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==Description==
==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|'''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|'''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:
'''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|'''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|'''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:
*'''Ammonia''' is a by-product of protein degradation which is transported in the portal vein and metabolised to urea in the liver via the urea cycle. In animals with PSS, ammonia is not removed from the portal blood as this bypasses the liver, leading to an increase in its blood concentration. 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.
**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.
**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 and intestinal degradation of urea by urease in the colon.
**Bacterial degradation of undigested amino acids 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.
*'''Mercaptans''' are products of the bacterial degradation of the amino acid methionine in the colon which are usually removed from the portal blood in the liver.
*'''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.
*'''Aromatic amino acids''' may be involved 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.
*'''GABA''' (gamma amino butyric acid) is an endogenous neurotransmitter which is produced from ammonia.
*'''Short-chain fatty acids''' (such as butyrate and propionate) make a questionable contribution to HE.
*'''Endogenous benzodiazepine receptor ligands''' are also 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.
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 of 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. The neurotransmitter '''GABA''' is produced from ammonia and, as the blood ammonia concentration rises, so too do the levels of GABA in the CNS. This transmitter imbalance is thought to increase the number of inhibitory GABA receptors present in the CNS.
HE may be precipitated by severel conditions in animals, all of which cause an increase in the blood concentrations of ammonia and/or mercaptans:
*'''Metabolic alkalosis'''
*'''Hypokalaemia'''
*'''Constipation''', increasing the length of time that colonic bacteria are able to act on undigested amino acids.
*'''Gastro-intestinal haemorrhage''', increasing the amount of protein available to GI bacteria.
*'''Diet with a high protein, purine or methionine content'''
*'''Azotaemia'''
*'''Hypermetabolic state or fever''', as may occur in many forms of systemic illness due to the effects of inflammatory cytokines and which leads to the catabolism of lean body protein.
*'''Dehydration''' increases the effective circulating ammonia concentraton.
==Signalment==
==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.
HE occurs in those breeds that often develop congenital 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. Acquired PSS may occur in animals with '''[[Hepatitis, Chronic|chronic hepatitis]]''', to which labrador retrievers, West Highland white terriers, English cocker spaniels and Dobermans are predisposed.
==Diagnosis==
==Diagnosis==
Typical signs include:
Typical signs include:
*'''Anorexia, depression''' and '''lethargy'''.
*'''Anorexia, depression''' and '''lethargy'''.
*'''Bizarre behaviour''', including aimless wandering, head pressing, circling, pacing and compulsive eating and drinking.
*'''Bizarre behaviour''', including aimless wandering, head pressing, circling, pacing, pica and compulsive eating and drinking.
*'''Central or amaurotic blindness''', where animals retain a menace response but will collide with objects when ambulatory.
*'''Central or amaurotic blindness''', where animals retain a menace response but will collide with objects when ambulatory.
*'''Comas''' and reactive '''seizures''' are uncommon.
*'''Comas''' and reactive '''seizures''' are uncommon.
*'''Gastrointestinal signs''' may be observed, including [[Stomach and Abomasum Consequences of Gastric Disease - Pathology|vomiting]].
*'''Gastrointestinal signs''' may be observed, including [[Stomach and Abomasum Consequences of Gastric Disease - Pathology|vomiting]].
Other signs that occur in animals with PSS or microvascular dysplasia include:
Other signs that occur in animals with congenital PSS or microvascular dysplasia include:
*Temporary '''resolution of clinical signs with antimicrobial therapy''', due to a reduction in the number of colonic bacteria.
*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.
*'''Prolonged recovery from sedation or anaesthesia''' because the metabolic capacity of the liver is reduced.
*'''Polyuria and polydipsia''' in 33% of cases
*'''Polyuria and polydipsia''' in 33% of cases and other signs of urinary tract disease.
====Cat====
====Cat====
===Laboratory Tests===
===Laboratory Tests===
Although many parameters are likely to be altered in animals with HE, most of these changes result from the underlying disease. '''Fasting hyperammonaemia''' provides an explanation for HE and should increase suspicion of congenital (or acquired) PSS. An '''ammonia tolerance test''' can also be performed, in which ammonium chloride is administered by orogastric tube or by high colonic infusion. Blood samples taken 30 minutes later should show an increased level of circulating ammonia. Since this procedure may be dangerous to the animal, it may be preferable to perform a '''modified ammonia tolerance test''' by feeding a meal containing 25% of the animal's daily requirement and measuring blood ammonia concentration 6 hours later.
===Diagnostic Imaging===
===Diagnostic Imaging===
Imaging is not required to make a diagnosis of HE but it may reveal abnormalities relating to the underlying cause.
==Treatment==
==Treatment==
The underlying cause of the HE should be treated, including surgical ligation of '''congenital''' PSS. In the meantime, the HE should be managed medically with a typical regime involving the following components:
*'''Withhold food'''
*'''Intra-venous fluid therapy''', which can also be used to correct any hypokalaemia or metabolic alkalosis which may be precipitating the HE.
*'''Enemas''' of warm water or lactulose to decrease the population of bacteria in the [[Colon - Anatomy & Physiology|colon]].
*Enemas to decrease the amount of bacteria in the [[Colon - Anatomy & Physiology|colon]].
*'''Antibiotics''' given orally or by per rectum to reduce the number of colonic bacteria. Suitable products include [[Penicillins|ampicillin]], [[Aminoglycosides|neomycin]] (which, although highly toxic when administered systemically, is also highly polar and therefore restricted to the GI tract) or [[Nitroimidazoles|metronidazole]].
*Oral antibiotics such as [[Penicillins|ampicillin]], [[Aminoglycosides|neomycin]] or [[Nitroimidazoles|metronidazole]] can be given initially reduce the amount of bacteria in intestines and hence decrease the production of ammonia.
*[[Drugs Acting on the Intestines#Osmotic Laxatives|'''Lactulose''']] can be given orally or by enema. It is a synthetic disaccharide which, when metabolised by the acidifying colonic bacteria, donates a hydrogen ion to ammonia to form ammonium ions. Because these ions are charged, the are not absorbed freely and are rather trapped in the colon and excreted in faeces. Lactulose also acts as an osmotic laxative, preventing constipation and reducing the time that colonic bacteria are able to act on undigested amino acids to form ammonia.
*[[Drugs Acting on the Intestines#Osmotic Laxatives|Lactulose]] PO
*When the animal is to be fed, a '''diet with a high carbohydrate, low protein (2g/kg/day) and low fat''' content is recommended. Both soluble and insoluble fibre may be beneficial in appropriate quantities as the former traps ammonia in the colon and the latter reduces intestinal transit time and prevents constipation. In an animals with PSS or severe hepatic insufficiency, it may not be advisable to restrict protein too assiduously as these animals are likely to be [[Hypoalbuminaemia|hypoalbuminaemic]].
*'''Seizures''' should be treated with anticonvulsant medication but benzodiazepines should be avoided as they may worsen the HE.
*A high carbohydrate, low protein (2g/kg/day) and low fat diet is recommended.