Physiopathology

3. Physiopathology

Hepatocellular dysfunction can cause multiple metabolic disturbances, which are compounded by malnutrition

Hepatocellular dysfunction is associated with a number of metabolic disturbances that alter the utilization of nutrients (Table 5). Alterations in protein, carbohydrate and fat metabolism reflect the influence of neuroendocrine mediators and are particularly prominent in the fasting state. Serum concentrations of glucagon and insulin are increased due to reduced hepatic degradation, with the effects of hyperglucagonemia predominating. This causes a more rapid depletion of hepatic glycogen stores, which results in premature protein catabolism to supply amino acids for gluconeogenesis. Fasting hypoglycemia is in many cases prevented by a compensatory decrease in peripheral glucose oxidation and increase in gluconeogenesis. Peripheral lipolysis is also enhanced, generating fatty acids for energy production (Marks et al., 1994). Prolonged inadequate food intake in dogs with chronic liver disease will therefore result in progressive loss of fat and muscle, which contributes to the malnutrition found commonly in liver disease (Figure 2).

Figure 2. Etiology of malnutrition in liver disease.

The liver has a large functional reserve and is able to preserve homeostasis and minimize catabolism for a long time, despite extensive damage. The appearance of metabolic alterations and clinical signs of liver dysfunction usually signify advanced disease.

Carbohydrate, Fat and Protein Metabolism

Carbohydrate - The liver is responsible for the maintenance of blood glucose levels because it is the primary organ for glucose storage (as glycogen) and provides glucose during fasting (through glycogenolysis). 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 hepatic encephalopathy (Bauer, 1996). 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 cirrhosis due to reduced hepatic clearance of glucocorticosteroids.

Lipid - 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, 1996).

Microscopic view of hepatic glycogen reserves (PSA X 40). (© Service d’anatomo-pathologie ENVN).

Through its synthesis of bile acids and secretion of bile, the liver plays an important role in the digestion and absorption of lipids and fat-soluble vitamins (A, D, E, K). Fat malabsorption is nevertheless not common in liver disorders, since some dietary tri glycerides still can be absorbed in the complete absence of bile acids (Gallagher et al., 1965).

In severe cholestatic liver disease, the reduced availability of enteric bile acids can cause malabsorption of fats, fat-soluble vitamins 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.

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.

Albumin has a relative priority for synthesis; hypoalbuminemia does not occur until the disease is chronic, and is compounded by malnutrition.

The liver furthermore synthesizes the majority of coagulation factors. Lack of synthesis in liver failure may lead to prolonged coagulation times (↑ PT, ↑ PTT) but only when factors are reduced to less than 30% of normal. Disseminated intravascular coagulation (DIC) is however the most common coagulopathy associated with liver disease, and is most likely to cause spontaneous hemorrhage (Center, 1999b). Decreased absorption of vitamin K in chronic biliary obstruction may also lead to prolonged clotting times, but these can be corrected by parenteral administration of vitamin K1.

In acute disease, functional proteins in skeletal muscle and other tissues are catabolized to meet the demands for synthesis of host defense proteins. In chronic liver disease, the etiology of the catabolic state is multifactorial (Mizock, 1999). 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 significance is now being questioned (Mizock, 1999).

L-carnitine is an essential cofactor for transport of long-chain fatty acids from the cytoplasm into mitochondria (Figure 3). The liver is a central organ for whole body L-carnitine homeostasis, and its metabolism can be impaired in multiple ways in chronic liver disease. L-carnitine deficiency in liver disease may occur due to insufficient intake of carnitine or its precursors, reduced hepatic synthesis, or increased turnover (Krahenbuhl & Reichen, 1997). L-carnitine supplementation has a protective influence against the development of ammonia-induced HE in experimental animals (Therrien et al., 1997) and may be protective against the development of hepatic lipidosis in cats (Twedt, 2004), but its usefulness in dogs is still undetermined.

Figure 3. Mode of action of l-carnitine. L-carnitine is incorporated into the enzyme chain needed to convey long-chain fatty acids though the mitochondrial membrane. This permits the transfer of fatty acids to the interior of the mitochondria. In case of deficiency, the transport system is disturbed and the production of energy is compromised.

The Liver Controls Many Metabolic Functions. Most Importantly, it:

- Maintains homeostasis of blood levels of glucose, amino acids and trace elements
- Synthesizes albumin and coagulation factors
- Detoxifies and excretes endogenous and exogenous waste products (i.e., NH3, drugs and toxins)
- Regulates immune function
- Regulates hormone balance.

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

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. B-complex deficiencies are common in people with liver disease and probably also occur in dogs.

Vitamin C can be synthesized in dogs but is not stored. Its synthesis may be affected by liver disease (Center, 1996a).

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. Deficiencies of vitamins E and K are most significant. Vitamin E is an important antioxidant that protects lipoproteins and cell membranes from lipid peroxidation. In addition, Vitamin E deficiency, common in chronic liver disease (Sokol, 1994), causes an increased susceptibility to oxidative stress, which perpetuates ongoing liver injury. Vitamin K deficiency is best recognized in dogs, since it develops rapidly and is readily detectable by measurement of coagulation times (Leveille-Webster, 2000).

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 the dog.

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. Copper may accumulate in the liver as a result of a primary metabolic defect in copper metabolism, or secondary to decreased hepatic copper excretion associated with longstanding cholestasis (Thornburg, 2000). In dogs with primary copper storage disease, copper accumulates in the liver before the development of hepatic damage or cholestasis. Excessive hepatic copper accumulation in Bedlington Terriers has been shown to result in mitochondrial injury, generation of reactive oxygen species and free radicals, and hepatocellular damage (Sokol et al., 1994).

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 hepatic encephalopathy.

Zinc is an essential cofactor in many biological processes. It has an antioxidant role, anti-fibrotic properties, and enhances ureagenesis (Dhawan & Goel, 1995; Marchesini et al., 1996).

Manganese is another trace element with antioxidant properties that can become deficient in cirrhosis.

Antioxidants

There is mounting evidence that free radicals play important roles in many liver diseases. 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). There is a wide range of both dietary and endogenous enzymatic antioxidant defense systems that hold the generation of free radicals in check. A disruption in this natural defense system results in oxidant stress (Figure 4).

Figure 4. Etiology of oxidant stress in liver disease.

This type of disruption may occur during liver disease (Table 6).

Detoxification and Excretion

The liver is the primary site of detoxification of both endogenous by-products of the 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 (Maddison, 2000). Ammonia is the substance most commonly linked with HE, although serum ammonia levels correlate poorly with the degree of HE (Figure 5).

Figure 5. Ammonia metabolism. A large part of ammonia is produced in the gastrointestinal tract by urease-producing bacteria.