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

Simon Johannes Gairing; Sven Danneberg; Leonard Kaps; Michael Nagel; Eva Maria Schleicher; Charlotte Quack; Sinah Engel; Stefan Bittner; Peter Robert Galle; Jörn Markus Schattenberg; Marcus-Alexander Wörns; Felix Luessi; Jens Uwe Marquardt; Christian Labenz

doi:10.1016/j.jhepr.2023.100671

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

JHEP Rep. 2023 Jan 18;5(4):100671. doi: 10.1016/j.jhepr.2023.100671. eCollection 2023 Apr.

Authors

Simon Johannes Gairing^{1

2}, Sven Danneberg³, Leonard Kaps^{1

2}, Michael Nagel^{1

2

4}, Eva Maria Schleicher^{1

2}, Charlotte Quack^{1

2}, Sinah Engel⁵, Stefan Bittner⁵, Peter Robert Galle^{1

2}, Jörn Markus Schattenberg^{1

6}, Marcus-Alexander Wörns^{1

2

4}, Felix Luessi⁵, Jens Uwe Marquardt³, Christian Labenz^{1

2}

Affiliations

¹ Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
² Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
³ Department of Medicine I, University Hospital Schleswig-Holstein, Lübeck, Germany.
⁴ Department of Gastroenterology, Hematology, Oncology and Endocrinology, Klinikum Dortmund, Germany.
⁵ Department of Neurology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
⁶ Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

Abstract

Background & aims: Blood biomarkers facilitating the diagnosis of covert hepatic encephalopathy (CHE) in patients with cirrhosis are lacking. Astrocyte swelling is a major component of hepatic encephalopathy. Thus, we hypothesised that glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes, might facilitate early diagnosis and management. This study aimed to investigate the utility of serum GFAP (sGFAP) levels as a biomarker of CHE.

Methods: In this bicentric study, 135 patients with cirrhosis, 21 patients with ongoing harmful alcohol use and cirrhosis, and 15 healthy controls were recruited. CHE was diagnosed using psychometric hepatic encephalopathy score. sGFAP levels were measured using a highly sensitive single-molecule array (SiMoA) immunoassay.

Results: In total, 50 (37%) people presented with CHE at study inclusion. Participants with CHE displayed significantly higher sGFAP levels than those without CHE (median sGFAP, 163 pg/ml [IQR 136; 268] vs. 106 pg/ml [IQR 75; 153]; p <0.001) or healthy controls (p <0.001). sGFAP correlated with results in psychometric hepatic encephalopathy score (Spearman's ρ = -0.326, p <0.001), model for end-stage liver disease score (Spearman's ρ = 0.253, p = 0.003), ammonia (Spearman's ρ = 0.453, p = 0.002), and IL-6 serum levels (Spearman's ρ = 0.323, p = 0.006). Additionally, sGFAP levels were independently associated with the presence of CHE in multivariable logistic regression analysis (odds ratio 1.009; 95% CI 1.004-1.015; p <0.001). sGFAP levels did not differ between patients with alcohol-related cirrhosis vs. patients with non-alcohol-related cirrhosis or between patients with ongoing alcohol use vs. patients with discontinued alcohol use.Conclusions: sGFAP levels are associated with CHE in patients with cirrhosis. These results suggest that astrocyte injury may already occur in patients with cirrhosis and subclinical cognitive deficits and that sGFAP could be explored as a novel biomarker.

Impact and implications: Blood biomarkers facilitating the diagnosis of covert hepatic encephalopathy (CHE) in patients with cirrhosis are lacking. In this study, we were able to demonstrate that sGFAP levels are associated with CHE in patients with cirrhosis. These results suggest that astrocyte injury may already occur in patients with cirrhosis and subclinical cognitive deficits and that sGFAP could be explored as a novel biomarker.

Keywords: Biomarkers; CHE; CHE, covert hepatic encephalopathy; Cognitive deficit; Complications of cirrhosis; GFAP; GFAP, glial fibrillary acidic protein; HE; HE, hepatic encephalopathy; HE2, grade 2 hepatic encephalopathy; MELD, model for end-stage liver disease; MHE, minimal hepatic encephalopathy; OHE, overt hepatic encephalopathy; OR, odds ratio; PHES, psychometric hepatic encephalopathy score; Psychometric hepatic encephalopathy score; ROC, receiver operating characteristic; SiMoA, single-molecule array; WBC, white blood cell; sGFAP, serum glial fibrillary acidic protein.