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New Approaches to Liver Disease



Veterinarians are regularly presented with patients suffering from liver disease. To help you to deal with these cases more effectively, this article highlights some advances in the diagnosis and dietary management of liver disease presented at the WALTHAM symposium on Liver Disease, held in Birmingham in April 1996.


Figure 1.Schematic of the structure of an hepatic acinus, the basic functional unit of the liver. Note that blood flows towards the central vein, while bile flow id toward the portal triad (P.T.), and away from the central vein. The concentration of nutrients including oxygen, metabolites (hormones, ammonia) and toxins (gut derived bacteriaand endotoxins) decreases as blood flows toward the central vein.

Pathophysiology
The basic functional unit of the liver is the hepatic acinus (Figure 1). Note that the blood flows toward the central vein, while bile flow is towards the portal triad (P.T.), and away from the central vein. The concentration of nutrients including oxygen, metabolites (hormones, ammonia) and toxins (gut-derived bacteria and endotoxins) decreases as blood flows toward the central vein.

The liver is involved in nearly all aspects of metabolism, so liver disease, regardless of cause, will affect virtually every homeostatic system in the body. From a clinical viewpoint, some liver functions are more important than others, their loss leading to clinical signs which cause owners to bring their pets to the veterinary clinic.

Table 1. Pathophysiologic consequences of liver disease


Changes in hepatic size - increased or decreased
Hepatic encephalopathy
Disturbances of macronutient metabolism (carbohydrate, protein, fat)
Disturbances of micronutrient metabolism
Alterations of regulatory hormones
Ascites
Coagulation disorders
Loss of detoxifying capacity
Loss of hepatic macrophage function

Diagnosis of liver disease
When diagnosing liver disease it is important to consider the clinical findings and the results of imaging studies and laboratory tests together. Diagnostic tests may not be specific to a particular type of liver disease, and abnormal results may have an extra-hepatic aetiology (Table 2) so in many cases a liver biopsy is necessary to establish the precise aetiology and prognosis.

Table 2. Extrahepatic disorders that can cause abnormal liver tests

Inflammatory bowel disease Immune-mediated haemolytic anaemia
Rickettsial infections Shock
Acute Pancreatitis Right-sided heart failure
Diabetes mellitus Protein-losing enteropathy
Hyperadrenocorticism Severe protein restriction
Hypoadrenocorticism Splenitis
Hypothyroidism Hyperthyroidism

1. Serum hepatic enzyme tests
Elevated serum hepatic enzyme concentrations indicate either:
  • hepatocellular injury or repair
  • retained bile
  • the action of drugs
The magnitude and duration of the increase is dependent on the type, severity and duration of the stimulus. They do not indicate the irreversibility of liver damage at one point in time.

ALT (alanine aminotransferase)
- found in hepatocellular cytoplasm
- released due to alterations in hepatocellular membrane permeability
- useful marker of hepatocellular injury
- half-life of hours, but decrease may take days in a clinical situation
- a unique glucocorticoid-induced isozyme can be identified in dogs

AST (aspartate aminotransferase activity)
- found in variety of tissues, especially skeletal muscle and liver
- appears to be released later and as a consequence of a more severe type of injury than ALT.

ALP (alkaline phosphatase)
- increases within hours of local impairment to bile flow
- usually the last enzyme to return to normal following resolution of an acute insult (in dogs)


GGT (gamma-glutamyltransferase)
- associated with the epithelial cells comprising the bile ductular system
- increases associated with impaired bile flow.

2. Tests of hepatobiliary function
Substances produced by the hepatocyte

Hepatocytes produce an enormous range of metabolites, some of which may be measured in serum to give an indication of hepatic function or disease status. These routinely measured plasma analytes reflect synthetic and metabolic activities of the liver but are insensitive to mild functional changes and cannot detect acute changes in function. They include glucose, albumin, prothrombin time (an indirect measure of coagulation factors), urea nitrogen (BUN), plasma ammonia and serum bile acids.

bstances dependent on hepatocellular uptake, metabolic processing and Bilirubin
Hyperbilirubinaemia is considered hepatobiliary in origin if the haematocrit and blood smear is normal, or indicates only mild anaemia. Interpretation of total, conjugated and unconjugated bilirubin levels is considered unreliable in dogs and cats.

Fasting serum total bile acid concentration (FSBA)
Reflects enterohepatic circulation and increases with pathology of the hepatobiliary system or portal circulation prior to the development of hyperbilirubinaemia. Useful for differential diagnosis of congenital portal vascular anomalies and supports diagnosis of chronic hepatitis/cirrhosis prior to the development of jaundice. The combination of ALT and FSBA is considered to provide the best sensitivity and specificity for establishing pathophysiology.

3. Hepatic imaging techniques
Since the early 1980's the range of imaging techniques used for diagnosis of liver disorders has greatly increased (Table 3). Contrast radiographic techniques such as cholecystography and portal venography are now widely used and detailed information about hepatic structures may be obtained using ultrasonography.

Various hepatic functions may be assessed non-invasively using scintigraphy, which uses radioactively labelled chemicals which are cleared from the blood by hepatocytes or the reticulo-endothelial cells, or absorbed into the portal system after administration per rectum.

Table 3. Summary of current imaging techniques for the canine or feline liver
  Information gained Applications Availability

  Structural Functional Primary Secondary  
Survey radiography   General abdominal Position/shape/ size of liver 1
Contrast radiography

cholecysto - graphy • • Identify gallbladder   1
portal venography • • • Portosystemic shunting   2
Hepatic arteriography • • • • • Hepatic arterivenous fistula   3
peritoneo - graphy • •   Diaphragmatic rupture Surface contour of liver 2
gastrography   Position / size / shape of liver   1
Ultra sonography

2 - dimensional gray scale • • • Evaluation of parenchymal / biliary lesions Position / size / shape of liver 2
Doppler   • • Portal hypertension Portosystemic shunting 3
Scintigraphy

radiocolloid • • Reticulo - endothelial function Position/size/ shape of liver 3
hepatobiliary • • • Biliary obstruction   3
portal scintigraphy   • • • Portosystemic shunting   3

Key: • - limited • • - useful • • • - detailed
1 - most general practices 2 - many specialist practices 3 - most university referral hospitals

Dietary Management of Liver Disease in Dogs
The challenge in management of patients with liver disease is attempting to simultaneously balance multiple therapies aimed at ameliorating clinical signs, treating specific causes where possible, and providing adequate time and nutritional support to allow the liver to heal.

The regenerative power of the liver is amazing. Following 70% hepatectomy, dogs can regenerate their full liver mass in a matter of weeks. However nutritional support (tube feeding) is an important factor in helping the liver to heal. Dogs which do not receive enteral feeding are far less likely to make a full recovery.

The nutritional needs of dogs with liver disease have not been fully established, but it is generally agreed that for the majority of nutrients, their requirements are at least equivalent to those of healthy dogs. However the needs of regenerating hepatocytes may increase the requirements for protein and certain micronutrients, and there may also be problems with nutrient absorption, metabolism and storage that result from hepatic disease. The current dietary recommendations for the management of liver disease in dogs are presented in Table 4.

Table 4. Dietary recommendations for dogs with liver disease
General
High palatability
High digestibility
Protein Restricted to a minimum of 2.1 g/kg/day (10-14% total calories)
High quality
Fat 2-3 g/kg/day (30-50% total calories)
Carbohydrate 5-8 g/kg/day (30-50% total calories)
Moderate level of soluble and insoluble fibre
Micronutrients Increase B-complex vitamins to twice adult maintenance
Consider vitamin C supplementation at 25 mg/kg/day
Supplement with Zn sulphate (2mg/kg/day) or Zn gluconate (3 mg/kg/day)
Restrict sodium

In the acute stages of liver disease, and in patients with necro-inflammatory lesions, the aim should be to prevent further weight loss. If the patient is unable to eat sufficient food, then some form of tube feeding should be considered. Thereafter the emphasis should be to restore body condition during the recovery period. Maintenance of body weight is the goal in patients with chronic liver disease.

Although some of the therapeutic veterinary diets marketed for the management of chronic renal failure are suitable for the management of liver disease, they are not ideal. Diets with very low protein levels should not be used. Maintenance of a positive nitrogen balance is necessary for hepatic repair as well as optimal control of hepatic encephalopathy (HE), so there is a strong case for progressive increase in protein intake from this basic level as long as the patient remains free of signs of HE. When treating puppies with portosystemic shunts it is important to ensure that the diet meets nutrient requirements for growth.

In the past, high fat diets were not advocated for dogs with chronic liver disease for two reasons:-

(1) It was assumed they had cholestasis, resulting in inadequate delivery of bile, and impaired digestion and absorption of fats. In reality only a relatively few dogs with chronic hepatobiliary disease develop this complication

(2) It was assumed that encephalopathic short chain fatty acids were derived primarily from dietary fat. In fact these fatty acids are derived from fermentation of soluble fibre in the large bowel, and may not be as encephalopathic as previously reported.

Carbohydrate metabolism may become severely deranged in dogs with liver disease, resulting either in glucose intolerance or inability to maintain normal plasma glucose levels. Complex carbohydrates are therefore preferable to simple sugars in the diet, by smoothing the post-prandial glycaemic response. This reduces the short term insulin requirements in the glucose intolerant patient and prolongs the delivery of glucose to the liver.

Soluble dietary fibre is useful in managing HE by increasing nitrogen elimination from the body via intestinal bacteria and inhibiting ammonia formation and absorption. It may also alter the production and absorption of other potential cerebral toxins. Insoluble fibre is also advocated to prevent constipation and reduce intestinal transit times and so reduce production and absorption of toxins from the colon.

Dietary supplementation with vitamin K is indicated in patients with prolonged clotting times or bleeding tendencies. Supplementation with fat soluble vitamins should be done with caution, and large doses reserved for patients with impaired fat absorption. Feeding several small meals throughout the day will help reduce fasting hypoglycaemia and increase the daily protein tolerance in patients with HE.

Key Points
  • Patients with liver disease may present with a multitude of clinical signs, depending on the severity and pathophysiology of the disease.
  • Of the serum hepatic enzyme tests available, the combination of ALT and FSBA is considered to provide the best sensitivity and specificity for establishing pathophysiology of liver disease in the dog.
  • A wide range of hepatic imaging techniques are now available to improve diagnosis of liver disease.
  • Broad guidelines for the dietary management of liver disease should be followed, then adapted to the individual patient in the light of clinical and laboratory findings.
Further Reading
Proceeding of the Waltham Symposium, "Liver Disease - practical perspectives", Birmingham 1996, Waltham Centre for Pet Nutrition, Waltham-on-the-wolds, U.K.


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