Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study)

Journal of Hepatology, Год журнала: 2021, Номер 75(6), С. 1346 - 1354

Опубликована: Авг. 5, 2021

Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic liver failure (ACLF). Herein, we aimed to evaluate safety and efficacy G-CSF in ACLF.In this multicenter, prospective, controlled, open-label phase II study, 176 ACLF (EASL-CLIF criteria) were randomized receive (5 μg/kg daily first 5 days every third day thereafter until 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. key secondary endpoints overall after 360 days, development ACLF-related complications, course function scores during entire observation period.Patients treated had a rate 34.1% compared 37.5% group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p 0.805). Transplant-free at did not differ between 2 arms (HR 0.998; 0.697-1.430; 0.992 HR 1.058; 0.727-1.548; 0.768, respectively). improve scores, occurrence infections, subgroups without alcohol-related ACLF, defined APASL criteria. Sixty-one serious adverse events reported G-CSF+SMT 57 group. In total, 7 drug-related reactions occurred study prematurely terminated due futility conditional power calculation.In contrast previous findings, no significant beneficial effect multicenter controlled trial, which suggests that it should be as ACLF. CLINICALTRIALS.NCT02669680 LAY SUMMARY: Granulocyte-colony considered novel We performed randomized, showed other clinical Therefore, treat disease outside studies.

Язык: Английский

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Helicobacter pylori infection and peptic ulcer disease in patients with advanced chronic liver disease

Frontline Gastroenterology, Год журнала: 2025, Номер unknown, С. flgastro - 102944

Опубликована: Янв. 6, 2025

Introduction Peptic ulcer disease (PUD) is more prevalent in patients with advanced chronic liver (ACLD) than the general population. Helicobacter pylori (Hp) infection main aetiological factor PUD. This study aims to assess incidence, testing rate and eradication of Hp PUD ACLD, along clinical impact complicated Methods retrospective included ACLD followed at outpatient clinic Unidade Local de Saúde Braga between 2018 2022. The rates were assessed, as well presence uncomplicated Results Of 740 295 (40%) tested for through oesophagogastroduodenoscopy (EGD) gastric biopsies, whom 125 (42%) positive Hp. these, 53 underwent eradication. EGD revealed 56 (19%). In multivariate analysis, positivity (OR 2.328; p=0.007), alcohol consumption 1.911; p=0.038) no statin intake 3.649; p=0.013) independent predictors total patients, 30 (4.1%) had (bleeding/perforation). 6 months after a episode, 12 (33%) novo/further hepatic decompensation, 8 (27%) died due decompensated ACLD. Conclusions low, while incidence was high. Complicated has significant morbidity are insufficient.

Язык: Английский

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Acute-on-chronic liver failure (ACLF): the ‘Kyoto Consensus’—steps from Asia

Hepatology International, Год журнала: 2025, Номер 19(1), С. 1 - 69

Опубликована: Фев. 1, 2025

Acute-on-chronic liver failure (ACLF) is a condition associated with high mortality in the absence of transplantation. There have been various definitions proposed worldwide. The first consensus report working party Asian Pacific Association for Study Liver (APASL) set 2004 on ACLF was published 2009, and "APASL Research Consortium (AARC)" formed 2012. AARC database has prospectively collected nearly 10,500 cases from countries Asia-Pacific region. This instrumental developing score grade ACLF, concept 'Golden Therapeutic Window', 'transplant window', plasmapheresis as treatment modality. Also, data key to identifying pediatric ACLF. European Liver-Chronic Failure (EASL CLIF) North American End Stage Disease (NACSELD) West added concepts organ infection precipitants development CLIF-Sequential Organ Assessment (SOFA) NACSELD scores prognostication. Chinese Group Severe Hepatitis B (COSSH) COSSH-ACLF criteria manage hepatitis b virus-ACLF without cirrhosis. literature supports these be equally effective their respective cohorts patients mortality. To overcome differences develop global consensus, APASL took initiative invited stakeholders, including opinion leaders Asia, EASL AASLD, other researchers field identify issues an evidence-based document. document presented hybrid format at annual meeting Kyoto March 2024. 'Kyoto Consensus' below carries final recommendations along relevant background information areas requiring future studies.

Язык: Английский

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Cell type-specific regulation of the pentose phoshate pathway during development and metabolic stress-driven autoimmune diseases: Relevance for inflammatory liver, renal, endocrine, cardiovascular and neurobehavioral comorbidites, carcinogenesis, and aging

Autoimmunity Reviews, Год журнала: 2025, Номер 24(5), С. 103781 - 103781

Опубликована: Фев. 24, 2025

Язык: Английский

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Combination of G-CSF and a TLR4 inhibitor reduce inflammation and promote regeneration in a mouse model of ACLF

Journal of Hepatology, Год журнала: 2022, Номер 77(5), С. 1325 - 1338

Опубликована: Июль 16, 2022

•We hypothesised that a TLR4 inhibitor, TAK-242, might mitigate the negative effects of G-CSF in ACLF.•G-CSF alone increases mortality and promotes inflammation rodent models ACLF.•The combination TAK-242 inhibits inflammation, hepatic regeneration prevents ACLF. Background & AimsAcute-on-chronic liver failure (ACLF) is characterised by high short-term mortality, systemic regeneration. Its treatment major unmet medical need. This study was conducted to explore whether combining Toll-like receptor-4 (TLR4) antagonist, with granulocyte-colony stimulating factor (G-CSF), could reduce whilst enhancing regeneration.MethodsTwo mouse ACLF were investigated. Chronic injury induced carbon tetrachloride; lipopolysaccharide (LPS) or galactosamine (GalN) then administered as extrahepatic insults, respectively. and/or daily. Treatment durations 24 hours 5 days LPS model 48 GalN model.ResultsIn LPS-induced ACLF, associated significant (66% after vs. 0% without G-CSF). Addition abrogated (0%) significantly reduced cell death, macrophage infiltration inflammation. In model, both when used individually, but their more effective. treatment, activation pro-regenerative anti-apoptotic STAT3 pathway. LPS-driven p21 overexpression, which indicative senescence inhibition hepatocyte While mitigated effect on senescence, G-CSF, co-administered resulted increase markers regeneration.ConclusionThe ACLF; thus, this be potential option for ACLF.Lay summaryAcute-on-chronic severe poor survival. Therefore, effective treatments are urgently needed. Herein, we have shown, using models, (which can promote regeneration) receptor plays key role inflammation) acute-on-chronic failure. Acute-on-chronic Two model. The

Язык: Английский

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Increased platelet aggregation in patients with decompensated cirrhosis indicates higher risk of further decompensation and death

Journal of Hepatology, Год журнала: 2022, Номер 77(3), С. 660 - 669

Опубликована: Март 30, 2022

Язык: Английский

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Loss of liver function in chronic liver disease: An identity crisis

Journal of Hepatology, Год журнала: 2022, Номер 78(2), С. 401 - 414

Опубликована: Сен. 15, 2022

Adult hepatocyte identity is constructed throughout embryonic development and fine-tuned after birth. A multinodular network of transcription factors, along with pre-mRNA splicing regulators, define the transcriptome, which encodes proteins needed to perform complex metabolic secretory functions mature liver. Transient hepatocellular dedifferentiation can occur as part regenerative mechanisms triggered in response acute liver injury. However, persistent downregulation key genes now accepted a strong determinant organ dysfunction chronic disease, major global health burden. Therefore, identification core factors regulators that preserve phenotype, thorough understanding how these networks become disrupted diseased hepatocytes, high clinical relevance. In this context, we review players differentiation discuss detail critical such HNF4α, whose impairment mediates breakdown function. Moreover, present compelling experimental evidence demonstrating restoration factor expression chronically injured reset identity, improve function ameliorate structural abnormalities. The possibility correcting phenotype severely damaged malfunctional livers may reveal new therapeutic opportunities for individuals cirrhosis advanced disease.

Язык: Английский

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The Potential Role of Cellular Senescence in Non-Alcoholic Fatty Liver Disease

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(2), С. 652 - 652

Опубликована: Янв. 7, 2022

Non-alcoholic fatty liver disease (NAFLD) represents an increasing global health burden. Cellular senescence develops in response to cellular injury, leading not only cell cycle arrest but also alterations of the phenotype and metabolic functions. In this review, we critically discuss currently existing evidence for involvement NAFLD order identify areas requiring further exploration. Hepatocyte can be a central pathomechanism as it may foster intracellular fat accumulation, fibrosis inflammation, due secretion senescence-associated inflammatory mediators. However, some non-parenchymal types, such hepatic stellate cells, beneficial by reducing extracellular matrix deposition thereby fibrosis. Deciphering detailed interaction between will essential discover novel therapeutic targets halting progression.

Язык: Английский

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Use of albumin infusion for cirrhosis-related complications: An international position statement

JHEP Reports, Год журнала: 2023, Номер 5(8), С. 100785 - 100785

Опубликована: Май 5, 2023

Background & AimsNumerous studies have evaluated the role of human albumin (HA) in managing various liver cirrhosis-related complications. However, their conclusions remain partially controversial, probably because HA was different settings, including indications, patient characteristics, and dosage duration therapy.MethodsThirty-three investigators from 19 countries with expertise complications were invited to organize an International Special Interest Group. A three-round Delphi consensus process undertaken complete international position statement on use for complications.ResultsTwelve clinically significant statements proposed. Short-term infusion should be recommended management hepatorenal syndrome (HRS), large volume paracentesis (LVP), spontaneous bacterial peritonitis (SBP) cirrhosis. Its effects prevention or treatment other further elucidated. Long-term administration can considered specific settings. Pulmonary edema closely monitored as a potential adverse effect cirrhotic patients receiving infusion.ConclusionsBased currently available evidence, suggests benefits multiple summarizes its safety profile. optimal timing strategy elucidated.Lay summaryThirty-three proposed 12 Based current short-term HRS, LVP, SBP, long-term setting where budget logistical issues resolved. pulmonary infusion.

Язык: Английский

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Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 24, 2023

Abstract Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE), but mechanism remains unclear. GABAergic neurons substantia nigra pars reticulata (SNr) contribute to motor deficit HE. The present study aims investigate effects oxidative on HE male mice. results validate existence both liver and SNr across two murine models induced by thioacetamide (TAA) bile duct ligation (BDL). Systemic mitochondria-targeted antioxidative drug mitoquinone (Mito-Q) rescues mitochondrial dysfunction injury SNr, so as restore locomotor impairment TAA BDL Furthermore, GAD2-expressing population (SNr GAD2 ) is activated Both overexpression uncoupling protein 2 (UCP2) targeted -targeted chemogenetic inhibition rescue TAA-induced These define key

Язык: Английский

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