MEDICINE

CPD article

Interpreting liver parameters

in cats and dogs — getting the
most out of my blood work
One of the first approaches to suspected liver disease will be blood work looking at liver parameters. These are
also commonly included in general and some preanaesthetic screening tests. Having undertaken such testing
it is important to derive as much useful information from the results as possible, as well as understanding
the strengths and weaknesses of the tests performed. This article reviews the interpretation of liver enzymes,
both cholestatic and hepatocellular, as well as tests of liver function and ancillary tests that could indicate
hepatobiliary disease. 10.12968/coan.2017.22.12.729

Kit Sturgess MA VetMB PhD CertVR DSAM CertVC FRCVS, RCVS Recognised Specialist in Small Animal Medicine, Advanced
Practitioner in Veterinary Cardiology, Vet Freedom Ltd, Brockenhurst, Hampshire SO42 7QT

Key words: small animal medicine | liver disease |clinical pathology | liver enzymes | bile acids | bilirubin

E
levated liver enzyme activity is commonly encountered as neoplasia, little or no increase in liver enzyme activity may occur
during routine biochemical testing including because few hepatocytes are being damaged at any one time. As
pre-anaesthetic screening, with the presence of liver liver enzymes tend to be used first as screening tests, significant
disease often being first recognised on the basis of liver disease can be missed and a client mistakenly told their pet’s liver
enzyme elevation on these routine tests. Elevated liver enzymes do is ‘normal’. As in-house and external laboratory reference intervals
not necessarily represent reduced of liver function — they reflect vary, especially for liver enzyme tests, it is preferable to talk about
hepatocellular membrane integrity or biliary epithelial necrosis, mild, moderate or marked increases rather than specific numbers
cholestasis or a form of induction phenomena. Similarly, very (Table 1); this also helps owners not to become too ‘number focused’.
high values do not necessarily reflect severe disease but are an
expression of the number of hepatocytes that are involved in the Inter-assay variation
process; as such they are neither prognostic nor do they indicate Like all tests there will be inter-assay variation between serial
whether changes are reversible. results. This is perhaps more profound with enzymatic tests and
Secondary liver tests may be appropriate, including bilirubin
and dynamic (pre- and post-prandial) bile acids as well as other
parameters such as albumin and urea that may also reflect liver
function. Urinalysis can also be of value in evaluating liver disease,
looking for ammonium biurate crystal and assessing the specific
gravity and presence of bilirubin (see below) or urobilinogen in
the urine.

What is ‘normal’
The concept of normality for blood values in liver disease is
potentially dangerous, in that we work to a reference interval.
This means that 95% of dogs/cats without liver disease will fall
into that interval but some will naturally sit above or below this
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interval without evidence of disease. Equally, some patients with

significant disease will sit within the reference interval. This is
particularly important in cases where liver mass is falling, as there Figure 1. Liver of a Doberman with end-stage failure; note the
may be insufficient hepatocytes left to cause liver enzymes to be small irregular liver (arrows) and ascites. Liver enzymes were
raised (Figure 1). Further, in some slowly-changing diseases such within their reference intervals in this case.

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Table 1. Classification of magnitude of biochemical changes§ in liver disease

Parameter Low High
Dog, cat, both
Marked Moderate Mild Reference Mild Moderate Marked
Total protein 35 42 47 54–77 80 90 100
(g/l) 35 42 47 54–80 90 100 110
Albumin (g/l) 15 20 24 26–42 Indicates dehydration
Globulin (g/l) 15 18 22 24–47 55 60 70
Urea (mmol/l) 1.0 1.5 1.8 2–9 13 20 35
1.5 2.5 3.5 4-12 15 23 40
Alkaline NA NA NA <50 500 200 800 500 1500 1000
phosphatase
(IU/l)
ALT (IU/l) NA NA NA <50 400 200 600 400 1000 600
AST (IU/l) NA NA NA <50; <70 250 7000 2000
Gamma-GT NA NA NA <20 30 150 300
(IU/l) NA NA NA <10 20 80 150
Total bilirubin NA NA NA <10 20 40 100
(µmol/l)
Bile acids (BA) NA NA NA <10 30 70 100
(µmol/l)
BA — post- NA NA NA <25 50 70 100
feeding (2 hour)
Glucose 1.0 1.5 2.0 2.5–5.5 8 15 25
(mmol/l) 1.5 2.2 3.0 3.5–6.6 10 18 25
Creatine kinase NA NA NA <190 <150 400 300 1000 5000
(IU/l)*
Cholesterol 1.5 2.5 3.0 3.8–7 10 20 30
(mmol/l) 1.0 1.3 1.4 1.5–6.0 9 18 25
Triglyceride Not been significantly associated with disease 0.5–2 2.5 3.5 5.0
(mmol/l) 0.5–1.5 2.0 3.5 5.0
Parameters commonly changed in liver disease, and the direction of change
§
Ammonia is a useful parameter in the assessment of liver function but it requires rapid, in-house analysis
*As AST and to some extent ALT are present in muscles, check creatine kinase, since if this is markedly elevated it may account for any elevation in
AST and ALT.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; gamma-GT = gamma-glutamyl transferase

some colorimetric assays. As a general rule of thumb, changes
of less than 10–15% are hard to interpret as being ‘real’ changes
as opposed to assay noise. This is particularly important when
using tests where the value is large, since what appears to be a big
numerical difference could be insignificant.
As an example, if an initial test gives an ALP of 3480 IU/L, on
a repeat test values between 2950 and 4000 IU/L are difficult to
interpret as clear evidence of change.
Logical interpretation of results is important to achieve the best
clinical outcome for the patient:
zzIs the test result correct?
measurements should be undertaken using the same
test system
zzUnder some circumstances a phenomenon know as substrate
depletion can occur when measuring enzyme activity; this
involves a change in the kinetics of the reaction, resulting in
a marked underestimation of the true enzyme activity.
zzIs the enzyme increase mild, moderate or severe?
zzIs the increase significant, i.e. does it explain the patient’s
clinical presentation?
zzIs the increase likely to reflect primary or secondary
hepatobiliary disease?
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zzAre there any spurious factors that may have affected the
result?
zzIs it repeatable or could it be a laboratory error?
zz There can be marked variation in results from the same
sample between different analysers therefore serial
zzWhat are the differential diagnoses for this enzyme elevation?
zzWhich other biochemical/haematologic parameters are
changed — do they indicate cause and/or support primary
hepatobiliary disease or suggest primary disease elsewhere?
zzWhat is the next step to support/deny my hypothesis?

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Mild increases in parameters

Minor/trivial increases in liver enzymes (less than 2X upper limit Raised ALP and/or ALT
in dogs; less than 1.5X upper limit in cats is commonly used to
define such an increase) are frequently encountered on routine
blood screens, particularly common in older dogs, and often Less than twice (dog); More than twice
unaccompanied by evidence of functional change. An approach to one and a half times (one and a half
such patients is illustrated in Figure 2. (cat) upper limit of times) upper limit
reference interval of reference interval
Liver enzymes
Liver enzymes can be considered in terms of primary and
secondary parameters and in terms of leakage enzymes and Patient Patient clinically unwell, Extend liver screen:
cholestatic enzymes. clinically well, likely to be a secondary gamma-GT, AST,
recheck in hepatopathy — look for CPK, bilirubin,
zzPrimary parameters
3–6 months disease elsewhere dynamic blie acid
zzAlkaline phosphatase (ALP, SAP, ALKP, ALPase, Alk Phos)
zzAlanine aminotransferase (ALT, ALAT [SGPT — serum
glutamate-pyruvate transaminase])
Results
zzSecondary parameters Results normal
abnormal
zzAspartate aminotransferase (AST [SGOT — serum glutamic
oxaloacetic transaminase])
zzGamma-glutamyl transferase (GGT, γ-GT)
Results still Patient clinically well Ultrasound scan of
zzGlutamate dehydrogenase (GLDH) abnormal recheck in 3–6 months liver abnormal
zzLactate dehydrogenase (LDH)
Alanine aminotransferase and alkaline phosphatase are
considered to be the primary parameters. Alanine aminotransferase
Results
is categorised as a leakage enzyme indicating hepatocellular injury, Results normal
abnormal
whereas ALP is categorised as an induction enzyme associated
with increased synthesis in response to cholestasis or other factors
such as glucocorticoid use (dogs) or neoplasia such as biliary Discuss with client Patient clinically unwell Ultrasound
carcinoma. It is critical to remember that increases in ALT reflect chronic monitoring and strong suspicion of scan
the number of cells damaged, not the severity of damage; equally, or further hepatopathy → FNAB liver of liver
increased ALP activity does not reflect the cause of cholestasis and investigation + gallbladder aspirate abnormal
therefore the severity of disease.
Figure 2. Approach to raised alkaline phosphatase (ALP) /alanine
HIGH LIVER ENZYME ACTIVITY DOES NOT aminotransferase (ALT) discovered during routine blood screening. AST =
NECESSARILY MEAN BAD OR SEVERE DISEASE aspartate aminotransferase; CPK = creatine phosphokinase; FNAB = fine needle
aspiration biopsy; gamma GT = gamma-glutamyl transferase.
The liver is the central metabolic powerhouse of the body,
hence will be affected by any metabolic stress that is present, liver enzyme activity is much more common than the prevalence
leading to secondary increases in liver parameters. Similarly, due of liver disease; this is due to the significant effect of systemic
to the high metabolic load, reduction in blood supply or oxygen disorders on the liver. The liver occupies an incredibly important
delivery will cause damage to liver cells — for example a period of location between the gastrointestinal tract and the systemic
low blood pressure during anaesthesia (Tables 2 and 3). circulation and is thus exposed to a wide variety of toxins, drug
Although ALT reflects hepatocellular damage and ALP reflects metabolites, endotoxins and infectious agents. A wide spectrum
biliary stasis, the two systems are not independent. Hepatocellular of non-hepatic (extrahepatic) factors may thus influence liver
damage and swelling will cause collapse of the bile canaliculi, enzyme activity.
resulting in secondary rise of ALP. Bile is a toxic substance and It should also be noted that enzymes will continue to leak from
back up of bile through the biliary system will start to cause repairing hepatic tissues, resulting in more prolonged elevations in
hepatocyte damage and therefore a secondary increase in ALT. liver enzyme activity than would be predicted following resolution
Looking at the magnitude of change can be helpful in suggesting of an acute insult.
which is the primary process and which secondary. However,
particularly in chronic disease, both hepatocellular and biliary Leakage enzymes
© 2017 MA Healthcare Ltd

involvement will develop, resulting in increases in both sets of Alanine aminotransferase

liver enzyme activities. Alanine aminotransferase (ALT) has reasonable to good sensitivity
The liver enzymes are either categorised leakage enzymes (ALT to hepatocellular injury but will also rise if there is marked muscle
and AST) or are associated with increased synthesis in response to damage. Following a hepatic insult, ALT begins to rise within 12
cholestasis (ALP and GGT). In the general population, increased hours and peaks at 24–48 hours. Artifactual elevation of ALT can

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A number of drugs commonly used in clinical practice are

Table 2. When serum transaminase* levels
may not reflect clinical hepatobiliary disease
Endocrinopathies Diabetes mellitus
Hyperadrenocorticism
Hyperthyroidism (cats) (Foster
and Thoday, 2000)
Gastrointestinal disease Pancreatitis
Inflammatory bowel disease
Neoplasia Metastatic disease
Drug induction Phenobarbital (dogs)
Corticosteroids (dogs)
Hypoxia/hypotension Congestive heart failure
Hypotensive crisis
Severe haemolytic anaemia
Status epilepticus
Myositis
Blunt abdominal trauma
*Alanine aminotransferase, aspartate aminotransferase
Table 3. When alkaline phosphatase levels
may not reflect clinical hepatobiliary disease
Bone growth/disorders Young animals
Osteosarcoma
Osteomyelitis
Endocrinopathies Diabetes mellitus
Hypothyroidism
Hyperadrenocorticism
Gastrointestinal disease Pancreatitis
Inflammatory bowel disease
Neoplasia Hepatic metastasis
Paraneoplastic induction
Drug induction Corticosteroids
Phenobarbital
Hypoxia/hypotension Congestive heart failure
Hypotensive crisis
Severe haemolytic anaemia
Status epilepticus
Systemic infection
occur if the serum sample suffers in vitro haemolysis or is lipaemic.
Half-life in cats is relatively short (6 hours) compared to dogs
(2.5 days) (Dossin et al, 2005) so when assessing recovery from
an acute liver insult (more than 48 hours previously), sampling
a cat the following day is reasonable (a significant fall would be
expected) whereas re-sampling a dog should ideally be carried out
after 2–3 days, when a 50% fall would be expected.
Increased serum ALT activity has the highest sensitivity
(80–100%) for inflammation, necrosis (Cornelius and Kaneko,
potentially hepatotoxic, e.g. benzodiazepines, phenobarbital,
potentiated sulphonamides, methimazole/carbimazole, and
paracetamol. Toxicity can be dose-dependent or idiosyncratic.
Aspartate aminotransferase
Aspartate aminotransferase is most often used to assess muscle
damage. However, in dogs, AST may have a higher sensitivity to
detection of metastatic disease in the liver than ALT (70–95% vs.
45%, respectively). Haemolysis also increases serum AST.
Cholestatic enzymes
Biliary disease results in increased cholestatic enzyme activity
(Guelfi et al, 1982).
Alkaline phosphatase
Alkaline phosphatase is an enzyme found in the membranes
of epithelial cells that line the bile canaliculi and sinusoids. It is
also present in bone, renal tubular and intestinal epithelial cells.
Alkaline phosphatase tends to be higher in young animals due to
bone growth; in an adult, bone ALP accounts for about one third of
measured ALP activity in healthy dogs. Although both the kidney
and intestines have high levels of ALP, cellular damage causes loss/
leakage into the lumen of the gut or renal tubules respectively and
the enzyme is not significantly reabsorbed to appear in the blood;
half life is also very short (<6 minutes in dogs and <2 minutes
in cats). Isoenzymes exist, such as a glucocorticoid-induced
isoenzyme (Dillon et al, 1980), but are not routinely individually
measured in veterinary medicine (Hoffman et al, 1977).
Cholestasis results in increased formation of ALP via induction
of enzyme expression and accumulation on the sinusoidal
hepatocyte membranes. This induction takes approximately
8 hours, thus ALP elevations may not be noted in the very acute
cholestatic process. An increased ALP activity can reflect a variety
of hepatic and post-hepatic processes, such as cholestatic liver
disease and canalicular cell necrosis (Cornelius and Kaneko
1960). An elevated ALP in the cat (Everett et al, 1977) always
warrants further investigation, due to the fact that cats have far
less ALP in their cells than dogs and ALP is readily excreted by the
kidneys. The half-life of ALP in the cat is approximately 6 hours
compared to 72 hours in dogs (Dossin et al, 2005). Following acute
cholestasis, levels should fall significantly (>50%) within 24–48
hours in cats and 3–4 days in dogs.
Alkaline phosphatase has a reasonably high sensitivity (80%)
but low specificity (51%) for hepatobiliary disease (Hoffmann,
1977). Although it is viewed as a cholestatic enzyme it is elevated
in many diseases that are considered more hepatic than biliary,
such as nodular hyperplasia in old dogs.
As with all liver parameters a variety of non-hepatobiliary
disease can cause ALP to be elevated.
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1960), vacuolar hepatopathy and primary neoplasia. Reduced Gamma-glutamyl transferase

sensitivity has been noted for the detection of liver failure due to Gamma-glutamyl transferase (GGT), found primarily in biliary
feline hepatic lipidosis (72%), hepatic congestion (70%), metastatic epithelial cells and hepatocytes, is a membrane-associated enzyme
neoplasia, portosystemic vascular anomalies and secondary as well as being present in microsomes and a small portion (<5%)
hepatic lipidosis (60%). in the cytoplasm. Although it is also found in the pancreas, gastro-

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intestinal tract, renal tubular epithelium, reproductive tract and

mammary tissue, these organs leak their enzyme into the respective
lumen and not into the circulation. Increases in serum GGT are
due to cholestasis, and it appears to be a more sensitive indicator
of hepatobiliary disease in the cat than ALP (Figure 3). One notable
exception in cats is in hepatic lipidosis, where ALP is often markedly
elevated whereas GGT remains within the reference interval
or is only mildly elevated. In the cat with extrahepatic bile duct
obstruction, serum GGT activity will increase up to 2-fold within 3
days, 2–6 fold within 5 days and 3–13 fold within a week.
Gamma-glutamyl transferase is relatively insensitive (50%)
for hepatobiliary disease but has good specificity (87%)(Noonan
and Meyer, 1979). In cats, GGT is more sensitive (86%) but less
specific (67%) than ALP for indicating hepatobiliary disease
(Center et al, 1986). Gamma-glutamyl transferase is elevated in
necroinflammatory liver disease, bile duct obstruction and/or
inflammatory intrahepatic cholestasis. In glucocorticoid-induced
hepatopathy, GGT shows much smaller increases than ALP
(Badylak and van Vleet, 1982).

Bilirubin
Bilirubin is formed during removal of red blood cells (RBCs)
through the monophagocytic system in the liver and spleen.
Haemoglobin from the RBCs is degraded to iron, globin and
biliverdin, and it is the latter that is further degraded to bilirubin.
The bilirubin is then released from the cell, binds to albumin and
is transported to the liver. In the liver the bilirubin is conjugated
with glucuronide in the hepatocyte. Once bound to glucuronide
the conjugated bilirubin is water soluble, is transported from the
hepatocytes across the bile canalicular membrane, and enters
the intestines via bile. Hyperbilirubinaemia can occur due to
prehepatic disease (haemolytic), primary intrahepatic disease,
and post-hepatic disease. Dogs can conjugate bilirubin in the
kidneys, hence up to ++ bilirubin in the urine can be normal,
especially in male dogs. Cats have a much higher renal threshold
for bilirubin (approximately 9 times greater) and are dependent
on hepatocyte conjugation only, with none occurring in the
kidneys, hence any bilirubin in feline urine is always abnormal.
Any conjugated bilirubin that escapes back into the circulation
becomes attached to albumin (delta-bilirubin) and has a half-life
in the circulation of approximately 10–14 days, thus even after
resolution of the cholestatic event icterus can persist for a period
of time. Duration of icterus can also be further extended due to
staining of elastin tissue.
Pre-hepatic bilirubinaemia is secondary to haemolysis of RBCs
and easily distinguishable from the other two causes by the presence
of marked concurrent anaemia. The level of anaemia that will
result in jaundice is dependent both on underlying liver function
and on the rate of the extravascular haemolysis, but it would be
very unusual if the anaemia was not at least moderate (packed cell
volume <23% (dog); <18% (cat)). Cats are more prone than dogs
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Figure 3. Liver mass in a cat; histology showed biliary cystic hyperplasia and
neutrophilic, lymphocytic, plasmacytic cholangitis. Alanine aminotransferase,
alkaline phosphatase and gamma-glutamyl transferase were mildly raised.
and excretion. This typically occurs only with more severe hepatic
disease; a list of the typical diseases that cause hyperbilirubinaemia
is given in Box 1.
Post-hepatic hyperbilirubinaemia (Figure  4) is secondary
to obstruction of the extrahepatic bile duct. The most common
causes include pancreatitis, cholelithiasis, biliary neoplasia and
pancreatic neoplasia. Any lesion at the level of the duodenal
papilla where the bile duct enters the duodenum can also cause
Box 1. Hepatic causes of
hyperbilirubinaemia
zzHepatic lipidosis
zzCholangitis (inflammatory/immune-mediated)
zzInfectious disease
zzViral: feline infectious peritonitis, adenovirus
zzBacterial: leptospirosis, salmonella, rickettsial
zzProtozoal: toxoplasmosis, neosporosis
zzParasitic (rare UK)
zzToxins: Amanita spp., aflatoxin, Sago palm, cyanobacteria
zzDrugs (various, e.g. anabolic steroids (dogs, cats), carprofen
(dogs), corticosteroids (dogs), diazepam and other
benzodiazepines (cats), methimazole and carbimazole (cats),
paracetamol (dogs, cats especially), phenobarbital (dogs),
potentiated sulphonamides (dogs), tetracyclines (cats))
zzNeoplasia (lymphoma, mast-cell tumour, hepatocellular
adenocarcinoma)

to becoming jaundiced following haemolysis, as their livers are not zzSepsis

able to handle increased bilirubin load as efficiently as dogs. zzHepatic lipidosis
Primary hepatic bilirubinaemia is often secondary to a zzCopper-associated hepatopathy
combination of decreased hepatocyte function and intrahepatic zzLysosomal storage disease
cholestasis leading to decreased bilirubin uptake, conjugation

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Figure 4. Jaundice in a cat secondary to post-hepatic biliary obstruction.
extrahepatic biliary obstruction, for example severe inflammatory
bowel disease causing inflammation of the papilla. With biliary
obstruction an increase in cholesterol is commonly noted together
with increases in cholestatic enzymes (GGT, ALP), but imaging
of the liver and biliary tree is usually necessary to distinguish
primary intrahepatic cholestasis from extra-hepatic cholestasis.
This allows appropriate further diagnostics and treatment options
to be deciphered.
Serum bile acids
Bile acids are primarily synthesized by hydroxylation of cholesterol
in the liver. A major function is to form micelles to enhance the
solubilisation of lipids within the intestine and hence facilitate the
digestion and absorption of fats. There is enterohepatic recycling
of the bile acids, with resorption in the ileum. Although we view
serum bile acids to assess hepatic function they more accurately
reflect hepatic circulation. Bile acids primarily increase in response
to portovascular shunts, hepatic disease and cholestasis; in the
presence of hyperbilirubinaemia there is no value in assessing bile
acids. They have diagnostic value when assessing:
zzPersistent elevation of liver enzymes
zzSuspicion of hepatic encephalopathy and cirrhosis
zzSuspected portosystemic shunts (Ruland et al, 2010)
zzEffectiveness of therapy in patients with hepatic disease.
Degree of elevation is not disease associated, although vacuolar
hepatopathies rarely cause rises above 75–100 µmol/L. Generally,
a pre-prandial increase above 10–15 µmol/L and a post prandial
increase above 25 µmol/L is a sensitive although not necessarily
specific indicator of reduced liver function. Breed- and age-specific
reference ranges are now available, with some breeds e.g. Maltese
terriers having higher than expected values (O’Leary et al, 2014).
Generally, the author is less concerned about mild elevations in
bile acids in older dogs and cats.
734
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Despite the initial promise, bile acids are not liver-specific
(Box  2), but their sensitivity can be increased by dynamic bile
acid testing. The test is performed pre- and 2 hours post feeding,
following a 12-hour fast. Occasionally anomalous results can
occur, with post-prandial bile acids being lower than pre-prandial.
Although this could reflect mislabelling of samples it is more
commonly due to the gall bladder having contracted shortly before
the pre-prandial bile acid sample was taken; it can be a repeatable
finding in some dogs. It is essential that serum samples are used;
heparinised plasma can give falsely elevated results.
Ammonia
Ammonia is a sensitive and specific indicator of liver function
but requires rapid analysis, with results being significantly
affected by hypocobalaminaemia or by outside influences such
as ammoniacal cleaners. Reduced ammonia levels can be seen
with administration of antibiotics, lactulose and enemas (and also
possibly by administration of probiotics). Causes of increased
ammonia include high-protein meals, improper handling of the
sample, hepatic dysfunction and inherited urea cycle disorders.
Ammonia has a similar sensitivity and specificity to dynamic bile
acid evaluation in the diagnosis of portovascular anomaly and
hepatic dysfunction (Center et al, 1985; Ruland et al, 2010).
In cases where there is subtle liver dysfunction, ammonia
tolerance testing can be performed.
Other direct and indirect markers of
hepatobiliary disease
With progressive liver dysfunction, decreased protein synthesis
together with altered glucose and lipid metabolism will occur.
Generally this will only be seen when there is marked loss of liver
function: at least 70–80% and is some cases >90% loss. While they
are not sensitive markers, when they occur they tend to indicate
serious and advanced liver disease, and can often be associated
with only modest rises in liver enzymes due to the low number of
viable cells still present in the liver.
Glutamate dehydrogenase
Glutamate dehydrogenase (GLDH) is a sensitive but non-specific
indicator of primary and secondary hepatopathies (Mühlberger
and Kraft, 1994). It is also raised where there are effusions, and is
induced in cases of diabetes mellitus. In liver disease, increases in
GLDH tend to reflect hepatocellular centrilobular injury.
Lactate dehydrogenase
Lactate dehydrogenase (LDH) is an enzyme that is
non tissue-specific but there are a variety of isoenzymes, with
LDH5 being more liver specific although also found in muscle.
Isoenzymes are not routinely measured in animals although they
are in man.
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Cholesterol
Hypercholesterolaemia can be a sign of cholestasis, due to reduced
cholesterol excretion in the bile.
Hypocholesterolaemia in hepatobiliary disease is usually an
indicator of significant loss of liver mass.
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Box 2. Causes of decreased and
increased serum bile acids
zzDecreased bile acids
zzDecreased gastric motility
zzHypermotile gastrointestinal (GI) tract
zzGI malabsorption
zzIleal disease/resection
zzIncreased bile acids
zzPancreatitis
zzGI tract disease
zzPre-hepatic jaundice
zzElevated cortisol levels — exogenous or
hyperadrenocorticism
Albumin and globulins
Decreased protein synthesis leads to hypoalbuminaemia. It may also
lead to hypoglobulinaemia (alpha- and betaglobulins are produced
by the liver but gammaglobulins are dependant on B-lymphocytes
and plasma cells for production), but this is less common. In acute
liver disease, albumin may fall slightly as a negative acute-phase
protein. In some instances hyperglobulinaemia may be seen,
either as an acute-phase reaction or in response to decreased
clearance of toxins and microbial agents by a reduced liver mass
(and hence reduced Kupffer cell numbers), or vascular anomalies
such as portosystemic shunts.
Blood urea nitrogen
Hepatic insufficiency can result in decreased conversion of
ammonia to urea, resulting in low urea levels. Urea level may
also by reduced by other factors such as polyuria/polydipsia and
reduced protein intake (inappetence; low protein diet).
Coagulation factors
The liver is responsible for synthesis of coagulation factors II
(prothrombin), VII, IX, X, XI, XII and XIII (enzymatic factors)
and I (fibrinogen), V and XIII (non-enzymatic factors). Therefore
severe liver dysfunction can result in prolongation of activated
clotting time, prothrombin time (PT) and activated partial
thromboplastin time (APTT) due to reduced production of
coagulation factors by the liver.
Haemostatic defects due to cholestasis are more common.
Cholestasis causes decreased digestion and absorption of
fat-soluble vitamins, hence a decrease in vitamin K-dependent
factors II, VII, IX and X. This is more commonly noted in cats,
and prior to any liver biopsy consideration to this point should
be given. Subcutaneous supplementation of vitamin K (1 mg/kg
q12 hours for 2–3 doses) may be appropriate (especially if APTT
and PT are prolonged). In more severe cases choice of biopsy
technique (ultrasound guided vs. laprascopic vs. surgical) and the
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use of a plasma transfusion should be considered.
Glucose
Hypoglycaemia can occur as a result of reduced hepatic glycogen
stores, delayed insulin clearance or decreased gluconeogenesis.
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KEY POINTS
zzInterpretation of changes in liver enzyme activities is different in cats
and dogs.
zzIncreased alkaline phosphatase (ALP) and gamma-glutamyl transferase
(GGT) activity primarily reflect biliary disease. Increased alanine
aminotransferase (ALT) activity primarily reflects hepatocellular damage.
zzThe magnitude of increase in enzyme activity indicates the number of
cells involved; it does not reflect whether the changes is reversible.
zzSevere liver disease can be present in patients with liver enzyme
activities within the reference interval.
zzLiver enzyme activities and serum bile acid levels will increase in both
primary and secondary hepatopathies.
zzOther biochemical and haematologic factors can provide additional
information and aid interpretation in patients with elevated liver enzyme
activities.
This typically occurs only with very severe liver dysfunction and is
often one of the last parameters to be affected. Hypoglycaemia is
also reported as a paraneoplastic syndrome associated with some
hepatocellular adenocarcinomas (Figure 5).
Haematological assessment
Microcytosis may be seen with severe hepatic dysfunction or
portosystemic shunts, due to altered iron metabolism or transport.
Acanthocytes (associated with deranged lipid metabolism) and
elliptocytes (e.g. in hepatic lipidosis) may also be seen. Codocytes
(target cells) can be seen in liver disease, due to decreased
lecithin-cholesterol acyltransferase (LCAT) activity in cholestasis:
decreased enzymatic activity increases the cholesterol to
phospholipid ratio in the red cells, producing an absolute increase
in surface area of the red blood cell membranes.
Conclusions
Abnormalities in liver enzymes are commonly encountered in
clinical practice but the full clinical value of the changes observed
is often lost. Combining a better understanding of factors that may
affect liver parameters with the clinical history and physical
examination can significantly impact on the management and
Figure 5. Computed tomography scan of a massive hepatocellular carcinoma
causing abnormal blood glucose levels in a dog.
735
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further investigation of a case, as the clinician is better informed of
the likely presence of hepatobiliary disease; the area of the liver
affected; progression or resolution of the problem; and potentially
the severity of the disease process. All these factors serve to better
inform the client and improve care of the patient, but ultimately
liver biopsy and/or bile culture is necessary to achieve a diagnosis
in cases with primary hepatopathies. CA
Conflict of interest: No conflict of interest.
 
Further reading
Center SA. Interpretation of liver enzymes. Vet Clin North Am Small Anim Pract.
2007;37(2):297–333, vii. doi:10.1016/j.cvsm.2006.11.009
Chapman SE, Hostutler RA. A laboratory diagnostic approach to hepatobiliary dis-
ease in small animals. Vet Clin North Am Small Anim Pract. 2013;43(6):1209–
1225, v. doi:10.1016/j.cvsm.2013.07.005
Webster CRL, Cooper JC. Diagnostic approach to hepatobiliary disease. IN:
Bonagura JD, Twedt DC, editors. Kirk’s Current Veterinary Therapy XV. St Louis
(MO): Saunders;2014: p569–575
References
Badylak SF, Van Vleet JF. Tissue gamma-glutamyl transpeptidase activity and he-
patic ultrastructural alterations in dogs with experimentally induced glucocorti-
coid hepatopathy. Am J Vet Res. 1982;43(4):649–655
Center SA, Baldwin BH, de Lahunta A, Dietze AE, Tennant BC. Evaluation of serum
bile acid concentrations for the diagnosis of portosystemic venous anomalies in
the dog and cat. J Am Vet Med Assoc. 1985;186(10):1090–1094
Center SA, Baldwin BH, Dillingham S, Erb HN, Tennant BC. Diagnostic value of
serum gamma-glutamyl transferase and alkaline phosphatase activities in hepa-
736
© MA Healthcare Ltd. Downloaded from magonlinelibrary.com by 144.082.238.225 on December 16, 2017.
tobiliary disease in the cat. J Am Vet Med Assoc. 1986;188(5):507–510
Cornelius CE, Kaneko JJ. Serum transaminase activities in cats with hepatic necro-
sis. J Am Vet Med Assoc. 1960;137:62–66
Dillon AR, Spano JS, Powers RD. Prednisolone induced hematologic, biochemical,
and histological changes in the dog. J Am Anim Hosp Assoc. 1980;16:831–837
Dossin O, Rives C, Germain JP, Lefebvre H. Pharmacokinetics of liver transami-
nases in healthy dogs: potential clinical relevance for assessment of liver damage.
23rd ACVIM Forum Proceedings, Baltimore, MD, USA, 1–4 June 2005; p 886
Everett RM, Duncan JR, Prasse KW. Alkaline phosphatases in tissues and sera of
cats. Am J Vet Res. 1977;38(10):1533–1538
Foster DJ, Thoday KL. Tissue sources of serum alkaline phosphatase in 34 hyper-
thyroid cats: a qualitative and quantitative study. Res Vet Sci. 2000;68(1):89–94.
doi:10.1053/rvsc.1999.0363
Guelfi JF, Braun JP, Benard P, Rico AG, Thouvenot JP. Value of so called cholestasis
markers in the dog: an experimental study. Res Vet Sci. 1982;33(3):309–312
Hoffmann WE. Diagnostic value of canine serum alkaline phosphatase and alkaline
phosphatase isoenzymes. J Am Anim Hosp Assoc. 1977;13:237–241
Hoffman WE, Renegar WE, Dorner JL. Alkaline phosphatase and alkaline phos-
phatase isoenzymes in the cat. Vet Clin Pathol. 1977;6(3):21–24. doi:10.1111/
j.1939-165X.1977.tb00772.x
Mühlberger N, Kraft W. [Diagnostic value of glutamate dehydrogenase determina-
tion in the dog]. Tierarztl Prax. 1994;22(6):567–573
Nilkumhang P, Thornton JR. Plasma and tissue enzyme activities in the cat. J Small
Anim Pract. 1979;20(3):169–174. doi:10.1111/j.1748-5827.1979.tb07026.x
Noonan NE, Meyer DJ. Use of plasma arginase and gamma-glutamyl transpepti-
dase as specific indicators of heptocellular or hepatobiliary disease in the dog.
Am J Vet Res. 1979;40(7):942–947
O’Leary CA, Parslow A, Malik R, Hunt GB, Hurford RI, Tisdall PLC, Duffy DL. The
inheritance of extra-hepatic portosystemic shunts and elevated bile acid con-
centrations in Maltese dogs. J Small Anim Pract. 2014;55(1):14–21. doi:10.1111/
jsap.12156
Ruland K, Fischer A, Hartmann K. Sensitivity and specificity of fasting ammonia
and serum bile acids in the diagnosis of portosystemic shunts in dogs and cats.
Vet Clin Pathol. 2010;39(1):57–64. doi:10.1111/j.1939-165X.2009.00178.x
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