Introduction

• Cause: underlying disorders eg congenital portosystemic shunts (PSS) Congenital portosystemic shunt (CPSS), urea cycle enzyme deficiencies or acquired PSS secondary to other hepatic disease.
• Signs: alteration in behavior, eg head pressing, disorientation, seizures, ataxia, depression and collapse +/- gastrointestinal signs, weight loss.
• Episodes may be related to feeding.
• Hypersalivation   is a common manifestation in cats.
• Diagnosis: signs and biochemical assays.
• Treatment: reduction in ammonia and mercapten production; antibiotics and reduced protein diet.
• Emergency if in hepatic coma.
• Prognosis: acute crisis can often be managed; long term prognosis depends on cause of liver dysfunction.

Pathogenesis

Etiology

Congenital portosystemic shunts

• Venous malformations connecting the portal and systemic circulations permitting portal blood to circumvent the liver.
• May be intra- or extrahepatic Congenital portosystemic shunt (CPSS):
  • Portocaval shunts.
  • Portoazygous shunts.
  • Persistent ductus venosus (less common).
• Blood is diverted away from the liver thus preventing toxins from being metabolized.

Acquired portosystemic shunts

• Secondary to chronic hepatic disease: end-stage hepatic fibrosis leads to increased resistance to intrahepatic blood flow causing collateral circulation pathways to develop which bypass the liver.
  Acquired shunts are very rare in cats.

Predisposing factors

General

• Portosystemic shunts Congenital portosystemic shunt (CPSS).
• Chronic hepatic disease Liver: chronic disease. 

• Urea cycle enzyme deficiencies Storage disease.

Pathophysiology

• Portal blood bypassing liver (congenital shunts) and/or hepatic dysfunction   →   toxins accumulating in the blood   →   neurological deficits.
• Toxins implicated include:
  • Ammonia.
  • GABA/benzodiazepine.
  • Glutamate.
  • Methionine.
  • Reduced branched chain amino acids.
  • Increased short chain fatty acids.
  • Increased aromatic amino acids.
  • Manganese.
  • TNF-alpha.
  • Reactive oxygen species/reactive nitrogen species.

• There are several theories as to the pathogenesis of hepatic encephalopathy and origin is probably multifactorial.
• Excess [blood ammonia ] produced by action of gut bacteria on dietary protein is probably important but still controversial since the degree of correlation between hepatic encephalopathy severity and blood ammonia concentration is variable. Ammonium ions are detoxified predominantly in the liver via the urea cycle, with resultant production of glutamine. In liver failure, hepatic ammonia detoxification is ineffective, leading to hyperammonemia. The brain lacks a urea cycle and relies on production of glutamine for detoxification of ammonia, wnhich is a direct neurotoxin acting via chloride channel inhibition. 
• Hepatic dysfunction   →   changes in the circulating amino acid composition - decrease in the concentration of branch chain amino acids and increase in the concentration of aromatic amino acids.
• Branch chain amino acids are required for the production of excitatory neurotransmitters, levels of which decrease.
• Aromatic amino acids are metabolized to produce 'false' neurotransmitters, which increase in concentration, thus causing the neurological signs.
• Manganese is excreted via the hepatobiliary route and its concentration increases in liver disease. Patients with chronic liver disease and hepatic encephalopathy have increased brain manganese concentration, although whether this is causative or coincidental is unknown. Manganese-induced neurotoxicity causes astrocyte dysfunction, neuronal loss and gliosis.
• Increases in brain glutamate (an excitatory neurotransmitter).
• Increased cerebral concentration of an endogenous benzodiazepine-like substance. The GABAergic theory suggests hepatic encephalopathy is due to increased circulating levels of GABA derived from the gastrointestinal tract, although the theory has been modified to include the involvement of endogenous benzodiazepines, which are also increased in hepatic encephalopathy patients.
• Circulating levels of tumor necrosis factor-a (THF-a), a proinflammatory cytokine are increased in liver failure patients and appear to correlate with HE severity. In liver failure, TNF-a production increases whilst TNF-a clearance may be reduced. Pathological derangements of the brain in HE may be induced in part by TNF-a excess. The TNF-a hypothesis links a nmber of the other hypotheses together. TNF-a increases CNS endothelial ammonia diffusion, enhances glutamate receptor-mediated neurotoxicity and is associated with significantly increased levels of GABA. Additionally, THF-a increases peripheral type benzodiazepine receptors and excess manganese potentiates in vitro production of TNF-a.

Diagnosis

Treatment

Outcomes