The
liver performs many vital functions with respect to nutrient
digestion and metabolism, detoxification and excretion, haematology
and coagulation, and hormonal balance. All of these functions
are impaired to varying degrees in dogs with hepatic insufficiency,
either as the result of loss of functional tissue mass or
portosystemic shunting.
Therapy for liver disease is aimed, where possible, at the
elimination of causative agents, the reduction of inflammation
and minimisation of fibrosis, the provision of optimum conditions
for hepatic regeneration and the control of complications
such as secondary bacterial infection, ascites and hepatic
encephalopathy. The liver has a phenomenal capacity for regeneration,
and nutritional support during this period of repair is a
vital component of therapy.
Hepatic Encephalopathy
Hepatic encephalopathy (HE) describes a complex of neurological
signs of central origin, which develop in animals with hepatic
insufficiency as a result of either portosystemic shunting
or critical loss of functional tissue (60-70%) arising from
acute or chronic hepatitis. Clinical signs associated with
HE may be acute in onset, chronic, progressive or episodic.
The exact pathogenesis remains controversial, and it is believed
that a number of factors are involved
The healthy liver serves as a barrier to potentially neurotoxic
substances derived from the alimentary tract. When hepatic
function is compromised and/or there is portosystemic shunting,
a number of toxic substances enter the peripheral and cerebral
circulation. Passage of neurotoxins across the blood-brain-barrier
may result in altered central nervous function, mediated through
various mechanisms including the modulation of neurotransmitters
or receptors. The major encephalopathic toxins are nitrogenous
and are derived mainly from the alimentary tract, being synthesised
by gastrointestinal flora or consumed in the diet. Neurotoxic
substances that have been implicated in HE include ammonia,
gamma-aminobutyric acid (GABA), low ratios of branched chain
to aromatic amino acids, and short chain fatty acids. Methionine
may also contribute to the pathogenesis of hepatic encephalopathy
since it is believed to act synergistically with ammonia and
short chain fatty acids. Furthermore, methionine can be metabolised
to neurotoxic mercaptans by intestinal micro-organisms.
Therapeutic goals in the management of HE are to prevent toxin
production and limit toxin absorption from the bowel. These
are largely achieved through the restriction of toxin-promoting
dietary constituents and by modification of the colonic microbial
flora and pH. The control of hyperammonaemia has conventionally
been the primary concern although, clearly, other toxic mechanisms
may be involved.
Dietary Management
Nutritional support plays a key role in the management of
hepatic insufficiency through
-
Reducing the metabolic demands placed upon the liver
-
Supporting hepatic function by providing non-protein calories
-
Overcoming nutritional deficiencies due to loss of hepatic
function
-
Managing major complications of hepatic insufficiency, namely
hepatic encephalopathy and ascites
-
Protecting against ongoing hepatocellular damage
-
Restricting the progression of inflammation and fibrosis
-
Providing essential nutrients for hepatocyte regeneration
and repair
Protein
The liver is the major site of protein synthesis, amino acid
metabolism, and the detoxification of nitrogenous waste products.
Hepatocellular dysfunction is associated with reduced synthesis
of serum proteins (including albumin, transport proteins and
clotting factors), and failure to metabolise and excrete bilirubin.
The reduced ability of the liver to detoxify and excrete nitrogenous
materials results in hepatic encephalopathy.
Protein malnutrition is common in patients with chronic liver
disease, where it is manifested by weight loss, loss of muscle
tissue and hypoalbuminaemia. Protein intake should not, therefore,
be restricted excessively or unnecessarily because of the
perceived need to manage hepatic encephalopathy. The protein
requirements of dogs with liver disease may exceed those of
normal maintenance due to increased protein turnover and the
demands of hepatocellular regeneration. Limiting protein intake
to below requirements will provoke utilisation of structural
proteins, which is associated with increased ammonia production.
Nevertheless, excessive protein intake should be avoided in
patients with liver disease, as it is associated with increased
production of ammonia, the principal encephalopathic toxin,
within the gastrointestinal tract. In addition, excess amino
acids are used for gluconeogenesis, with production of ammonia
as a by-product.
High quality proteins, by virtue of their high digestibility
and close approximation to the animal’s requirements,
are recommended for patients with liver disease because they
fulfil needs with minimal nitrogenous waste (ammonia) production.
Animal proteins are generally of a higher quality than those
found in plants. Traditionally, diets based on dairy products
(cottage cheese, milk) or eggs have been suggested. There
has been a tendency to avoid meat based foods because of the
suggestion that dogs with surgically created portosystemic
shunts suffered exacerbated hepatic encephalopathy and reduced
survival time when fed exclusively meat as opposed to a milk-based
diet. However, it is important to recognise that this may
well not be true of meat based diets that are protein restricted
and properly balanced with respect to fat, carbohydrate and
micronutrient content. The potential benefits of dairy products
probably relate to factors such as the relatively high ratio
of carbohydrate to protein, their influence on intestinal
transit and colonic pH, as well as differing amino acid composition.
Similarly, proteins of vegetable origin can provide dietary
fibre that reduces ammonia production and absorption in the
colon and assists ammonia elimination in faeces.
Dietary protein intake should, therefore, be moderately restricted
in dogs with hepatic insufficiency, to prevent or reduce the
clinical signs of hepatic encephalopathy. Nevertheless, the
maintenance of a positive nitrogen balance is important for
the preservation of body condition and protein synthesis.
Fat
The liver plays a central role in the synthesis, storage and
transport of lipids, and also the digestion and absorption
of dietary fat through the synthesis and secretion of bile
salts. Hepatocellular dysfunction can result in altered serum
triglyceride and cholesterol concentrations, lipid accumulation
within the liver, and decreased synthesis of bile salts. Although
bile salts facilitate the absorption of long chain fatty acids,
only 30%-40% of dietary triglyceride absorption is dependant
upon bile acid secretion so that malabsorption only becomes
significant when there is severe cholestasis.
Dietary fats are beneficial for patients with liver disease
as they enhance palatability, increase energy density, have
a protein sparing effect and reduce carbohydrate intolerance.
Fat intake can be fairly liberal in many dogs with liver disease,
although moderate restriction is indicated in those dogs with
hepatic lipid accumulation or cholestasis resulting in steatorrhoea.
Carbohydrate
Both complex carbohydrates and dietary fibre are important
in the management of liver disease. Hepatocellular dysfunction
is accompanied by derangements in carbohydrate metabolism
that result in glucose intolerance and inability to maintain
blood glucose concentrations. Dietary provision of complex
carbohydrates, rather than simple sugars, can be of benefit
by smoothing out the postprandial glycaemic response thereby
reducing insulin requirements and the glucose load presented
to the liver. Carbohydrates also promote an insulin to glucagon
ratio that favours an anabolic state in which amino acids
absorbed from the small intestine are converted to protein
rather than glucose. This reduces the production of ammonia
that accompanies the utilisation of amino acids for gluconeogenesis.
Dietary fibre can play an important role in the management
of hepatic encephalopathy by modifying the production, absorption
and elimination of ammonia and other neurotoxic microbial
by-products from the large intestine. The effectiveness of
soluble fibre appears to be due to a combination of increased
nitrogenous incorporation into intestinal bacteria, with their
subsequent elimination in faeces, and inhibition of ammonia
generation by colonic bacteria because of a reduction in colonic
pH. Through these dual mechanisms, fibre may alter the production
of a number of potential cerebral toxins in addition to ammonia.
These effects probably account for the therapeutic benefits
of vegetable-based diets and strongly advocate the inclusion
of both soluble and insoluble (which decreases colonic transit
times and prevents constipation) fibre in diets for the management
of liver disease in dogs. Provision of dietary fibre can thus
allow for a higher protein intake without risking the development
of hepatic encephalopathy.
Vitamins and Minerals
The liver is involved in the absorption, metabolism, transport
and storage of many micronutrients. Deficiencies may occur
in dogs with liver disease because of inadequate dietary intake,
either due to anorexia or improper diet formulation, or as
a result of increased metabolic demands, derangements in intermediary
metabolism or micronutrient activation, increased renal excretion,
or impaired hepatic storage. Examples of the importance of
hepatobiliary function on micronutrient availability include:
-
bile salt excretion is essential for the absorption of fat
soluble vitamins (A, D, E, K)
-
conversion of vitamins A, B, D and K into metabolically
active factors.
-
storage of copper
Deficiencies
of certain vitamins and minerals are known to be common in
humans with a variety of chronic hepatobiliary disorders.
Comparable data on the situation in companion animals is scant.
The requirement for B vitamins increases with calorie intake
and a doubling of maintenance dietary requirements has been
recommended. A deficiency of vitamin E is thought to contribute,
in a permissive way, to ongoing hepatic injury due to the
production of superoxide radicals and peroxides. Vitamin E
supplementation may, therefore, provide benefit in the management
of copper-associated liver disease in dog.
Therapeutic supplementation of other vitamins should be done
with caution. Over-supplementation with vitamin A can lead
to hepatotoxicity; with vitamin D can lead to hypercalcaemia
and renal failure; and with vitamin K to haemolytic anaemia.
Supplementation with larger doses of fat soluble vitamins
should be reserved for those patients with impaired fat absorption.
Zinc deficiency occurs in patients with liver disease due
to poor dietary intake, reduced intestinal absorption and
increased urinary losses. Zinc is important cofactor for hepatic
ornithine transcarbamylase, which is a key enzyme in the detoxification
of ammonia through the synthesis of urea. Zinc deficiency
may also increase ammonia production through upregulating
the activities of glutamine synthetase and adenosine monophosphate
deaminase in muscle. Several clinical trials have reported
that oral zinc supplementation in humans significantly improves
mental status of patients with overt hepatic encephalopathy.
Zinc supplementation may provide benefit in dogs with chronic
hepatitis and hepatic fibrosis by inhibiting the accumulation
of collagen and protecting against free radical damage. Dietary
supplementation with zinc also provides protection from liver
injury associated with hepatocellular copper accumulation.
Zinc inhibits the absorption of copper from the gastrointestinal
tract through the induction of metallothionein, a carrier
protein that irreversibly chelates copper within enterocytes.
A similar process also occurs in the liver, trapping copper
in an unavailable form. Modification of the enteric absorption
and hepatocellular influence of copper is beneficial not only
in patients with specific copper-storage liver disease, but
in any patient with cholestasis where biliary elimination
of copper is reduced. The conservation of copper within hepatocytes
is believed to result in cellular injury that contributes
to tissue damage induced by the primary or underlying disease
process. Restriction of dietary copper intake will also have
a primary impact upon copper accumulation and associated effects.
Dietary intakes of sodium should be moderated in patients
with liver disease associated with hypoalbuminaemia and/or
with portal hypertension, where excessive sodium intake can
precipitate the formation or recrudescence of ascites.
General Dietary Considerations
Many animals with severe liver disease will be anorectic and
may object to the introduction of a new diet. The palatability
of the diet is therefore an essential consideration. Improved
acceptance of the diet may be achieved through gradual introduction
by mixed feeding with the pet's accustomed diet; serving only
fresh food; warming the food to body temperature; and feeding
small meals throughout the day. The latter practice will also
help to reduce the prevalence of fasting hypoglycaemia and
increase daily protein tolerance, thereby improving the management
of HE. Benzodiazepine appetite stimulants should be avoided
because they may exacerbate HE. Patients should not be allowed
to become constipated, since this will result in increased
production and absorption of toxins from the colon.
In the acute stages of liver disease and in patients with
necroinflammatory lesions, the primary nutritional objective
should be to prevent further weight loss. Thereafter the emphasis
should be to restore body condition during the recovery period.
Maintenance of bodyweight is the goal in patients with chronic
liver disease. If, in the acute stages, the patient is unable
to meet goals for voluntary calorie intake, then a form of
tube feeding should be considered.
