Hepatic encephalopathy: investigational drugs in preclinical and early phase development

ABSTRACT

Introduction

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome, in patients with liver disease, which affects life quality and span. Current treatments are lactulose or rifaximin, acting on gut microbiota. Treatments aiming ammonia levels reduction have been tested with little success.

Areas covered

Pre-clinical research shows that the process inducing HE involves sequentially: liver failure, altered microbiome, hyperammonemia, peripheral inflammation, changes in immunophenotype and extracellular vesicles and neuroinflammation, which alters neurotransmission impairing cognitive and motor function. HE may be reversed using drugs acting at any step: modulating microbiota with probiotics or fecal transplantation; reducing peripheral inflammation with anti-TNFα, autotaxin inhibitors or silymarin; reducing neuroinflammation with sulforaphane, p38 MAP kinase or phosphodiesteras 5 inhibitors, antagonists of sphingosine-1-phosphate receptor 2, enhancing meningeal lymphatic drainage or with extracellular vesicles from mesenchymal stem cells; reducing GABAergic neurotransmission with indomethacin or golexanolone.

Expert opinion

A factor limiting the progress of HE treatment is the lack of translation of research advances into clinical trials. Only drugs acting on microbiota or ammonia reduction have been tested in patients. It is urgent to change the mentality on how to approach HE treatment to develop clinical trials to assess drugs acting on the immune system/peripheral inflammation, neuroinflammation or neurotransmission to improve HE.

KEYWORDS:

• Hepatic encephalopathy
• hyperammonemia
• microbiota
• immune system
• peripheral inflammation
• neuroinflammation
• neurotransmission

Article highlights

• Hepatic encephalopathy (HE) reduces life quality and span in patients with liver diseases.

• Current treatments (lactulose or rifaximin) of HE act on microbiota.

• Hyperammonemia, peripheral inflammation, neuroinflammation, and altered neurotransmission also contribute to HE.

• Drugs acting at any of these steps improve HE in preclinical animal models.

• Progress of HE treatment is limited by the lack of translation of research advances into clinical trials.

• Urges to develop clinical trials to assess drugs acting on the immune system/peripheral inflammation, neuroinflammation, or neurotransmission to improve HE.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was funded by: Ministerio de Ciencia e Innovación Spain / PID2020-113388RB-I00; Consellería Educación Generalitat Valenciana / CIPROM 2021/082; European Regional Development Funds / ERDF; MCIN/AEI/https://doi.org/10.13039/501100011033 and by European Union Next Generation EU/PRTR / Juan de la Cierva - Incorporación (IJC2020-043918-I); YMA has a contract Margarita Salas from Valencia University.