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Liver
disease can be frustrating to diagnose. Although in the dog (in
contrast to the cat), it is uncommon for a patient to have normal
clinical pathology values in the presence of significant liver
disease, enzymology and other clinical pathology tests rarely
indicate the type of liver pathology present. In addition, even
liver “specific” enzymes such as ALT can be increased in
non-primary hepatic disease and care must be taken in interpreting
slight or even moderate increases. This lecture will focus on the
tests that may be utilised in the diagnosis of liver disease and the
non-hepatic causes for changes in these tests that the clinician
should be aware of when interpreting clinical pathology results.
Diagnostic
tests
Liver
enzymology
Alanine
aminotransferase (ALT, formerly SGPT).
ALT is a liver specific
enzyme in the dog and cat. The highest cellular concentrations occur
in the cytosol therefore the enzyme is released following severe,
acute and diffuse hepatocellular necrosis. In general, serum levels
are not regarded as significant unless they are two to three times
above normal. Mild-moderate increases in ALT (up to four to five
times normal) may occur with non-hepatic disorders such as
inflammatory GI disease, cardiac failure and haemolytic anaemia.
The
serum half-life of ALT is less than 24 hours. Levels peak two to
three days after hepatic insult and return to normal in one to three
weeks if hepatic insult resolves. A persistent increase indicates
continuing hepatocellular insult. ALT levels may also be moderately
increased in animals on anticonvulsant therapy and glucocorticoids
and with biliary stasis.
Alkaline
phosphatase (ALP). ALP is bound to membranes of bile canaliculi
and bile ducts. Values are increased by any condition causing
cholestasis, either intra- or extra-hepatic. Cholestasis results in
increased synthesis and regurgitation of the enzyme from the biliary
system into the serum.
Isoenzymes.
Other isoenzymes of ALP are also found in bone, intestine,
kidney tubules and the placenta. However, the half-life of the
intestinal, renal and placental isoenzymes are so short (two to six
minutes) that serum elevations of ALP would rarely occur from these
organs. Usually an elevation in ALP is due to hepatic or bone
isoenzymes. However, exogenous and endogenous glucocorticoids can
induce a specific isoenzyme and thus result in elevated serum levels
in the dog (but not in the cat). The value in measuring the ALP
isoenzyme in the diagnosis of hyperadrenocorticism is highly
questionable as the isoenzyme is increased by hepatic pathology as
well as hyperadrenocorticism.
ALP
levels will be increased in young growing animals (bone isoenzyme)
and in destructive bone disease. ALP is also increased in certain
carcinomas and mammary gland tumours, and with anticonvulsant
therapy in dogs, but not cats.
ALT
vs. ALP—does their relative increases help determine the
location of liver pathology (intra- or extra-hepatic)?
 Serum
enzymology is not particularly helpful in determining whether an
animal has hepatic or post-hepatic disease. Post-hepatic
obstruction of the biliary tract almost invariably causes
secondary hepatocellular damage and hence both ALT and ALP will be
elevated. ALP is elevated by both intra- and extra-hepatic
cholestasis thus is increased in hepatic and post-hepatic disease.
The
relative degree of increase of each enzyme is also not helpful; in
fact, if ALP is substantially increased and ALT normal or only
slightly increased, non-hepatic disease such as
hyperadrenocorticism or exogenous corticosteroid administration is
more likely to be present.
It
is important to be aware that serum enzymes are not liver function
tests and there is no correlation between the magnitude of the
enzyme increase and the severity or reversibility of the
condition. Occasionally, cases of severe liver dysfunction, e.g.,
biliary cirrhosis, neoplasia or portacaval shunt, may be
associated with minimal or no increases in serum enzymes.
Gamma
glutamyl transpeptidase (GGT). GGT levels are increased in most
conditions that cause elevation in ALP, i.e., cholestasis,
glucocorticoid therapy, hyperadrenocorticism. However, unlike ALP,
GGT is not elevated with increased osteoblastic activity (e.g.,
growing dogs) and may not be elevated in dogs on anticonvulsant
medication. ALP is slightly more sensitive than GGT for detection of
cholestatic disease in dogs
Serum protein
Serum
albumin. Albumin is synthesised only in the liver. A loss of
greater than 70% of liver function is required before
hypoalbuminaemia occurs. Hypoalbuminaemia most commonly occurs in
cirrhosis and portosystemic encephalopathy but will also occur in
severe diffuse necrosis. Albumin concentrations may also be
decreased in renal and gut disease, severe cutaneous burns, protein
malnutrition, in the presence of acute phase reactants, and in
patients with exudative effusions (which cause sequestration of
albumin).
Serum
globulins. Increased serum globulin levels may occur in
inflammatory hepatic disease or when the hepatic reticuloendothelial
system is compromised. Decreased levels will often occur in
portosystemic encephalopathy as a large proportion of globulins are
synthesised in the liver.
Bilirubinaemia
and bilirubinuria
Dogs
(males more than females) have a low resorptive threshold for
bilirubin. They also have renal enzyme systems that produce and
conjugate bilirubin to a limited extent. Therefore, mild
bilirubinuria (up to 2+) can occur in normal dog urine of greater
than 1.025 specific gravity.
Slight
bilirubinuria may occur in starvation and febrile states
and mild bilirubinaemia and bilirubinuria can also occurs with sepsis.
Bilirubinuria will develop well before overt jaundice in dogs due to
the low renal threshold.
Is
the relative ratio of conjugated vs. unconjugated bilirubinaemia
helpful in determining whether hepatic pathology is intra- or
extra-hepatic?
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While
an animal with only conjugated bilirubinaemia would most likely have
post-hepatic jaundice (due to biliary tract or pancreatic disease
most commonly), the majority of animals with hepatic or post-hepatic
jaundice will have both unconjugated and conjugated bilirubinaemia.
Post-hepatic obstruction will cause secondary hepatocellular damage
and, as previously mentioned, bilirubin excretion is the first
process to become disordered in primary hepatocellular disease.
Cholesterol
Very
low serum cholesterol concentrations may occur in patients with
congenital or acquired portosystemic shunts and fulminant hepatic
failure. Increased serum cholesterol in a jaundiced patient usually
indicates major bile duct occlusion particularly in cats. However,
cholesterol concentrations are also increased in non-hepatic
diseases such as pancreatitis, diabetes mellitus,
hyperadrenocorticism and hypothyroidism which if present
concurrently can confuse interpretation.
Bile
acids
Serum
bile acids are a sensitive and specific measure of hepatobiliary
function in the cat and dog. They should be considered when other
routine clinical pathology results do not permit an unequivocal
diagnosis of liver disease to be made. It is not necessary to do
the test if the patient is jaundiced and not anaemic, nor if liver
enzyme changes permit an unequivocal diagnosis of liver disease to
be made.
Bile
acids are useful as a screening test for hepatic encephalopathy
(except in Maltese Terriers). Their major advantage in this context
is the lack of stringent requirements for sample collection and
processing in contrast to blood ammonia determination.
Occasionally,
bile acids can be normal in patients with hepatic disease. We have
observed this in some cases of hepatic neoplasia. The level of serum
bile acid increase roughly correlates with the severity of the
hepatobiliary disorder but the level gives no indication of
reversibility or the type of the lesion and hence prognosis.
Serum
bile acid concentrations are usually not affected by steroid
administration but occasionally can be markedly altered due to
alteration of hepatic architecture as a result of hepatic glycogen
accumulation. Serum bile acids are therefore useful but not
infallible for differentiating elevated ALP values due to steroids
(endogenous or exogenous) or hepatobiliary disease.
Other
diagnostic procedures
Radiology
Plain
radiographs may be helpful in confirming hepatomegaly, the presence
of a small liver, or asymmetric enlargement of a liver lobe.
However, although the liver is the largest solid organ in the body,
its plain film evaluation is unreliable. Contrast radiography is
primarily indicated in diagnosing portacaval shunts.
Ultrasound
Ultrasound
examination of the liver may assist in differentiating homogeneous
enlargement from cellular infiltration and in differentiating
hepatic from post-hepatic cholestasis.
Biopsy
Hepatic
biopsy is usually the only method by which the type of hepatic
pathology can be characterised. Hepatic biopsy (via exploratory
laparotomy or ultrasound guided) should be considered in all dogs
with obstructive jaundice and in those with evidence of chronic
hepatocellular disease.
The
pretenders
A
number of diseases may be confused with hepatic disease because of
clinical signs or clinicopathological abnormalities. Increased liver
enzymes, ALT, and ALP may occur in pancreatitis, diabetes mellitus,
and hyperthyroidism. Moderately increased bilirubin can occur in a
variety of non-hepatic diseases as well as in conditions such as
prolonged anorexia, catabolic states, and infection. Mild increases
in ALT may be observed in animals with cardiac pathology.
Substantial increases in ALP with moderate increases in ALT will
occur in most dogs with hyperadrenocorticism.
Causes of hepatic
disease in dogs
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Chronic
hepatitis
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Chronic
progressive hepatitis-idiopathic, immune mediated?
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Bedlington
Terriers, WHW Terriers—copper toxicity
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Lobular
dissecting hepatitis
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Leptospirosis
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Viral
- adenovirus
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Drug
induced- primidone, phenytoin
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Suppurative
cholangiohepatitis
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Non-suppurative
(lymphocytic) cholangiohepatitis
Acute
hepatitis
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Toxins
e.g., thiacetarsamide, anticonvulsants
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Aflatoxin,
bacterial endotoxin, blue green algae
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Bacterial
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Leptospira, Salmonella, Clostridia
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Viral-
adenovirus I (ICH), canine herpes
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Toxoplasmosis
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Dirofilariasis—caval
syndrome
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Acute
pancreatitis
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Acute
haemolytic anaemia
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Heat
stroke
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Surgical
hypotension or hypoxia
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Trauma
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Cirrhosis
End-stage
fibrosis of many inflammatory hepatic diseases. Aetiology
undetermined in majority of cases.
Glucocorticoid
hepatopathy
The
canine liver is uniquely sensitive to the effects of
exogenous or endogenous corticosteroids.
Neoplasia
The
liver is a frequent site for both primary and
metastatic neoplasia.
Primary
neoplasms
Portosystemic
or hepatic encephalopathy |
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