INTRODUCTION

HE comprises a spectrum of neurologic abnormalities associated with moderate to severe liver insufficiency. In dogs and cats, it occurs most commonly with portosystemic shunting of blood. Fulminant hepatic failure is an important cause of HE in humans but is seen less commonly in veterinary medicine. Congenital urea cycle enzyme deficiencies may also lead to HE.

CAUSES

In dogs and cats, congenital extrahepatic or intrahepatic portal-to-systemic venous communications are the most frequent cause of HE; up to 95% of affected animals demonstrate neurologic symptoms.¹ These communications are generally a single vessel, but multiple extrahepatic² and intrahepatic³ congenital portosystemic shunts have been reported. Hepatic arteriovenous malformations cause portal hypertension, multiple extrahepatic portosystemic shunts, and ascites, and may cause symptoms of HE. In young dogs, hepatic microvascular dysplasia⁴ and, rarely, congenital urea cycle deficiencies⁵ can also cause symptoms of HE. In older animals, portosystemic shunts develop secondary to portal hypertension that results from chronic liver disease. In cats, hepatic lipidosis often is associated with symptoms of HE. Other causes of chronic and acute hepatic failure that can result in symptoms of HE are discussed in Chapter 127, Hepatic Failure.

PATHOPHYSIOLOGY

In 1893, Marcel Nencki and Ivan Pavlov described the physiologic consequences of a surgically created, end-to-side portocaval shunt (Eck fistula) and showed that clinical signs in this canine model worsened after a meat meal, linking HE to the concept of “meat intoxication.”⁶ Ever since this description, HE has been thought of as a condition caused by gut-derived toxins that are not metabolized by a diseased or failing liver. Research over the last century has elaborated on this concept and demonstrated the complexity of this condition. However, recent work on several aspects of HE including cerebrospinal fluid amino acid alterations,^7,8 glutamate neurotoxicity,⁹ the generation of reactive oxygen species,¹⁰ and the mitochondrial permeability transition¹¹ emphasizes the central role of elevated blood ammonia concentrations in animals with HE. Other substances that are considered synergistic with ammonia toxicity include mercaptans, free fatty acids, phenols, and bile salts¹² (see Chapter 127, Hepatic Failure, Table 127-2 for a summary of toxins implicated in HE).

Ammonia is produced in the intestinal tract as the end product of amino acid, purine, and amine breakdown by bacteria, the metabolism of glutamine by enterocytes, and the breakdown of urea by bacterial urease.¹³ It is then absorbed into the portal blood and rapidly converted to urea or glutamine in the normal liver. In animals with portosystemic shunting of blood or significant liver disease, high levels of ammonia are present in the systemic circulation. The permeability of the blood-brain barrier to ammonia increases in animals with HE, and experimental studies suggest that HE coma is associated with brain ammonia concentrations in the low millimolar range.¹⁴ These concentrations of ammonia decrease excitatory neurotransmission, in part by down-regulating the N-methyl-D-aspartate (excitatory) receptors,⁹ yet at the same time block chloride extrusion from the postsynaptic neuron, decreasing inhibitory neurotransmission.¹⁵

The brain has no urea cycle; consequently, ammonia in the central nervous system (CNS) is removed by transamination of glutamate into glutamine in astrocytes.¹⁶ Glutamine concentrations in the cerebrospinal fluid are elevated in dogs with HE⁸ and often are an accurate indicator of the degree of neurologic dysfunction in humans with HE.⁹ Glutamine is exchanged across the blood-brain barrier for tryptophan, leading to increased levels of tryptophan and tryptophan metabolites in the CNS (Figure 103-1).⁷ The tryptophan metabolites serotonin and quinolinate are important agonists of inhibitory and excitatory neurotransmission, respectively, although the exact alterations in both of these systems in patients with HE are complex and incompletely understood. Glutamine is also transported from astrocytes into neurons, where it is converted to glutamate.¹⁷ Overstimulation of the N-methyl-D-aspartate receptors by both glutamate and ammonia can cause seizures and neurotoxicity, in part as a result of free radical formation.

Figure 103-1 Diagram of the proposed effect of ammonia on tryptophan metabolism. Ammonia is metabolized to glutamine, which shares an antiport transport mechanism across the blood-brain barrier with tryptophan. An increase in tryptophan transport leads to an increased flux through the serotonin and quinolinic acid pathways.

γ-Aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the CNS, and alterations of GABA neurotransmission have been proposed as an important component of HE. In spite of several different observations implicating “increased GABAergic tone” in HE, studies have excluded the possibility of increased amounts of GABA in the CNS and changes in the number of GABA receptors or affinity of the receptor for its ligands in patients with HE.¹⁸ It is likely that if increased GABA neurotransmission exists in animals with HE, it is due to increased brain concentrations of endogenous GABA ligands, including endogenous benzodiazepines and neurosteroids. Increased levels of endogenous benzodiazepine receptor ligands have been found in the portal blood and systemic circulation of some dogs with portosystemic shunts.¹⁹ Elevated levels of ammonia and manganese (also seen in liver disease) increase expression of the peripheral-type benzodiazepine receptor, a heterooligomeric protein complex on the outer mitochondrial membrane of astrocytes. Activation of the peripheral-type benzodiazepine receptor increases mitochondrial cholesterol uptake and the synthesis of neurosteroids that may then act on GABA receptors.²⁰

There is also evidence that amino acid imbalances play a role in patients with HE. Dogs with portocaval shunts have a decreased ratio of branched chain (valine, leucine, isoleucine) to aromatic (phenylalanine, tyrosine, tryptophan) amino acids.²¹ Because these classes of amino acids compete for transport across the blood-brain barrier, the increased relative concentration of the aromatic amino acids means that they will be preferentially transported. This leads to an increased synthesis of false neurotransmitters and a reduction in the synthesis of dopamine and norepinephrine. Coma was induced in normal dogs infused with the aromatic amino acids tryptophan and phenylalanine; addition of the branched chain amino acids to the infusion prevented coma.²²