Elevated serum levels of glial fibrillary acidic protein are associated with covert hepatic encephalopathy in patients with cirrhosis

Gairing, Simon Johannes; Danneberg, Sven; Kaps, Leonard; Nagel, Michael; Schleicher, Eva Maria; Quack, Charlotte; Engel, Sinah; Bittner, Stefan; Galle, Peter R.; Schattenberg, Jörn M.; Wörns, Marcus‐Alexander; Luessi, Felix; Marquardt, Jens U.; Labenz, Christian

doi:10.1016/j.jhepr.2023.100671

Cited by 7 publications

(3 citation statements)

References 26 publications

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“…Furthermore, there is growing evidence supporting the potential clinical use of serum GFAP levels in neuroinflammatory and neurodegenerative diseases (10). Of particular relevance to the current study, a recent report found that serum GFAP was increased in patients with hepatic encephalopathy associated with cirrhosis (21). However, it remains unclear whether concentrations of tau or NFL in the blood might be altered in patients with ALF-induced brain injury.…”

Section: Introductionmentioning

confidence: 82%

“…While previous studies have shown that elevated blood GFAP concentration is a suitable parameter for predicting unfavorable outcomes in patients with moderate to severe traumatic brain injury ( 27 ), the use of GFAP in the early detection and diagnosis of ALF-associated brain injury in humans or large animals has not been well explored. A recent study showed elevated GFAP in the blood of patients with hepatic encephalopathy associated with cirrhosis, which was correlated with ammonia and IL6 levels in serum ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive analysis of brain injury parameters in a preclinical porcine model of acute liver failure

Felgendreff,

Hosseiniasl,

Felgendreff

et al. 2024

Front. Med.

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IntroductionAcute liver failure (ALF) is defined as acute loss of liver function leading to hepatic encephalopathy associated with a high risk of patient death. Brain injury markers in serum and tissue can help detect and monitor ALF-associated brain injury. This study compares different brain injury parameters in plasma and tissue along with the progression of ALF.MethodALF was induced by performing an 85% liver resection. Following the resection, animals were recovered and monitored for up to 48 h or until reaching the predefined endpoint of receiving standard medical therapy (SMT). Blood and serum samples were taken at Tbaseline, T24, and upon reaching the endpoint (Tend). Control animals were euthanized by exsanguination following plasma sampling. Postmortem brain tissue samples were collected from the frontal cortex (FCTx) and cerebellum (Cb) of all animals. Glial fibrillary acidic protein (GFAP) and tau protein and mRNA levels were quantified using ELISA and qRT-PCR in all plasma and brain samples. Plasma neurofilament light (NFL) was also measured using ELISA.ResultsAll ALF animals (n = 4) were euthanized upon showing signs of brain herniation. Evaluation of brain injury biomarkers revealed that GFAP was elevated in ALF animals at T24h and Tend, while Tau and NFL concentrations were unchanged. Moreover, plasma glial fibrillary acidic protein (GFAP) levels were negatively correlated with total protein and positively correlated with both aspartate transaminase (AST) and alkaline phosphatase (AP). Additionally, lower GFAP and tau RNA expressions were observed in the FCTx of the ALF group but not in the CB tissue.ConclusionThe current large animal study has identified a strong correlation between GFAP concentration in the blood and markers of ALF. Additionally, the protein and gene expression analyses in the FCTx revealed that this area appears to be susceptible, while the CB is protected from the detrimental impacts of ALF-associated brain swelling. These results warrant further studies to investigate the mechanisms behind this process.

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Section: Introductionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of brain injury parameters in a preclinical porcine model of acute liver failure

Felgendreff,

Hosseiniasl,

Felgendreff

et al. 2024

Front. Med.

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“…These dMRS findings are supported by the GFAP histological observations (i.e., decreased length and number of astrocytic processes) pointing toward a less restricted and ramified cellular architecture, explaining increased diffusivities for astrocytic metabolites in the BDL rats. A recent study showed increased serum GFAP levels in cirrhotic patients ( Gairing et al, 2023 ), suggesting that the presence of astrocyte injury and astrocyte activation are two mechanisms that may lead to increased serum GFAP concentrations. It is worth mentioning that, using dMRS in a model of reactive astrocytes, Ins has been revealed as a specific intra-astrocytic marker whose diffusion closely reflects astrocytic morphology, enabling the non-invasive detection of astrocyte hypertrophy ( Ligneul et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Diffusion of brain metabolites highlights altered brain microstructure in type C hepatic encephalopathy: a 9.4 T preliminary study

Mosso,

Briand,

Pierzchala

et al. 2024

Front. Neurosci.

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IntroductionType C hepatic encephalopathy (HE) is a decompensating event of chronic liver disease leading to severe motor and cognitive impairment. The progression of type C HE is associated with changes in brain metabolite concentrations measured by 1H magnetic resonance spectroscopy (MRS), most noticeably a strong increase in glutamine to detoxify brain ammonia. In addition, alterations of brain cellular architecture have been measured ex vivo by histology in a rat model of type C HE. The aim of this study was to assess the potential of diffusion-weighted MRS (dMRS) for probing these cellular shape alterations in vivo by monitoring the diffusion properties of the major brain metabolites.MethodsThe bile duct-ligated (BDL) rat model of type C HE was used. Five animals were scanned before surgery and 6- to 7-week post-BDL surgery, with each animal being used as its own control. 1H-MRS was performed in the hippocampus (SPECIAL, TE = 2.8 ms) and dMRS in a voxel encompassing the entire brain (DW-STEAM, TE = 15 ms, diffusion time = 120 ms, maximum b-value = 25 ms/μm2) on a 9.4 T scanner. The in vivo MRS acquisitions were further validated with histological measures (immunohistochemistry, Golgi-Cox, electron microscopy).ResultsThe characteristic 1H-MRS pattern of type C HE, i.e., a gradual increase of brain glutamine and a decrease of the main organic osmolytes, was observed in the hippocampus of BDL rats. Overall increased metabolite diffusivities (apparent diffusion coefficient and intra-stick diffusivity—Callaghan’s model, significant for glutamine, myo-inositol, and taurine) and decreased kurtosis coefficients were observed in BDL rats compared to control, highlighting the presence of osmotic stress and possibly of astrocytic and neuronal alterations. These results were consistent with the microstructure depicted by histology and represented by a decline in dendritic spines density in neurons, a shortening and decreased number of astrocytic processes, and extracellular edema.DiscussiondMRS enables non-invasive and longitudinal monitoring of the diffusion behavior of brain metabolites, reflecting in the present study the globally altered brain microstructure in BDL rats, as confirmed ex vivo by histology. These findings give new insights into metabolic and microstructural abnormalities associated with high brain glutamine and its consequences in type C HE.

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Elevated serum neurofilament light chain levels are associated with hepatic encephalopathy in patients with cirrhosis

Wang,

Xue,

et al. 2024

Metab Brain Dis

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Elevated serum levels of glial fibrillary acidic protein are associated with covert hepatic encephalopathy in patients with cirrhosis

Cited by 7 publications

References 26 publications

Comprehensive analysis of brain injury parameters in a preclinical porcine model of acute liver failure

Comprehensive analysis of brain injury parameters in a preclinical porcine model of acute liver failure

Diffusion of brain metabolites highlights altered brain microstructure in type C hepatic encephalopathy: a 9.4 T preliminary study

Elevated serum neurofilament light chain levels are associated with hepatic encephalopathy in patients with cirrhosis

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