Hepatic Encephalopathy

Description

Hepatic encephalopathy (HE) is characterised by a complex of neurological abnormalities that occur due to congenital or acquired abnormalities in hepatic structure or function. HE is usually associated with some form of portosystemic shunt (PSS) in dogs and cats, although it may also be caused by a marked reduction in functional hepatic mass. Other causes of HE, such as microvascular dysplasia, congenital defects of enzymes of the urea cycle, arginine deficiency or organic acidaemias, are very rare or of only experimental interest. The clinical signs of HE are associated with increases in the blood concentration of several metabolites:

• Ammonia, a by-product of protein degradation which is transported in the portal vein and metabolised to urea in the liver via the urea cycle. Alterations at any stage in this pathway may result in HE. Ammonia is generated in normal animals through the following physiological processes:
  • Hepatic catabolism of body proteins and of proteins absorbed from the gut, including those obtained after gastro-intestinal haemorrhage.
  • Metabolism of glutamine by enterocytes of the small intestine, the source of 25% of the energy used by these cells.
  • Bacterial and intestinal degradation of urea by urease in the colon.
  • Bacterial degradation of undigested amino acids in the colon.
• Mercaptans, products of the bacterial degradation of the amino acid methionine in the colon.
• Aromatic amino acids, especially when the ratio of aromatic to branched chain amino acids is very high. This is considered to be a significant component in the pathogenesis of HE in horses.
• Endogenous benzodiazepine receptor ligands are of questionable importance.

HE represents a reversible alteration in cerebral metabolism whose pathogenesis is not yet fully understood. An increased blood concentration of ammonia is the most commonly cited cause by HE and it is known that this metabolite is able to cross the blood brain barrier and exert a directly toxic effect on neurones of the central nervous system (CNS). Since the cells of the CNS are not able to express the constituent enzymes of the urea cycle, they convert ammonia into glutamine rather than urea. Glutamine is a potent neurotransmitter in the CNS and its levels correlate with the clinical signs observed in HE. Increased concentrations of ammonia in the cerebro-spinal fluid are reported to have additional effects on cerebral metabolism, including reducing levels of the excitatory neurotransmitter serotonin and increasing the levels of NMDA (N-methyl-D-aspartate) and peripheral-type benzodiazepine receptors. Aromatic amino acids (especially tryptophan and its metabolites) share an antiport transporter with ammonia in the blood brain barrier and dogs with congenital PSS are therefore reported to have increased levels of these amino acids in their CSF.

Signalment

HE occurs in those breeds that often develop PSS, of which small breeds of dog are most at risk. Most dogs with PSS present before the end of their first year of life. Microvascular dysplasia and congenital defects of the urea cycle are very rare.

Diagnosis

Clinical Signs

Dog

Typical signs include:

• Anorexia, depression and lethargy.
• Bizarre behaviour, including aimless wandering, head pressing, circling, pacing and compulsive eating and drinking.
• Central or amaurotic blindness, where animals retain a menace response but will collide with objects when ambulatory.
• Comas and reactive seizures are uncommon.
• Gastrointestinal signs may be observed, including vomiting.

Other signs that occur in animals with PSS or microvascular dysplasia include:

• Temporary resolution of clinical signs with antimicrobial therapy, due to a reduction in the number of colonic bacteria.
• Prolonged recovery from sedation or anaesthesia because the metabolic capacity of the liver is reduced.
• Polyuria and polydipsia in 33% of cases

Cat

Typical signs include:

• Hypersalivation or ptyalism is the most commonly reported clinical feature but this is rarely reported in dogs.
• Seizures occur in 50% of cases but are uncommon in dogs.
• Compulsive behaviour is less common than in dogs.

Laboratory Tests

Biochemistry

• Hypoproteinaemia
• Mild to moderate increase in alanine aminotransferase (ALT) and alkaline phosphatase (ALP)
• Decreased blood urea nitrogen (BUN)
• Hypoglycaemia in a small number of dogs

Other Tests

• Fasting hyperammonaemia
• Increased postprandial ± preprandial bile acids

Diagnostic Imaging

Radigraphy

Abdominal radiography shows microhepatica and often renomegaly. Renomegaly may relate to an altered splanchnic blood flow or to an increased metabolic activity of the kidney due to hyperammonaemia. These findings in a young dog are highly suggestive of Portosystemic Shunt.

Confirmation of a Portosystemic Shunt requires visualisation of the shunting blood vessel. This may be done with either ultrasonography or contrast portography or at surgery.

Treatment

Surgical management

• Surgical ligation of shunt is recommended in cases of Portosystemic Shunt.

Medical management

• Enemas to decrease the amount of bacteria in the colon.
• Oral antibiotics such as ampicillin, neomycin or metronidazole can be given initially reduce the amount of bacteria in intestines and hence decrease the production of ammonia.
• Lactulose PO
  • This is a synthetic disaccharide which is metabolised by the acidifying colonic bacteria. Ammonia is converted into ammonium ions, which cannot be absorbed and hence trapped in the colon and excreted in the faeces. Lactulose also acts as an osmotic laxative, allowing more faeces and bacteria to be washed out.
• A high carbohydrate, low protein (2g/kg/day) and low fat diet is recommended.
  • The aim is to provide adequate nutrients and energy to support hepatic tissue repair, reduce the metabolic load on the liver and minimise the development of hepatic encephalopathy

Prognosis

In cases of PSS, the prognosis in dogs for resolution of clinical signs after total surgical ligation is excellent. However, the response of cat to surgical intervention in cats is less promising than in dogs.

References

• Hall, E.J, Simpson, J.W. and Williams, D.A. (2005) BSAVA Manual of Canine and Feline Gastroenterology (2nd Edition) BSAVA
• Nelson, R.W. and Couto, C.G. (2009) Small Animal Internal Medicine (Fourth Edition) Mosby Elsevier.
• Ettinger, S.J. and Feldman, E. C. (2000) Textbook of Veterinary Internal Medicine Diseases of the Dog and Cat Volume 2 (Fifth Edition) W.B. Saunders Company.

From Pathology

Clinical

• non-specific neurological signs (attributed to the retention of ammonia and gamma aminobutyric acid in liver failure and their effects on the brain)
  • dullness
  • apparent unawareness of surroundings
  • pointless or compulsive movements
  • mania
  • generalised convulsions

NB: usually soon followed by death

Microscopically

• lesions in the brain vary in expression
  • most species may show myelin degeneration consisting of vacuoles between the grey and white matter
  • the horse may show very little visible neural changes, perhaps an increase in astrocytes

Causes

Portosystemic Shunting

Chronic liver damage

• due to ingestion of toxic compounds over a long period of time
• E.g. ragwort

Also known as:

Portosystemic encephalopathy Hepatic coma

See also:

Hepatic Encephalopathy in Horses