PSYLIVER-PILOTE: Involvement of the Autonomic Nervous System in Hepatocellular Carcinoma (HCC)

Summary

Chronic liver diseases affect 1.5 billion people worldwide and can lead to cirrhosis and hepatocellular carcinoma (HCC), which ranks as the third leading cause of cancer-related mortality globally. Despite advances in the treatment of hepatitis B and C, metabolic diseases, and addiction, HCC incidence continues to rise. In France, between 2010 and 2015, the five-year survival rate for liver cancer (90% of which is HCC) was 18% for men and 19% for women. Treatment of HCC is based on the BCLC classification (Barcelona Clinic Liver Cancer), which evaluates both cancer progression and liver function (Child-Pugh classification). Patients at early stages (0 or A) have a survival rate of over 5 years, while those at more advanced stages (C or D) have significantly lower survival rates, highlighting the importance of better early detection tools.

Current screening for HCC in cirrhotic patients involves biannual US-scan. However, ultrasound sensitivity for detecting tumors smaller than 2 cm is around 25%. Therefore, developing personalized strategies to predict and detect early-stage HCC is crucial to improving patient outcomes. Various clinical and biological scores have been developed to assess the risk of developing HCC in cirrhotic patients, but these scores remain imperfect. Molecular heterogeneity in HCC, as revealed by transcriptomic studies, could explain the variability in outcomes and treatment responses. This heterogeneity in occurrence, phenotype, and progression of HCC suggests individual singularities that are not yet well understood.

These individual singularities are likely linked to the autonomic nervous system (ANS), particularly in the central nervous system (CNS), which regulates various physiological processes. The ANS consists of the sympathetic nervous system (SNS), mainly adrenergic, and the parasympathetic nervous system (PNS), mainly cholinergic. These two systems function antagonistically but with different temporal dynamics. A better understanding of the interaction between tumor cells and their environment through the ANS could lead to the identification of new biomarkers to predict HCC development and therapeutic targets.

The role of the ANS in cancer development has been explored in various cancers, including prostate, stomach, pancreatic, breast, and ovarian cancers, where the ANS regulates inflammation and immune responses. In chronic liver diseases, the liver is innervated by both sympathetic and parasympathetic fibers, and this innervation plays a role in regulating metabolism, liver regeneration, and fibrosis progression. Chronic liver disease etiologies, such as alcohol consumption, metabolic syndrome, and viral hepatitis, disrupt the balance between the SNS and PNS, contributing to liver dysfunction. The severity of liver damage is linked to autonomic dysfunction, and heart rate variability, a marker of PNS activity, is correlated with survival in patients with terminal-stage HCC.

Our recent research has shown that patients with HCC exhibit a reconfiguration of the intrahepatic ANS, with a consistent cholinergic orientation at the neuro-hepatic synapse. Patients with parasympathetic orientation (as compared to sympathetic orientation) have more aggressive tumors, shorter survival, and, from a pharmacological perspective, anticholinergics increase sensitivity to targeted HCC therapies. Tumor cells and cytotoxic lymphocytes are most strongly associated with cholinergic receptor enrichment and depletion, respectively.

In this context, the PSYLIVER-PILOTE study builds on these findings by investigating the involvement of the ANS in HCC through non-invasive extra-hepatic measures. The SNS and PNS are connected to brain regions involved in cognitive, emotional, and social information processing, such as the anterior cingulate cortex, insula, ventromedial prefrontal cortex, amygdala, and hypothalamus. These brain areas are involved in cognitive control and emotional processing. Additionally, experimental data from polyvagal theory and neurovisceral integration theory highlight the role of the ANS in regulating cognitive, emotional, and social processes, as well as psycho-behavioral traits. For instance, confronting a person with cognitive tasks and emotional or social information alters the balance of sympathetic and parasympathetic activity. Similar changes are observed in psycho-behavioral disorders like depression, emotional dysregulation, stress, and aggression.

Thus, the PSYLIVER-PILOTE study aims to identify extra-hepatic markers of ANS activity associated with HCC, analyzing both electrophysiological indices (from the peripheral nervous system) and psycho-behavioral indices (from the central nervous system). This project could open new avenues for early HCC detection and the development of personalized treatments

Conditions

• Hepato Cellular Carcinoma
• Cirrhosis
• Autonomic Nervous System
• Central Nervous System

Interventions

OTHER

Measurements of autonomic nervous system (ANS) activity at rest and during sensory stimulation.

Participants are informed that they will need to watch the screen, on which images will appear around a central symbol. They must click the mouse button as quickly as possible when they see an "x" sign and do nothing when they see a "+" sign appear in the center of the screen. Sensory stimulation is carried out using OpenSesame software. It is divided into four blocks of seven minutes each, with a break systematically offered to participants between each block. Each block comprises three phases: rest (sitting with hands on knees, palms facing upwards and eyes closed) for two minutes, responding to stimuli according to instructions for three minutes, and a second rest phase for two minutes. In fact, participants are only active for a total of 12 minutes. The blocks are presented in the same order for all participants: Go block, neutral Go/NoGo block, emotional Go/NoGo block, then social Go/NoGo block.

OTHER

Self-administered questionnaires to assess psycho-behavioral traits

Participants answer self-questionnaires on tablets by selecting the answer that seems most appropriate to them. They are told that there are no right or wrong answers and that they should answer as honestly as possible based on what they think and feel at that moment. The self-questionnaires are the QA-10 items, the short version of the UPPS-P, the BPAQ-SF, the CERQ, the DEX, the PSS-10, the HAD, and the ISI.

OTHER

Analysis of nocturnal cardiac activity (at home): electrocardiographic (ECG) recording of heart activity during one night.

The investigator presents the NeuroCoach test kit to the participant and gives it to them. This kit consists of a recorder, two electrodes, a single-use pouch for nighttime use, a prepaid envelope for returning the equipment, and installation instructions. The investigator explains the installation instructions for the device, which the participant will set up independently at home. The equipment used is CE 60601-1 certified (general requirements for basic safety and essential performance of medical electrical equipment). There is a risk of temporary local skin irritation where the electrodes come into contact with the skin. A prepaid envelope will be given to the patient to return the device.

OTHER

Calculation of the NRS score. A study of the liver biopsy will be carried out to analyze ANS activity at the intrahepatic level.

Liver biopsy is performed as part of routine care. After pathological analysis as part of routine care, the biopsy sample will be sent to the Unité PaThLiv laboratory (UMR UCBL1 INSERM U1350; PathLiv team) for NRS histological scoring.

OTHER

Intervention name 5 * (Limit: 100 characters) Optionnal biocollection

Venous blood samples (taken during two visits): for a total volume of 32mL(serum, plasma) for the biobank will be aliquoted and stored in cryotubes. Each sample taken will be labeled with the patient's anonymized code (the patient's first and last names will not appear on the tubes). The tubes will be transported to the laboratory (PaThLiv Unit - UMR UCBL1 INSERM U1350; PathLiv Team).

Sponsors & Collaborators

• Hospices Civils de Lyon

  lead OTHER

Study Design

Allocation

NON_RANDOMIZED

Purpose

DIAGNOSTIC

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-04-17

Primary Completion

2028-04-17

Completion

2028-04-17

Countries

• France

Study Locations