ConclusionsThe PERIOD score is helpful for accurately predicting the risk of MAFLD–CKD. PRO‐C3 can also be used to assess liver fibrosis in people with MAFLD–CKD.

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Recompensation in cirrhosis: unravelling the evolving natural history of nonalcoholic fatty liver disease

Cited by 76 publications

References 102 publications

Lipid droplets in steatotic liver disease

Lipid droplets in steatotic liver disease

Meta‐analysis: Efficacy and safety of fibroblast growth factor 21 analogues for the treatment of non‐alcoholic steatohepatitis and non‐alcoholic steatohepatitis‐related fibrosis

Serum PRO‐C3 is useful for risk prediction and fibrosis assessment in MAFLD with chronic kidney disease in an Asian cohort

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