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Review
. 2025 Jan 15;40(1):100.
doi: 10.1007/s11011-024-01512-7.

Ammonia and beyond - biomarkers of hepatic encephalopathy

Juan-José Gallego #  1   2 , María-Pilar Ballester #  1   3 , Alessandra Fiorillo  1 , Franc Casanova-Ferrer  1 , Adrià López-Gramaje  2 , Amparo Urios  1 , Yaiza María Arenas  2 , María-Pilar Ríos  4 , Lucía Durbán  4 , Javier Megías  2 , Teresa San-Miguel  2 , Salvador Benlloch  4   5   6 , Paloma Lluch  3 , Rajiv Jalan  7   8 , Carmina Montoliu  9   10
Affiliations
Review

Ammonia and beyond - biomarkers of hepatic encephalopathy

Juan-José Gallego et al. Metab Brain Dis. .

Abstract

Ammonia is a product of amino acid metabolism that accumulates in the blood of patients with liver cirrhosis, leading to neurotoxic effects and hepatic encephalopathy (HE). HE manifestations can range from mild, subclinical disturbances in cognition, or minimal HE (mHE) to gross disorientation and coma, a condition referred to as overt HE. Many blood-based biomarkers reflecting these neurotoxic effects of ammonia and liver disease can be measured in the blood allowing the development of new biomarkers to diagnose cirrhosis patients at risk of developing HE. The effect of ammonia on the brain is modulated by severity of systemic inflammation, and both hyperammonemia and inflammation can induce oxidative stress, which may mediate the neurological alterations associated to HE. This review aims to provide the latest evidence on biomarkers of HE beyond ammonia. We present different approaches to predict overt HE based on the combination of blood ammonia with some analytical and clinical parameters. Magnetic resonance analysis of brain images could also provide sensitive diagnostic biomarkers based on neuroimaging parameters. Some reports suggest that markers of systemic inflammation, oxidative stress, and central nervous system-derived components, may serve as additional biomarkers of HE. The involvement of extracellular vesicles and microbiota in the pathophysiology of mHE and HE has recently acquired importance and it would be interesting to explore their usefulness as early biomarkers of the disease. It is important to have a biomarker or a combination of them for early diagnosis of mHE to improve its treatment and prevent progression to overt HE.

Keywords: Ammonia; Biomarker; Brain injury markers; Extracellular vesicles; Hepatic encephalopathy; Inflammation; Microbiota; Minimal hepatic encephalopathy; Neuroimaging.

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Conflict of interest statement

Declarations. Ethics approval: Not applicable. Consent to participate: Not applicable. Conflict of interest: Rajiv Jalan is the inventor of OPA, which has been patented by UCL and licensed to Mallinckrodt Pharma. He is also the founder of Yaqrit Discovery, Hepyx Limited (spin out companies from University College London), and Cyberliver. He has research collaborations with Yaqrit Discovery. Yaq-001 was licensed by Yaqrit Ltd. from UCL. The other authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Summary of biomarkers from different origin as mHE and OHE diagnosis, risk stratification, and severity detection. See text for details explanation
See this image and copyright information in PMC

References

    1. Abdelhak A, Foschi M, Abu-Rumeileh S et al (2022) Blood GFAP as an emerging biomarker in brain and spinal cord disorders. Nat Rev Neurol 18:158–172. 10.1038/s41582-021-00616-3 - PubMed
    1. Ahn JM, Kim CH, Um SH et al (2017) Validation study associating glutaminase promoter variations with hepatic encephalopathy in East Asian populations. J Gastroenterol Hepatol 32:901–907. 10.1111/jgh.13618 - PubMed
    1. Albillos A, Lario M, Álvarez-Mon M (2014) Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 61:1385–1396. 10.1016/j.jhep.2014.08.010 - PubMed
    1. Albillos A, Martin-Mateos R, Van der Merwe S et al (2022) Cirrhosis-associated immune dysfunction. Nat Rev Gastroenterol Hepatol 19:112–134. 10.1038/s41575-021-00520-7 - PubMed
    1. Arguedas MR, DeLawrence TG, McGuire BM (2003) Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis. Dig Dis Sci 48:1622–1626. 10.1023/a:1024784327783 - PubMed

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