Appropriate Restriction of Protein in Liver Disease Dr Liesel van der Merwe BVSc (Hons) MMedVet (Med) Small Animals.

Liver disease can manifest in many different forms:
portosystemic vascular anomalies (PSVA/“shunts”),
chronic or acute hepatitis, suppurative or non-suppurative
cholangiohepatitis, toxic hepatitis, hepatic lipidosis,
fibrosis and neoplasia.
It is likely that protein deficiency occurs in veterinary
patients with active necroinflammatory disorders, and
possibly those treated with glucocorticoids. In many
of these conditions the patient is ill, not eating properly,
and the liver is undergoing active damage due to
inflammation and/or infection or toxic damage. The
patient will require protein to provide “building blocks”
for regeneration and recovery. Protein and sufficient
energy will also be required to maintain lean muscle
As a rule of thumb – protein should not be restricted
in liver disease unless hepatic encephalopathy (HE) is
present. Hepatic encephalopathy manifests in various
ways. Mild changes include poor appetite, being
a poor doer, intermittent gastrointestinal signs, and
lethargy. More severe clinical signs can include disorientation,
central blindness, stupor and seizures.1, 2
Most veterinary patients with liver disease are not in
hepatic failure and do not suffer from hepatic encephalopathy.
Common hepatic disorders in dogs, which are not
often associated with HE, are vacuolar hepatopathy,
chronic infections, chronic active hepatitis, major bile duct occlusion, primary or metastatic neoplasia and
microvascular dysplasia. 1 Less common disorders,
which are associated with HE are: cirrhosis (“end
stage” liver), portosystemic vascular anomalies and juvenile
fibrosing liver disorders. 1
Common hepatic disorders in cats which are not
associated with HE include: mild hepatic vacuolar
change, hepatic lipidosis syndrome, cholangitis/cholangiohepatitis
(associated with pancreatitis and inflammatory
bowel disease), major bile duct occlusion,
primary or metastatic neoplasia.1 Much less common
disorders which are associated with HE are biliary cirrhosis
and portosystemic vascular anomalies.1
Encephalopathic Toxins:
Although a variety of toxins have been identified in
influencing HE, the most common one is nitrogen,
both dietary and edogenous, which is detoxified in
the urea cycle in the liver.2,4
Ingestion of a meat-based high protein diet, gastrointestinal
bleeding (ulcers or verminosis), azotaemia
(increase blood levels of nitrogenous waste products)
and hypokalaemia (increases neurological sensitivity
to ammonia) are the most common event initiators
for HE in animals with severe liver disease with decreased
functional parenchyma or with PSVA.4
The liver has a very large reserve functional capacity,
so this only occurs if a large portion is damaged or if
the shunt fraction is significant.
Ammonia that escapes this urea cycle and enters the
systemic circulation can be metabolized to glutamine
by extrahepatic cells such as astrocytes and skeletal
muscle.5 Glutamine is either excreted in urine or metabolized
back to ammonia for re-entry into the urea
cycle. In severe liver failure (be it from acute toxic
damage or large portosystemic shunts), the astrocytes
have to take on a larger detoxification role. Astrocytes
contain glutamine synthetase and detoxify ammonia
by converting glutamate to glutamine. 5 Glutamine is
however able to enter the astrocytes’ mitochondria
where it is metabolized back to ammonia, leading to
mitochondrial damage and cell swelling. Astrocyte
swelling is a hallmark histopathologic change observed
in acute HE. 5
Ammonia itself is neutrotoxic, and elevations in blood
ammonia cause neurological derangements. Recent
studies have demonstrated an important role for ammonia
and inflammation in the development of hepatic
encephalopathy in dogs with a congenital portosystemic
shunt. 5
Manipulation of nitrogen:
Different proteins have different influences on blood
ammonia and amino acid concentrations. Proteins
containing haeme groups (red meat) are especially
encephalogenic whereas diets containing dairy- and
vegetable-protein are less so. Plant and dairy derived
proteins have been shown to prolong time to development
of HE and lessen its effects in dogs.3 Condon
and colleagues investigated the occurrence and severity
of neurologic symtoms as well as the survival
time of dogs with experimentally induced portosystemic
shunting and HE, when they were fed different
protein sources (eg, meat, fish, and milk).6
Clinical signs occurred more rapidly and were more
severe in dogs fed a meat protein diet when compared
to dogs fed a fish diet. The best results were
seen with a diet based on milk protein. The survival
time of dogs fed fish- or milk-derived proteins was almost
twice as long as that of dogs fed a meat-based
diet. 6 In patients with HE, non-meat protein sources
such as soy or dairy protein may produce lower blood
ammonia concentrations than meat sources.5
Dietary manipulation of protein is not the only mechanism
to manage the build up of ammonia in the blood
stream. Protein tolerance can be increased by using
lactulose, antibiotics and soluble fibre.

Lactulose lowers the gastrointestinal pH trapping
the NH3 as Nh4+in the GIT. Lactulose also
changes the intestinal flora from a proteolytic to a
fermentative type and decreases food and faecal
transit time, preventing constipation and allowing
less time for absorption of ammonia.
Antibotics: Urease producing bacteria are also responsible
for the production of a lot of ammonia in
the GIT and appropriate antibiotic treatment (metronidazole
at 7.5 mg/kg oid / bid rather than the
normal 15mg/kg bid) or neomycin (22mg po bid
will limit the numbers of this bacteria, and thus the
amount of free ammonia available for uptake.
Fibre fermentation increases faecal bulk, increases
the unstirred water layer adjacent to the enterocyte,
decreases intestinal transit time, binds enteric
toxins, stimulates enteric IgA production and alters
resident enteric flora all of which are beneficial.

Portosystemic vascular anomalies (PSVA)
The most frequent cause of HE are PSVA, which
have an incidence of between 1 and 5% of the population
and are more common in pure bred animals
and certain breeds such as Yorkshire Terriers and Irish
Wolfhounds.5 Furthermore, all chronic liver diseases
associated with formation of fibrosis develop portal
hypertension, which may lead to acquired portosystemic
shunting and then may result in HE.5
Most PSVA are diagnosed in young growing dogs and
cats. It is especially important to consider maximising
protein tolerance by using other modalities of managing
HE when dealing with immature animals. These
animals still need to grow, so protein restriction to
prevent HE needs to be strictly balanced against the need for protein for growth.
In these patients my approach is to maintain the highest
protein diet I can get away with without getting
any neurological signs (a puppy diet or an adult gastrointestinal
/maintenance diet), whilst adding the
other medications to reduce the ammonia such as
lactulose and metronidazole/neomycin.
If surgery is not an option for whatever reason, then
once the patient is adult, decisions can be made on
switching from controlling clinical signs of HE with
medical supplements to rather controlling them with
dietary protein reduction. Once again, unless HE is
present, dietary protein reduction is not indicated.
Chronic inflammatory liver disease
Patients with acute liver disease are hypermetabolic
and require a higher protein intake to maintain a positive
nitrogen balance.1,2 Animals with more chronic
liver disease, like humans with cirrhosis, are likewise
thought to be hypermetabolic, needing protein intake
higher than maintenance values. Insufficient dietary
protein will result in increased catabolism of skeletal
muscle mass which leads to increased ammonia production
and a decreased alternative route for ammonia
detoxification to glutamine.1,5
Because no specific measurement is available for
clinical identification of malnutrition, estimation of
protein-energy malnutrition is based on sequential
assessments including weight changes (unintentional
weight reduction); serum concentrations of proteins
produced by the liver (albumin, alpha-globulins, fibronectin,
fibrinogen); body condition scoring; and
the serum creatinine concentration.1,5
In patients with liver disease, not exhibiting any signs
of HE, a high quality and highly digestible protein
source (as can be found in most commercially available
gastrointestinal diets should be provided. Patients
with acute or chronic liver disease where a large
percentage (> 70%) of the liver capacity is reduced,
also have decreased glycogen storage and decreased
gluconeogenesis, which results in protein catabolism
and fasting hypoglycemia. Diets should thus provide
of dietary calories in the form of easily digested, complex,
soluble carbohydrates such as rice, corn, wheat,
or barley. In addition, providing small frequent meals
may help maintain euglycemia and a positive nitrogen
Hepatic lipidosis
Protein-restricted diets containing high concentrations
of lipids are not suitable for cats with hepatic lipidosis
(HL).1 In a small group of obese cats with HL induced
by food deprivation, recovery was facilitated by
feeding a diet supplemented with protein derived vs.
lipid- or carbohydrate-derived energy. Cats with HL,
although stressed and ill, are relatively inactive which
complicates calculation of energy requirements.1
Considering all this, as well as the inability of cats to
down-regulate protein turnover, normal energy and
protein intake has been fed to most patients with HL.
In the rare patient which shows HE, a restricted protein
diet can be used as long as it meets minimal protein
requirements for healthy cats. Recovery of cats with
HE and of those on restricted protein diets is poor.1
In patients with HE, most commonly seen in end stage
fibrosis or patients with shunts, dietary protein should
be limited to minimize excess ammonia production.
Titrate to the highest amount possible. 1,2,4
1. Centre SA, 1998 Nutritional Support for Dogs and Cats with
Hepatobiliary Disease. Journal of Nutrition. 128: 2733S–
2. Norton RD, Lenox CE et al., 2016 Nutritional Considerations
for Dogs and Cats with Liver Disease. Journal of
American Animal Hospital Association. Vol 52:1–7.
3. Proot S, Biourge V, et al., 2009. Soy Protein Isolate versus
Meat-Based Low-Protein Diet for Dogs with Congenital
Portosystemic Shunts,Journal of Veterinary Internal Medicine
4. Tivers MS, Handel I et al., 2015 Attenuation of Congenital
Portosystemic Shunt Reduces Inflammation in Dogs. PLOS
ONE | DOI:10.1371/journal.pone.0117557
5. Weingarten MA, Sande AA. Acute liver failure in dogs and
cats.2015 Journal of Veterinary Emergency and Critical
Care 25(4): 455–473)
6. Condon RE. 1971 Effect of dietary protein on symptoms
and survival in dogs with a van Eck fistula. American Journal
of Surgery. (121)107 – 114

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