Hepatic Encephalopathy Model

Model Introduction

The hepatic encephalopathy (HE) model is a biomedical tool used to study brain dysfunction caused by liver insufficiency and/or portosystemic shunting (PSS). Based on clinical characteristics, the model is classified into three types:

1. Type A (Acute): Simulates HE associated with acute liver failure.
2. Type B (Bypass): Simulates HE caused solely by portosystemic bypass without intrinsic liver disease.
3. Type C (Chronic): Simulates HE occurring on the basis of chronic liver disease or cirrhosis, usually accompanied by extensive portosystemic collateral circulation. The core principle is to induce liver injury through surgery (resection, devascularization, shunting) or chemical agents, leading to pathological manifestations such as hyperammonemia, cerebral edema, and neurological dysfunction in animals.

Research Applications

This model is widely applied in the following areas:

1. Pathogenesis Research: Exploring molecular genetic, anatomical, pathological, and biochemical metabolic changes related to HE.
2. Diagnosis and Imaging Research: Utilizing large animal models to study brain imaging changes and neurodevelopmental evolution.
3. Evaluation of Therapeutic Interventions: Screening new drugs for HE treatment and observing the auxiliary therapeutic effects of artificial or bio-artificial livers.
4. Minimal Hepatic Encephalopathy (MHE) Research: Simulating neuropsychological abnormalities in the subclinical stage.

Key Points of Experimental Design

1. Animal Selection
   • Small Animals (Rodents): High reproducibility and cost-effectiveness; mice are predominantly used for molecular genetics.
   • Large Animals (Pigs, Dogs, Macaques, etc.): Anatomy and physiology closer to humans; suitable for repeated blood sampling, imaging studies, and artificial liver experiments.
2. Modeling Methods and Parameters
   • Type A HE Model:
     • Non-hepatic Surgery: Total hepatectomy or hepatic devascularization (portacaval anastomosis + hepatic artery ligation).
     • Drug Induction:
       • Thioacetamide (TAA): SD rats 300 mg/kg i.p. (4 days); C57BL/6 mice 300 mg/kg (2 days) or 100 mg/kg (3 days).
       • Carbon tetrachloride (CCl₄): 2.5 mL/kg (1:4 in mineral oil) i.p.
       • D-Galactosamine (D-GalN): New Zealand White rabbits 4.25 mmol/kg via ear vein injection.
       • Azoxymethane (AOM): C57BL/6 mice 100 mg/kg i.p.
   • Type B HE Model:
     • Surgery: End-to-side portacaval anastomosis (PCA) or modified selective portacaval end-to-side anastomosis.
   • Type C HE Model:
     • Drugs: TAA in drinking water (initial concentration 0.03%) for 12-20 weeks.
     • Surgery: Common bile duct ligation and resection.
     • Composite Model: Bile duct ligation (BDL) supplemented with 10% ammonium acetate feeding; or CCl₄ gavage for 6 weeks followed by portal vein ligation.
   • Minimal HE (MHE) Model:
     • Drugs: TAA 200 mg/kg i.p. every other day (total 2 doses) or twice weekly (for 8 weeks).
     • Surgery: Calibrated portal vein stenosis (reducing volume by approx. 66%).

Key Monitoring Indicators

1. Biochemical and Physiological Indicators
   • Blood/Brain Ammonia: Significantly increased levels.
   • Glutamine: Elevated concentration.
   • Intracranial Pressure: Monitoring for intracranial hypertension.
2. Pathological Indicators
   • Astrocytes: Observation of foot process swelling or Alzheimer Type II astrocytosis.
   • Brain Tissue: Degree of cerebral edema and inflammatory activation.
   • Liver Tissue: Cirrhotic features and regenerative nodules.
3. Neurological and Behavioral Indicators
   • Consciousness Status: Staged observation from mild abnormalities to coma.
   • Electrophysiology: EEG patterns or evoked potential examinations (especially in MHE models).
   • Imaging: Morphological evolution of the brain in large animals.