Introduction

• Signs: alteration in behavior (sometimes profound), eg head pressing, disorientation, seizures, ataxia and collapse, and depression. Episodes may be related to feeding.
• Cause: exact cause is unknown but results from the liver being unable to remove toxic products of gut metabolism and to synthesize factors necessary for normal brain function.
• Underlying disorders: congenital portosystemic shunts Congenital portosystemic shunt (CPSS) , urea cycle enzyme deficiencies, or acquired portosystemic shunts secondary to other hepatic disease, eg severe parenchymal liver damage due to cirrhosis, neoplasia, drugs, infection or toxins.
• Diagnosis: demonstration of hepatic dysfunction and response to treatment.
• Treatment: fluid therapy, surgery, diet change, medical therapy, eg antibiotics, lactulose, 10% betadine solution enemas, emergency if in hepatic coma.
• Prognosis: good to fair.

Pathogenesis

Etiology

Congenital portosystemic shunts

• Venous malformations connecting the portal and systemic circulations permitting portal blood to circumvent the liver.
• Blood is diverted away from the liver thus preventing toxins from being metabolized.
• May be intra- (more common in large breed dogs) or extrahepatic (more common in small breed dogs).
• Persistent ductus venosus and portocaval or portoazygous shunts are most common Congenital portosystemic shunt (CPSS).
• Other conditions include congenital hepatic microvascular dysplasia and hepatic veno-occlusive disease Liver: congenital diseases.

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 by-pass the liver.

Predisposing factors

General

• Portosystemic shunts.
• Chronic hepatic disease.

• Urea cycle enzyme deficiencies.

Pathophysiology

• Portal blood by-passing the liver and/or hepatic dysfunction leads to toxins accumulating in the blood, causing neurological deficits.
• Toxins implicated include ammonia, methionine, increased aromatic amino acids and reduced branched chain amino acids, increased short chain fatty acids.
• Other proposed abnormalities include increases in brain glutamate (an excitatory neurotransmitter), manganese, TNF-alpha, reactive oxygen species/reactive nitrogen species and increases in the cerebral concentration of an endogenous benzodiazepam-like substance.

• 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, which is a direct neurotoxin acting via chloride channel inhibition.
• Hepatic dysfunction → changes in the circulating amino acid composition - decrease in the concentration of branched chain amino acids (valine, leucine, isoleucine), and increase in the concentration of aromatic amino acids (tyrosine, phenylalamine, free tryptophan).
• Branch chain amino acids are required for the production of excitatory neurotransmitters, levels of which decrease.
• 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 concentrations, although whether this is causative or coincidental is unknown. Manganese-induced neurotoxicity causes astrocyte dysfunction, neuronal loss and gliosis.
• Aromatic amino acids are metabolized to produce 'false' neurotransmitters, which increase in concentration, thus causing the neurological signs.
• 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 (TNF-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 number of the other hypotheses together. THF-a increases CNS endothelial ammonia diffusion, enhances glutamate receptor-mediated neurotoxicity and is associated with significantly increased levels of GABA. Additionally, TNF-a increases peripheral type benzodiazepine receptors and excess manganese potentiates in vitro production of THF-a.

Timecourse

• Non-treated portosystemic shunts will eventually lead to hepatic failure and uncontrolled neurological signs (over months to years).

Diagnosis

Treatment

Outcomes