Page 1118 - Small Animal Clinical Nutrition 5th Edition

1164 Small Animal Clinical Nutrition

VetBooks.ir Box 68-1. Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a neurologic syndrome that may
arise due to liver dysfunction and portosystemic shunting (Figure
1). HE is categorized as acute or chronic, based on duration of signs
and relative importance of the two main etiologic factors. Striking
differences exist in the pathogenesis of acute and chronic HE.
Because acute HE occurs rarely in dogs and cats, this summary will
focus on chronic HE. Chronic HE results from disturbances in vari-
ous neurotransmitter systems caused by a variety of gut-derived
toxins and compounds.These toxins and compounds reach the sys-
temic circulation when liver function is compromised and collateral
circulation develops (Figure 2).
The pathogenesis of HE remains partly unknown due to the
complex interplay between various pathogenetic factors and neu-
rotransmitter systems. However, there seems to be consensus that
the main neurotransmitter systems involved in HE are the GABA-
ergic (the most abundant inhibitory neurotransmitter system in the
brain) and the glutamatergic (the most important excitatory neuro-
transmitter system in the brain). Other neurotransmitters that may
play a role include catecholamines, serotonin and opioids. Without
doubt, ammonia is the main causative agent behind neurologic
changes. Other contributing factors may include accumulation of
manganese (Mn), increased concentrations of neurosteroids and
peripheral benzodiazepine receptor ligands and changes in the
molar ratio between branched-chain amino acids (BCAA) and aro-
matic amino acids (AAA) in plasma and cerebrospinal (CSF) fluid.
An abundance of evidence suggests that GABA-ergic tone is
increased in HE. Although the nature of this increase is partly
unknown, ammonia plays a key role.The role of increased concen-
trations of endogenous benzodiazepine receptor ligands in HE, an
attractive hypothesis postulated in the late 1990s, has been aban-
doned. However, neurosteroids, which increase in people with HE,
may have a direct influence on the GABA-ergic tone.
Although total brain glutamate is decreased in HE, intrasynaptic
glutamate is increased, leading to down regulation of various post-
synaptic glutamatergic receptor types.
Methionine, degraded by gut bacteria to the mercaptans meth-
anethiol and dimethyldisulfide, has been implicated in the patho-
genesis of HE, alone or synergistically with ammonia and free fatty
acids. However, previous diagnostic methods overestimated the Figure 1. The effect of portosystemic shunting on hepatic extrac-
importance of these compounds; in rats and dogs, there was no tion of bile acids and ammonia. (Adapted from Center SA. Hepatic
correlation between the severity of HE and the concentrations of vascular diseases. In: Guilford WG, Center SA, Strombeck DR, et
methanethiol and dimethyldisulfide. Thus these compounds do not al, eds. Strombeck’s Small Animal Gastroenterology, 3rd ed.
play an important role in the pathogenesis of HE. On the other Philadelphia, PA: WB Saunders Co, 1996; 805, 813.)
hand, S-adenosylmethionine (SAMe), an important precursor of
liver glutathione, may play a role in the treatment of chronic liver Although a consistent decrease in the molar ratio between BCAA
disease because liver glutathione, an important antioxidant com- and AAA in plasma and in CSF has been reported in longstanding
pound, is depleted in liver disease. HE in many species, the importance of this molar ratio change in
In human HE patients, a relation was found between high Mn the pathogenesis of HE remains unclear. It may play a role in the
concentrations in blood and/or the globus pallidus and hyperinten- reported dopaminergic dysfunction in HE, but others have not con-
sity of the magnetic resonance imaging signal in the globus pal- firmed this hypothesis. The main beneficial effect of correction of
lidus. High Mn concentrations in the globus pallidus were accom- the BCAA:AAA ratio by infusions or diet is reversal of the catabol-
panied by a loss of dopamine binding sites. Binding of Mn to ic state in patients with HE.
dopamine receptors may have resulted in auto-oxidation of Cats develop HE if fed foods deficient in arginine. Cats affected
dopamine and formation of free radicals that caused tissue dam- with hepatic lipidosis have low serum arginine concentrations.
age. No studies have been done to confirm increased Mn concen- Because animal-origin protein is generally rich in arginine, most
trations in the brains of dogs and cats with HE. commercial cat foods and foods for stress and recovery are well