in cats or toxicosis (Hardy, 1990). HE is more common in dogs than in cats.
Congenital portosystemic shunts represent the most common cause of HE. They generally occur as single vessels that provide direct vascular communication between the portal venous supply and the systemic venous circulation (caudal vena cava or azygous vein), bypassing the liver, and are not associated with portal hypertension. Approximately 25% to 33% of congenital portosystemic shunts are intrahepatic and the remainder are extrahepatic in dogs and cats (Berent and Tobias, 2009). The majority of intrahepatic portosystemic shunts occur in large or giant breed dogs, whereas most extrahepatic portosystemic shunts are seen in small and toy breed dogs (Berent and Tobias, 2009). In animals with congenital portosystemic shunts, the liver has been deprived of growth factors from birth and is therefore abnormally small with a hypofunctional parenchymal mass.
Acquired portosystemic shunts are usually multiple, extrahepatic and occur in animals with chronic portal hypertension secondary to hepatic arteriovenous malformations, noncirrhotic portal hypertension, or chronic hepatitis and cirrhosis (Berent and Tobias, 2009). Portosystemic shunts (congenital or acquired) occur far more commonly in dogs than in cats.
Hepatic microvascular dysplasia is a microscopic malformation of the hepatic micro-vasculature resulting in shunting of portal blood into the systemic circulation. Micro-vascular dysplasia can occur as an isolated disease or in association with macroscopic portosystemic shunts and can occur with or without concurrent portal hypertension. Hepatic microvascular dysplasia has been reported most commonly in the cairn terrier and Yorkshire terrier (Christiansen et al., 1995).
Urea-cycle enzyme deficiencies are rare congenital errors of metabolism in which one of the enzymes involved in ammonia metabolism fails.
Parenchymal hepatic diseases severely decrease the capacity of the liver to remove toxic products of intestinal metabolism and synthesize factors necessary for normal cerebral function.
The pathophysiology of HE is complex, multifactorial and incompletely understood (Box 4.2). The reader is referred to the cited references for a more detailed description of HE pathophysiology.
Clinical presentation
Neurological signs of HE are mainly consistent with forebrain involvement and include alterations in behaviour or personality, obtundation that may progress to stupor and coma, continuous pacing, aimless wandering, circling, head pressing, hypersalivation (particularly in cats), blindness and seizures. The neurological signs are often intermittent. Several factors can precipitate or exacerbate neurologic signs of HE (Box 4.3).
Non-neurological signs of HE vary depending on the underlying hepatic disease and include polyuria-polydipsia, vomiting, diarrhoea, weight loss, decreased endurance, ascites, icterus (rarely) and, in case of congenital portosystemic shunt, retarded or insufficient growth and signs of lower urinary tract disease (stranguria, pollakiuria, hematuria, dysuria) due to ammonium biurate crystalluria. Copper-coloured irises unusual for the breed have been reported in cats with congenital portosystemic shunts (Plate 1).
Diagnosis
Haematological changes include mild to moderate microcytic, normochromic nonregenerative anaemia. Serum biochemistry abnormalities include decreased albumin, urea, glucose and cholesterol levels. In animals with parenchymal hepatic disease, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin are often elevated and vitamin K-dependent clotting factor levels may be decreased. Ammonium biurate crystals can be identified in the urine sediment in approximately half of the dogs with HE (Rothuizen, 2009).
Box 4.2. Theories on hepatic encephalopathy pathophysiology (Maddison, 1992; Rothuizen, 2009; Bismuth et al., 2011; Poh and Chang, 2012; Kilpatrick et al., 2014).
• Neurotoxic effect of ammonia and other substances (e.g. phenols, mercaptans and short-chain fatty acids) derived from intestinal degradation;
• Impairment of cerebral energy metabolism possibly due to excess amount of neurotoxic substances;
• Astrocyte swelling due to:
i. intra-astrocytic accumulation of glutamine as a result of hyperammonaemia;
ii. hyponatraemia, inflammatory cytokines and benzodiazepines;
• Increased cerebral concentrations of endogenous benzodiazepine-like substances;
• Up-regulation of the translocator protein (formerly referred to as the peripheral benzodiazepine receptor), which results in increased cholesterol uptake and synthesis of neurosteroids (e.g. allopregnanolone and tetrahydradeoxycorticosterone) which have potent positive allosteric modulator properties on the GABAA receptor system;
• Imbalance between excitatory amino acid neurotransmission mediated by glutamate, and inhibitory amino acid neurotransmission mediated by gamma-aminobutyric acid;
• Alterations in monoamine neurotransmission as a result of perturbed plasma amino acid metabolism;
• Manganese-induced neurotoxicity resulting in astrocyte dysfunction, neuronal loss and gliosis;
• Formation of reactive oxygen species and reactive nitrogen species;
• Increased circulating levels of tumour necrosis factor (TNF)-alpha, interleukins 1 and 6.
Box 4.3. Factors that can precipitate or exacerbate neurologic signs of HE.
• Feeding (particularly food rich in protein and fatty acids);
• Bacterial production of ammonia in large intestine (e.g. following constipation);
• Gastrointestinal haemorrhage;
• Hypokalaemia (due to diarrhoea, anorexia, vomiting, salivation, ascites);
• Hypovolaemia;
• Alkalosis;
• Fever;
• Infection;
• Renal disease resulting in reduced excretion of ammonia;
• Administration of CNS depressant undergoing hepatic metabolism.
The diagnosis of hepatobiliary disease can be confirmed by the presence of increased levels of fasting plasma ammonia and fasting (e.g. 12-h) and post-prandial (e.g. 2-h) total serum bile acid concentrations. The sensitivity and specificity of fasting ammonia in the diagnosis of portosystemic shunts has been reported as 91% and 84% in dogs and 83% and 86% in cats, respectively (Ruland et al., 2010). The sensitivity and specificity of serum bile acids in the diagnosis of portosystemic shunts has been reported as 78% and 87% in dogs and 100% and 84% in cats, respectively (Ruland et al., 2010). Dogs and cats with congenital urea-cycle enzyme deficiencies have hyperammonaemia and low bile acid concentrations (Rothuizen, 2009).
Definitive diagnosis of portal vascular anomalies requires ultrasonography (Figs 4.3a–c), portovenography, scintigraphy (transcolonic or trans-splenic),
