Hepatic encephalopathy (HE) represents a disease state characterized by cerebral dysfunction related to underlying intrinsic liver disease or abnormal hepatic perfusion.¹ The pathophysiology of HE is complex and incompletely understood. While the role of ammonia in HE is well characterized, a multitude of other chemicals are also implicated in its pathogenesis. These include, but are not limited to, glutamate, GABA, endogenous benzodiazepines, aromatic amino acids, mercaptans, opioids, manganese, and alterations in the tryptophan-serotonin system.¹

Diseases Causing Hepatic Encephalopathy

Causes of HE may be categorized as type A (acute), B (bypass), or C (chronic/cirrhosis).^2,3 Type A represent acute fulminant liver dysfunction, for example after exposure to hepatotoxicants (e.g., xylitol, amanita mushrooms, sago palm). Type B refer to abnormal liver perfusion secondary to congenital portosystemic shunting (PSS) and is the most common type seen in animals.¹ Type C develops during the terminal stages of chronic hepatopathies where portal hypertension and acquired shunting develop. Different pathological lesions are noted with acute and chronic cases of HE. The prominent feature of acute HE is cytotoxic brain oedema. Chronic cases have only minimal oedema but develop brain histological changes (e.g., Alzheimer type II astrocytosis) after chronic exposure to hyperammonaemia.⁴ Hyperosmotic therapies (e.g., mannitol, hypertonic saline) would generally be appropriate for acute HE.⁵ Corticosteroids are contraindicated, however, since they may promote water retention and could worsen brain oedema.⁶

Diagnosing Hepatic Encephalopathy

A diagnosis of HE requires three concurrent features: signs compatible with cerebral dysfunction, hyperammonaemia, and documented abnormal liver function. The clinical signs associated with HE in animals vary in severity. Common symptoms include altered mentation, lethargy, head pressing, inappropriate vocalizing, and seizures. These symptoms may be episodic in nature and triggered by inciting events (e.g., after ingesting a protein meal). Some symptoms are species specific (e.g., ptyalism in cats). Certain clinical presentations (e.g., young small breed dogs with neurological dysfunction) may increase our index of suspicion for HE.

If HE is suspected, measurement of ammonia is a reasonable next diagnostic step. Most ammonia comes from the breakdown of dietary proteins by urease producing bacteria in the GI tract. The unionized form of ammonia (NH₃) can leave the GI tract and is transported to the liver via the portal circulation, while ammonium ions (NH₄⁺) remain trapped within the lumen. A complex series of biochemical events (the urea or Ornithine cycle) occurs in periportal hepatocytes resulting in the conversion of ammonia (NH₃) to urea [(NH₂)₂CO] for renal excretion. An alternative means of ammonia handling (transamination) occurs within the perivenous hepatocytes, as well as the brain and skeletal muscles. Transamination involves the addition of ammonia to glutamate (i.e., amination) producing glutamine, catalyzed by glutamine synthase. Under normal circumstances, amination is an effective ammonia handling mechanism since it produces the relatively inert glutamine. Glutamate is the major excitatory neurotransmitter in the mammalian CNS. Any excess glutamate is taken up by astrocytes that limits excitatory stimulation. Within astrocytes, glutamate undergoes amination to produce glutamine that eventually enables regeneration of glutamate. In patients with severe liver dysfunction or in situations where ammonia bypasses the liver due to shunting, the opportunity for ammonia detoxification via the urea cycle or transamination may be missed.

Ammonia can cross the blood-brain barrier and may interfere with the glutamine-glutamate recycling system. Ammonia inhibits glutamine release from astrocytes. While glutamine is usually considered inert, it is osmotically active and excessive intracellular accumulation promotes cellular swelling. This is achieved by the insertion of specific aquaporin-4 channels into astrocyte cell membranes.⁷ Intracellular glutamine moves into the mitochondria, where deamination occurs producing glutamate and ammonia. This process leads to the deleterious production of reactive oxygen and nitrogen species secondary to ammonia liberation.¹ To this extent, movement of the relatively innocuous glutamine into mitochondria leading to the production of damaging reactive oxygen and nitrogen species is described as the ‘Trojan horse’ hypothesis, due to similarities with its mythical counterpart.

The liver normally has a huge reserve capacity meaning severe disease must be present in order for hyperammonaemia to develop. A clinical diagnosis of HE, therefore, requires documentation of severe liver dysfunction in light of appropriate clinical signs and hyperammonaemia. Despite its infamous association with HE, ammonia concentration is imperfectly associated with the severity of HE. Alternative differentials for hyperammonaemia may also be encountered (e.g., cobalamin deficiency).⁸ A recent study investigated various diagnostic tests for identification of congenital PSS in dogs, with abnormal fasting bile acids plus documentation of hyperammonaemia in dogs making PSS quite likely. Normal bile acids with a normal ammonia tolerance test in symptomatic dogs, in contrast, effectively ruled out PSS.⁹ Alternative indicators of liver function (e.g., protein C) are used at some institutions.¹⁰ Hyperbilirubinaemia is not a feature of congenital PSS but may be seen in dogs with HE due to intrinsic liver disease.¹¹

The non-ammonia contributors to HE unfortunately are much harder to assess in individual patients since laboratory assays for these substances are rarely available. From a mechanistic perspective, it is helpful to consider the cumulative effects of the non-ammonia factors as tipping the balance between CNS excitation and inhibition. Glutamate reuptake, for instance, is inhibited in hyperammonaemic states and promotes an excitatory environment that could lower the seizure threshold.^1,12 Overall a predominant inhibitory tendency is most common in animals with HE. The major inhibitory neurotransmitter in the CNS is GABA. Most GABA is of intestinal origin and excessive blood concentrations of GABA may occur if there is acute intrinsic liver failure. Excessive agonism of GABA receptors consequently produces an inhibitory effect. In addition, endogenous benzodiazepines may be produced in animals with HE, which would further stimulate central GABA receptors.¹³

Another interesting contribution to HE in some patients involves the abnormal production of catecholamine neurotransmitters from aromatic amino acids (e.g., phenylalanine, tyrosine, tryptophan). In patients with liver dysfunction or PSS, the ability to convert aromatic amino acids to the typical neurotransmitters may be overwhelmed. In this situation, false neurotransmitters (e.g., octopamine, phenylethanolamine) may be synthesized that also exert an inhibitory effect. Branched chain amino acid concentrations (e.g., leucine, valine) may also be decreased in these patients. Manganese elimination is impaired in dogs with chronic hepatopathies and elevated manganese concentrations are also noted in dogs with congenital PSS.¹⁴ The tryptophan-serotonin system may also be disrupted in HE patients although its significance is controversial in individual patients.¹ Glutamine, from the amination of glutamate, is exchanged across the blood-brain barrier for tryptophan.¹⁵ Tryptophan is a precursor to serotonin, as well as quinolinic acid that acts upon NMDA receptors.

Managing Hepatic Encephalopathy

When faced with a patient with suspected or confirmed HE, the potential for comorbidities contributing to their clinical signs should be considered. The presence of an inflammatory focus has been associated with worsening of HE symptoms.^16-18 Clinical indicators of inflammation (e.g., SIRS criteria, C reactive protein) have also been associated with more severe HE symptoms in dogs.^19,20 Occult sources of infection including blood stream infections, aspiration pneumonia, and urinary tract infections should be considered in patients with HE. Urinary tract infections may be particularly relevant, since many dogs with PSS have urate uroliths that could act as a nidus for infection. Animals with inflammation are also more likely to have a prothrombotic tendency compared to normal dogs. One study identified a hypercoagulable tendency was more common in dogs with PSS that had HE.²¹ Arginine is an essential amino acid in cats and a key player in the urea cycle. A deficiency in arginine may occur in cats with hepatic lipidosis following a period of anorexia and may lead to hyperammonaemia in the absence of PSS or intrinsic liver pathology.^22,23

Several putative factors may augment the severity of HE symptoms, including:

• Hypokalaemia
• Hyponatraemia
• Metabolic alkalosis
• Gastrointestinal bleeding
• Protein ingestion
• Hypoglycaemia
• Dehydration
• Constipation
• Renal insufficiency
• Diuretic administration²⁴

Hypokalaemia promotes metabolic alkalosis increasing the ratio of NH₃:NH₄⁺ form. Hypokalaemia also significantly increases renal ammonia production and excretion.²⁵ Interestingly, a recent study in dogs did not find any of the aforementioned metabolic derangements were necessarily more likely to be present in dogs with HE at admission to a teaching hospital.²⁴ That said, attention to presence of metabolic derangements is important since therapeutic measures to correct them have been associated with successful amelioration of HE symptoms.²⁴

Most classic treatments for HE are aimed at attenuating the effects of hyperammonaemia. Lactulose is a nonabsorbable disaccharide and is broken down in the gut to acidic byproducts. These products convert unionized NH₃ to NH₄⁺, effectively trapping it within the gut and preventing absorption. Lactulose can either be given orally or as a retention enema in more severely compromised animals. It is also an osmotic cathartic, increasing gastrointestinal transit time that may have additional benefits in the HE patient. Due consideration for patient fluid balance is needed after lactulose administration in case excessive fluid loss via the GI tract occurs. Several antibiotics have been used in the management of patient with HE, with ampicillin and metronidazole being commonly chosen in small animals. Neomycin was used historically but has fallen out of favor given aminoglycoside nephrotoxicity concerns. The rationale behind antibiotic prescription is to reduce the number of urease producing bacteria in the gut. In the long-term an optimized diet consisting of a highly digestible protein source (rather than protein restriction) is recommended. Levetiracetam is the current anti-epileptic drug of choice in animals that have seizures as part of their HE syndrome, although preemptive administration in animals with PSS prior to surgery may not afford protection against seizres²⁶ as was initially reported²⁷.

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