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Aging Influences Hepatic Microvascular Biology and Liver Fibrosis in Advanced Chronic Liver Disease.

ABSTRACT: Advanced chronic liver disease (aCLD) represents a major public health concern. aCLD is more prevalent and severe in the elderly, carrying a higher risk of decompensation. We aimed at understanding how aging may impact on the pathophysiology of aCLD in aged rats and humans and secondly, at evaluating simvastatin as a therapeutic option in aged animals. aCLD was induced in young (1 month) and old (16 months) rats. A subgroup of aCLD-old animals received simvastatin (5 mg/kg) or vehicle (PBS) for 15 days. Hepatic and systemic hemodynamic, liver cells phenotype and hepatic fibrosis were evaluated. Additionally, the gene expression signature of cirrhosis was evaluated in a cohort of young and aged cirrhotic patients. Aged animals developed a more severe form of aCLD. Portal hypertension and liver fibrosis were exacerbated as a consequence of profound deregulations in the phenotype of the main hepatic cells: hepatocytes presented more extensive cell-death and poorer function, LSEC were further capillarized, HSC over-activated and macrophage infiltration was significantly increased. The gene expression signature of cirrhosis significantly differed comparing young and aged patients, indicating alterations in sinusoidal-protective pathways and confirming the pre-clinical observations. Simvastatin administration for 15-day to aged cirrhotic rats improved the hepatic sinusoidal milieu, leading to significant amelioration in portal hypertension. This study provides evidence that aCLD pathobiology is different in aged individuals. As the median age of patients with aCLD is increasing, we propose a real-life pre-clinical model to develop more reliable therapeutic strategies. Simvastatin effects in this model further demonstrate its translational potential.

SUBMITTER: Maeso-Diaz R

PROVIDER: S-EPMC6675529 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Aging Influences Hepatic Microvascular Biology and Liver Fibrosis in Advanced Chronic Liver Disease.

Maeso-Díaz Raquel R Ortega-Ribera Martí M Lafoz Erica E Lozano Juan José JJ Baiges Anna A Francés Rubén R Albillos Agustín A Peralta Carmen C García-Pagán Juan Carlos JC Bosch Jaime J Cogger Victoria C VC Gracia-Sancho Jordi J

Aging and disease 20190801 4

Advanced chronic liver disease (aCLD) represents a major public health concern. aCLD is more prevalent and severe in the elderly, carrying a higher risk of decompensation. We aimed at understanding how aging may impact on the pathophysiology of aCLD in aged rats and humans and secondly, at evaluating simvastatin as a therapeutic option in aged animals. aCLD was induced in young (1 month) and old (16 months) rats. A subgroup of aCLD-old animals received simvastatin (5 mg/kg) or vehicle (PBS) for ...[more]

PMID: 31440376

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Project description:Background & aimsAssessment of hepatic steatosis by transient elastography (TE)-based controlled attenuation parameter (CAP) might predict hepatic decompensation. Therefore, we aimed to evaluate the prognostic value of CAP in patients with compensated advanced chronic liver disease (cACLD) and decompensated cirrhosis (DC).MethodsA total of 430 patients who underwent TE (liver stiffness ≥10 kPa) and CAP measurements were included in this retrospective analysis. Half of patients (n = 189) underwent simultaneous HVPG measurement. In cACLD patients, first hepatic decompensation was defined by new onset of ascites, hepatic encephalopathy or variceal bleeding. In patients with DC, the following events were considered as further hepatic decompensation: requirement of paracentesis, admission for/development of grade 3/4 hepatic encephalopathy, variceal (re-)bleeding or liver-related death.ResultsFirst hepatic decompensation occurred in 25 of 292 (9%) cACLD patients, while 46 of 138 (33%) DC patients developed further hepatic decompensation during a median follow-up of 22 and 12 months respectively. CAP was not predictive of first (cACLD; per 10 dB/m; hazard ratio [HR]: 0.97, 95% confidence interval [95% CI]: 0.91-1.03, P = 0.321) or further hepatic decompensation (DC; HR: 0.99, 95% CI: 0.94-1.03, P = 0.554) in adjusted analysis. Using the well-established CAP cut-off of ≥248 dB/m for hepatic steatosis, the incidence of first (cACLD; P = 0.065) and further hepatic decompensation (DC; P = 0.578) was similar in patients with hepatic steatosis or without. Serum albumin levels (per mg/dL; HR: 0.83, 95% CI: 0.77-0.89, P < 0.001) and MELD-Na (per point; HR: 1.15, 95% CI: 1.04-1.28, P = 0.006) in cACLD and MELD-Na (per point; HR: 1.12, 95% CI: 1.05-1.19, P < 0.0001) in DC patients were the only parameters independently associated with first and further hepatic decompensation, respectively.ConclusionControlled attenuation parameter does not predict the development of first (cACLD)/further (DC) hepatic decompensation, while serum albumin levels and MELD-Na are of prognostic value.

Dataset Information

Aging Influences Hepatic Microvascular Biology and Liver Fibrosis in Advanced Chronic Liver Disease.

Publications

Aging Influences Hepatic Microvascular Biology and Liver Fibrosis in Advanced Chronic Liver Disease.

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