Hepatic Encephalopathy

Brain neurons require a stable extracellular environment to maintain their metabolic function. Changes in this environment cause certain types of brain dysfunction known as metabolic encephalopathies. Hepatic encephalopathy develops when the liver does not synthesize substances needed by the brain (for example, glucose) or does not break down toxins. The most common cause is intra or extrahepatic portosystemic shunt. Intrahepatic shunts are congenital and extrahepatic shunts can be either congenital or acquired. Congenital shunts typically occur in young animals, while acquired shunts are characteristic of adult or old animals.

In dogs, acquired shunts are usually associated with terminal liver cirrhosis secondary to chronic active hepatitis. In cats, they are far less frequent and are associated with hepatic lipidosis.

The pathogenesis of hepatic encephalopathy is not fully understood, but it appears to be associated with the following:

1. Ammonia. A toxin produced by intestinal bacteria that passes into the blood. Under normal conditions, is metabolised in the liver and 81%-87% is converted into urea. When blood levels are very high, it crosses the blood-brain barrier, where its toxic effect causes nervous symptoms. Interestingly, the brain naturally synthesizes higher concentrations of ammonia than those found in the blood. The astrocytes detoxify ammonia by transforming glutamate (also neurotoxic) into glutamine. CFS glutamate levels are increased in hepatic encephalopathy. Many, but not all, animals with hepatic encephalopathy have elevated blood ammonia levels, so its pathological significance is unclear.
2. Increased aromatic amino acids, which are metabolised by the liver (tryptophan, tyrosine and phenylalanine) and a decrease in branched chain amino acids (valine, leucine and isoleucine). This alters the monoamine brain neurotransmitters, increases the production of serotonin, and decreases norepinephrine and dopamine secretion. These changes can also be found in liver pathologies that do not cause encephalopathy.
3. Altered levels of gamma-aminobutyric acid (GABA) and glutamate in the brain. The pathological significance of this is not clearly understood.
4. Increased levels of endogenous benzodiazepines in the brain. Although administration of benzodiazepine antagonists improves nervous symptoms, the mechanism of action is unknown.

To sum up, increased levels of ammonia, mercaptans, indoles, skatoles, short-chain fatty acids, among others, are detected, but the mechanism that triggers hepatic encephalopathy is still unclear.

Symptoms

In the case of a congenital shunt, symptoms generally appear early - before one year of age and especially in the first months of life. Affected animals are usually the smallest of the litter and are in poor general condition.

Nervous symptoms consist of changes in consciousness (stupor, coma) and/or behaviour (frequent aggression in cats, distrust, hysteria) and intermittent seizures (more frequent in cats). Other symptoms, such as circling, ataxia, and visual deficits may also be observed. Ptyalism is very common in cats. Nervous symptoms are exacerbated after meals.

Systemic symptoms are related to hepatic dysfunction, and consist of vomiting (frequent), weight loss, anorexia, polyuria, polydipsia, diarrhoea and ascites.

Interpretation of laboratory tests

General Tests

• Complete blood count: Moderate non-regenerative microcytic anaemia with poikilocytosis. Red blood cells may appear as echinocytes.
• Biochemistry. BUN, GLU and ALB are usually decreased. GPT may be normal or slightly elevated. In acute cases, both GPT and BIL are extremely elevated. This increase in BIL interferes with the determination of bile acids. COL may be increased if liver function is altered, or decreased if the cause is a portosystemic shunt.
• Urine test: Uroliths or ammonia biurate crystals may be found in urine. Urine-specific gravity is decreased.

Test values are generally more abnormal in cats than in dogs.

Specific tests

• Ammonia: Often elevated.
  Reference values:
  • Dogs: 45 – 120 μg/dL
  • Cats: 30 – 100 μg/dL
• Pre- and post-prandial bile acid challenge: Three blood samples are drawn: the first on an empty stomach, the second two hours after eating, and the third 12 hours after eating. Two-hour post-prandial values are extremely elevated in animals with a shunt, because they cannot eliminate bile acids. Acid levels are normal in the pre-prandial and 12-hour post-prandial sample. It is advisable to perform the third determination to rule out cholestasis, in which both pre-prandial and 12 hour postprandial values will be elevated.
  Reference values:
  • Pre-prandial: Dogs and cats: <10 μmol/L
  • Post-prandial (2 hours):
    • Dogs: < 25 μmol/L
    • Cats: < 20 μmol/L
• Ammonia tolerance test: Value are abnormal in only 1% of cases and the test is dangerous for the animal. It is not recommended.

Considerations

Benzodiazepines and barbiturates should be monitored because they can worsen nervous symptoms.

Uraemic encephalopathy

Causes convulsions, altered consciousness, delirium, etc. It may be associated with ataxic breathing that does not respond to hypoxia, eye movements, facial muscle tremor, etc. The pathogenesis is complex and is associated with hypertension, elevation of cerebral ionic Ca, etc.

Laboratory tests show extremely elevated levels of BUN, CRE, and P, as well as metabolic acidosis, although these values are not directly proportional to the severity of the disease.

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