Pathophysiological Mechanisms

Pathophysiological Mechanisms

Hepatocellular dysfunction is associated with a number of metabolic disturbances that alter the utilization of nutrients (Table 5). These are compounded by cats’ nutritional peculiarities, which are due to their development as strict carnivores. Cats have very high daily protein requirements and they utilize protein for gluconeogenesis and energy production, even when the diet is high in carbohydrates. They have very limited ability to down-regulate this continuous protein catabolism (Zoran, 2002). Hepatic glycogen stores are relatively small in cats, and blood glucose concentrations are maintained through gluconeogenesis from amino-acids.

Cats are obligate carnivores with high daily dietary requirements for protein and certain amino acids (arginine, taurine), and a limited ability to digest, absorb and metabolize carbohydrates. Other nutrients considered essential in feline diets are vitamins A, D, niacin and arachidonic acid.

Hepatocellular dysfunction often causes metabolic disturbances that are compounded by malnutrition, which is a common complication of liver disease. Anorexia and malnutrition furthermore predispose cats to the development of idiopathic hepatic lipidosis.

Anorexia and malnutrition therefore rapidly result in augmented protein catabolism and peripheral lipolysis, and progressive loss of fat and muscle. The major consequences of malnutrition are decreased immunocompetence, decreased tissue synthesis and repair, and altered intermediary drug metabolism.

Protein, Fat and Carbohydrate Metabolism

Protein

The liver has an essential role in protein synthesis and degradation. It controls serum concentrations of most amino acids, with the exception of branched chain amino acids (BCAA), which are regulated by skeletal muscle. The liver synthesizes the majority of circulating plasma proteins and is the only site of albumin synthesis (Center, 2000a). Albumin has a relative priority for synthesis, although hypoalbuminemia is relatively uncommon in feline liver disease; it does not occur until the disease is chronic and is compounded by malnutrition.

The liver furthermore synthesizes the majority of the coagulation factors. Lack of synthesis in liver failure may lead to prolonged coagulation times, but only when factors are reduced to less than 30% of normal. Disseminated intravascular coagulation (DIC) is yet the most common coagulopathy associated with liver disease, and the most likely to cause spontaneous hemorrhage. Decreased absorption of vitamin K in chronic cholestasis may also lead to prolonged clotting times, but these can be corrected by parenteral administration of vitamin K1 (Bauer, 1996).

In acute disease, functional proteins in skeletal muscle and other tissues are catabolized to meet the demands for the synthesis of host defense proteins. In chronic liver disease, the etiology of the catabolic state is multifactorial (Bauer 1996; Krahenbuhl & Reichen 1997). Plasma concentrations of aromatic amino acids (AAA) increase in liver disease due to increased peripheral release and decreased hepatic clearance, but BCAA levels decrease because of enhanced utilization as an energy source by muscle. This imbalance between AAA and BCAA has been implicated in the pathogenesis of HE, although its clinical significance in the cat is unknown.

Protein catabolism is increased in all liver diseases. Protein breakdown is augmented in patients with infections or gastrointestinal hemorrhage, which can precipitate HE due to increased ammonia production.

Deficiency of specific amino acids may furthermore play a role in feline liver disease. Cats have a relatively high dietary requirement for arginine (recommended allowance: 1.93 g/1,000 kcal ME: NRC 2006) because they lack alternative synthetic pathways, and thus rely on dietary arginine to drive the urea cycle. Arginine-free diets will result in hyperammonemia and HE within hours, whereas diets low in arginine will propagate HE in a later stage. Cats also need dietary taurine, (recommended allowance: 0.1 g/1,000 kcal ME: NRC 2006) which is essential to conjugate bile acids and promote choleresis; in addition, it has a mild antioxidant function. Dietary requirements are higher when cats are fed canned diets, since these promote increased growth of enteric flora, deconjugation of bile acids and degradation of taurine (Kim et al., , 1996). NRC 2006 recommends an allowance of 1.0 g of taurine/kg dry diet, whereas the allowance for canned diets is 1.7 g/kg diet.

Cats may furthermore develop L-carnitine deficiency in liver disease, due to insufficient intake of L-carnitine or its precursors, reduced hepatic synthesis, or increased turnover. L-carnitine supplementation may be protective against the development of hepatic lipidosis in obese and anorexic cats, although this is still unproven (Biourge, 1997).

Carbohydrate

The liver is responsible for the maintenance of blood glucose levels because it is the primary organ for glycogen storage and glycogenolysis. In liver disease, serum concentrations of glucagon and insulin are increased due to reduced hepatic degradation, with the effects of hyperglucagonemia generally predominating (Marks et al., , 1994; Center 2000a). Liver disease results in more rapid depletion of hepatic glycogen stores, and glucose needs are then supplied through catabolism of muscle proteins to amino acids. This causes muscle wasting and increases the nitrogen load, which may potentiate hyperammonemia and HE. Fasting hypoglycemia may occur in severe acute liver disease and portosystemic shunts due to inadequate glycogen storage and gluconeogenesis. In contrast, a mild hyperglycemia can occur in chronic liver disease (esp. cirrhosis) due to peripheral insulin resistance related to an increase in glucagon levels.

Fat

The liver has an important function in the synthesis, oxidation and transport of lipids. Liver disease causes an increase in peripheral lipolysis in order to generate fatty acids for energy production, resulting in fat depletion, while the rate of hepatic fatty acid oxidation increases (Bauer, 1994; Marks et al., , 1996).

Through its synthesis of bile acids and secretion of bile the liver plays an important role in the digestion and absorption of fat and fat-soluble vitamins (A, D, E, K). Fat malabsorption is nevertheless not common in liver disorders, since some dietary triglycerides can still be absorbed in the complete absence of bile acids. However, in severe cholestatic liver disease the reduced availability of enteric bile acids can cause malabsorption of fats, fat-soluble vitamins (especially vitamins E and K) and some minerals.

The liver is the only site of cholesterol synthesis. Hypocholesterolemia may occur in acute liver failure and portosystemic shunts, whereas hypercholesterolemia is seen in obstructive jaundice (Center, 2000a).

Micronutrient Metabolism

Vitamins

The liver stores many vitamins and converts them to metabolically active forms. Liver disease can therefore result in deficiency of vitamins stored in the liver, such as B-complex vitamins. Vitamin deficiencies are augmented by increased demands for hepatocyte regeneration, reduced metabolic activation and increased urinary losses (Center, 1998). Vitamin C can be synthesized in cats but is not stored. Its synthesis may be affected by liver disease (Center, 2000a; Marks et al., , 1994).

Deficiencies of the fat-soluble vitamins A, D, E and K can occur in any condition that impairs the enterohepatic circulation of bile acids or fat absorption; vitamin E deficiency is particularly common in chronic liver disease (Center, 1996). Deficiencies of vitamins E and K are most significant.

- Vitamin E is an important antioxidant that protects lipoproteins and cell membranes from lipid peroxidation. Vitamin E deficiency is important since it causes an increased susceptibility to oxidative stress, which perpetuates ongoing liver injury (Sokol, 1994).

- Vitamin K deficiency is less common but more easily recognized since it develops rapidly and results in a clinically detectable bleeding tendency.

Minerals and Trace Elements

Iron, zinc and copper are the main trace elements stored in the liver. Both iron and copper can be hepatotoxic in high levels, but only copper appears to be a potential hepatotoxin in companion animals. The liver is central to the maintenance of copper homeostasis, since it takes up most of the absorbed copper and regulates the amount retained by controlling excretion through the biliary tract. Hepatic copper accumulation is rare in cats, but it has been reported in cats with cholestatic liver disease (Fuentealba & Aburto, 2003) and as a possible primary copper hepatotoxocosis (Meertens et al., , 2005). In physiological hepatic concentration, copper is complexed by proteins but excessive hepatic accumulation of copper results in mitochondrial injury, generation of reactive oxygen species and free radicals*, and hepatocellular damage (Sokol et al., , 1994).

Zinc is an essential cofactor in many biological processes; it has an antioxidant role, anti-fibrotic properties, and enhances ureagenesis (Marchesini et al., , 1996).

Zinc deficiency is common in chronic liver disease, due to poor dietary intake, reduced intestinal absorption and increased urinary loss. Deficiency results in low resistance to oxidative stress and reduces ammonia detoxification in the urea cycle, thus promoting HE.

Antioxidants

Free radicals are generated in many types of liver disease, and play an important role in perpetuating hepatic pathology. They damage cellular macromolecules via lipid peroxidation and other mechanisms, and can initiate and perpetuate liver injury. Their production is increased in inflammation, cholestasis, immunological events, and exposure to heavy metals and toxins (Sokol et al., , 1994; Feher et al., , 1998). Endogenous enzymatic antioxidant defense systems that hold the generation of free radicals in check may become deficient during liver disease (Table 6). All antioxidant systems work synergistically to prevent cellular damage. A disruption in these natural defense systems results in oxidant stress (Figure 14). Nutritional antioxidants include vitamins E and C as well as SAMe whereas taurineand zinc have also a weak antioxidant effect.

Figure 14. Etiology of oxidant stress in liver disease.

Detoxification and Excretion

The liver is the primary site of detoxification of both endogenous by-products of intermediary metabolism (e.g., ammonia) and exogenous substances absorbed from the gastrointestinal tract. All of these may play a role in the etiology of HE. The precise pathogenesis is likely to be multifactorial, and may be based on inter-related changes in reduced hepatic clearance of gut-derived substances such as ammonia, altered amino acid neurotransmission and endogenous benzodiazepines. Ammonia is the substance most commonly linked with HE, although serum ammonia levels correlate poorly with the degree of HE (Maddison, 2000). A large part of this ammonia is produced in the gastrointestinal tract by urease-producing bacteria (Figure 15).

Figure 15. Ammonia metabolism.