Anatomy

There are various shunt types. Intrahepatic shunts occur most commonly in large breeds (e.g., Doberman Pinschers, Labrador Retrievers, Golden Retrievers, Old English Sheepdogs, Irish Wolfhounds). In contrast, extrahepatic shunts predominate in smaller breeds (e.g., Yorkshire Terriers, Maltese Terriers, Miniature Schnauzers). Extrahepatic shunts predominate in cats although intrahepatic shunts have also been reported.

Pathophysiology

The basis for the neurologic dysfunction that occurs in HE is incompletely understood. The encephalopathy occurring in acute or chronic hepatic failure is usually reversible with amelioration of the underlying hepatic disease. This potential for structural and functional reversal of the neurological abnormalities in HE is consistent with a metabolic encephalopathy.

HE is a complex pathophysiologic state that is probably multifactorial in origin.¹ It is generally accepted that gut-derived substances of bacterial and protein metabolism are important in the pathogenesis. Evidence for this includes the observation that reduction of gut bacterial flora or dietary protein often result in improvement of neurologic function without altering underlying hepatic disease.

Although ammonia has long been implicated as being the most likely neurotoxin involved in HE, actual mechanisms are not well understood despite decades of research. Evidence is accumulating that brain glutamatergic system and astrocytic (glial) function is significantly deranged in HE as a result of their role in detoxifying ammonia.^2,3 Other theories proposed in the past (e.g., alteration in monoamine or catecholamine neurotransmitters because of perturbed aromatic amino acid metabolism, alteration in amino acid neurotransmitters, increased brain γ-aminobutyric acid [GABA], increased cerebral levels of an endogenous benzodiazepine-like substance) have little support today.

There are several observations that provide support for a central role for ammonia in the pathogenesis of HE.⁴ Encephalopathy can be precipitated in cirrhotic patients by ingestion of ammonia-generating substances (e.g., protein, urea, ammonium salts). Congenital hyperammonemia caused by urea cycle disorders causes HE and coma in children and dogs. In addition, therapy decreasing intestinal production and absorption of ammonia (e.g., low-protein diet, lactulose administration, reduction of gut bacteria by antibiotics) usually results in improvement of clinical signs. Also of interest is the observation that metabolic derangements that increase movement of ammonia across cell membranes or increase ammonia production can precipitate HE in susceptible patients. Such derangements include alkalosis (which facilitates brain uptake of ammonia by increasing the concentration of ammonia base) and profound hypokalemia (which potentiates alkalosis and increases renal ammonia production).

Further evidence of the role of ammonia includes studies where administration of sodium benzoate to human patients with chronic HE-induced clinical and electroencephalogram (EEG) improvements paralleled reductions in blood ammonia. Sodium benzoate decreases blood ammonia concentrations by promoting its excretion in the form of hippurate. Other treatments that enhance ammonia excretion (e.g., L-dopa, which increases renal blood flow and hence renal ammonia excretion) have also been reported to ameliorate HE in human patients.

However, although blood ammonia concentrations are increased in most patients with HE, correlation between blood ammonia and degree of HE is poor, and some patients are encephalopathic without hyperammonemia. In addition, some medications may influence severity of HE without altering blood ammonia concentrations. Conversely, treatment of human patients with a monoamine oxidase inhibitor decreased blood ammonia concentrations, but failed to improve the encephalopathy.

That glutamate plays a central role in HE is suggested by the finding that there are many alterations of brain glutamate in various models of HE, and virtually all aspects of the glutamate system are altered (e.g., synthesis, metabolism intercellular trafficking, function and expression of glutamate transporters and receptors).² Many of these functions occur in astrocytes (glial cells), cells that are consistently altered histopathologically in HE.

History

Clinical signs are usually noticed in dogs and cats younger than 1 year of age, but patients can present at any age. Typical clinical signs in the dog include episodic lethargy and depression with periods of disorientation, aimless wandering, compulsive pacing, head pressing against walls, amaurotic blindness, and/or coma. Occasionally, seizures may be the presenting complaint in dogs. Neurologic signs can be related to a meal in approximately 25% of cases.

Episodes of anorexia and gastrointestinal signs such as vomiting are common in dogs. Other key features of clinical history may include dramatic but temporary resolution of clinical signs with antimicrobial therapy plus prolonged recovery from sedation or anesthesia. Polyuria and polydipsia occur in approximately one-third of dogs with HE. The mechanism has not been elucidated but may be related to central or primary (psychogenic) neuronal stimulation of the thirst center as a manifestation of HE, alterations in portal vein osmoreceptors, or a renal concentrating defect.

Clinical presentation of cats with HE is similar to dogs but has some unique aspects. Hypersalivation is the most frequently reported clinical abnormality in cats with HE but is rarely reported in dogs. Seizures also appear to occur more frequently in cats than dogs with HE. Seizures occurred in approximately 50% of feline cases reported in the literature. In contrast, seizures are not a particularly common feature of canine HE. Inappropriate aggression is also relatively frequently in cats compared to dogs. In contrast, compulsive behavior (head pressing, circling, aimless wandering) is observed more frequently in dogs than cats. Neurologic signs such as disorientation, ataxia, and stupor are frequently observed in both species. Figure 17-1 outlines the diagnostic approach to patients with signs of encephalopathy. Gastrointestinal abnormalities such as vomiting, diarrhea, and anorexia are reported less frequently in cats than dogs. Polyuria and polydipsia are also less frequently reported in cats than dogs. Risk factors that may precipitate HE in susceptible patients include alkalosis, hypokalemia (which may result from profuse vomiting or diarrhea or from excessive diuretic therapy with furosemide or other loop diuretics), anesthetics and sedatives (attributed to both increased cerebral sensitivity to the drugs and to impaired drug elimination; benzodiazepines are relatively safe), gastrointestinal hemorrhage (a common precipitating cause of HE is gastroduodenal ulceration which is common in patients with hepatic disease), transfusion of stored blood (it may contain high concentrations of ammonia), constipation (it increases colonic absorption of neurotoxic products of bacterial protein digestion), and methionine administration.

Figure 17-1 Diagnostic approach to patients with signs of hepatoencephalopathy. ALP, Alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; GME, granulomatous meningoencephalomyelitis; PT, prothrombin time; PTT, partial thromboplastin time; UA, urinalysis.