Download I have a blood machine – are those raised liver enzymes significant?

I have a blood machine – are those
raised liver enzymes significant?
The identification of liver biochemical abnormalities should suggest certain
diagnostic possibilities and guide further investigations. Liver biochemical
abnormalities are often non-specific; measured enzymes may be isoenzymes
from another tissue or the same enzyme from a different tissue source. An
understanding of the liver biochemical tests is essential when investigating the
patient in question. Evaluation of liver biochemical tests must be interpreted in
light of the history, medications and clinical findings. The magnitude and
duration of increase is also dependent on the type, severity and duration of
the stimulus and the species. They do not indicate the prognosis or the
irreversibility of liver disease at any one point in time. Also because the liver is
involved in so many functions no single laboratory test in this category reflects
the complete functional state of the liver.
1. What are these liver enzymes
Remember that our reference ranges typically reflect a 95% confidence
interval implying that 5% of ‘normal’ patients will have values outside that
range. In a panel of 20 tests, there is 100% probability that at least one test
will be outside the reference range.
Liver biochemical test abnormalities are categorised into groups that reflect 1)
hepatocellular injury, 2) cholestasis or 3) tests of impaired metabolic function
or synthetic capacity.
Hepatocellular injury: ALT and AST
Canine and feline hepatocyte cytoplasm is rich in ALT and contains lesser
amounts of AST. Altered permeability of the hepatocellular membrane caused
by injury or a metabolic disturbance results in a release of this soluble
enzyme. Conceptually ALT and AST should be thought of as hepatocellular
"leakage "enzymes. Subsequent to an acute, diffuse injury, the magnitude of
increase crudely reflects the number of affected hepatocytes. It is however
neither specific for the cause of liver disease or predictive of the outcome. At
least a 2 fold increase is needed before significance is attached. The plasma
half-life of ALT activity is between 3 h and 4 days in the dog and significantly
shorter in the cat, however ALT concentrations may take days to decrease
following an acute insult. Persistent increases of only ALT are characteristic of
chronic hepatitis in the dog and should be investigated as early diagnosis and
prompt therapy improves patient survival. Hepatitis often begins in dogs 2-5
years of age with only an ALT increase. Females are over represented and
breed associated hepatitis is well known. Whilst a fall in ALT activity can be a
bad prognostic indicator if it reflects loss of hepatocytes, a gradual decline in
ALT following an acute insult usually indicates a good prognosis; in dogs
activities should fall by 50% every 3-4 days and have returned to normal
within 2-3 weeks. Activities decline more slowly than one would predict
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considering the half life of ALT because serum ALT is derived both from
leaky, damaged cells and from regenerating hepatocytes. ALT increases
immediately following acute injury but will also increase, more slowly, in
cholestatic liver disease. Extrahepatic bile duct obstruction and consequent
bile stasis lead to accumulation of toxic bile salts which cause hepatocyte
damage and enzyme leakage. The rises in ALT activity often do not reach the
magnitude of the increase in cholestatic marker enzymes. Similarly,
cholangitis in cats only causes a moderate increase in ALT. Rises in ALT are
also seen in some cases of primary and metastatic hepatic neoplasia if there
is leakage from tumour cells or tumour associated necrosis. However
significant hepatic neoplasia may cause only minimal elevation in ALT.
Small increases in ALT can also be caused by microsomal enzyme induction
after administration of hepatotoxic drugs and the rise in activity tends to be
dose dependent.
Azathioprine
Barbiturates (Phenobarbital, primidone)
Glucocorticoids (only in dogs)
Griseofulvin
Halothane
Ketoconazole
Mebendazole
Paracetamol (acetaminophen)
Sulphonamides
Table 1- Important hepatotoxic drugs known or suspected to cause increases
in ALT.
A variety of tissues, notably skeletal muscle and liver, contain high AST.
Hepatic AST is contained predominantly in hepatic mitochondria (80%) but
also soluble in the cytoplasm. Skeletal muscle inflammation invariably causes
a serum AST increase that exceeds the serum ALT activity and can be further
defined as of muscle origin by the measurement of the serum creatine kinase
activity (CK), a specific muscle enzyme.
Markers of cholestasis and drug induction: ALP and GGT
These enzymes have a membrane bound location at the canalicular surface;
ALP associated with the canalicular membrane and GGT associated with
epithelial cells comprising the bile ductular system. With cholestasis, surface
tension in the caniliculi and bile ductules increases and these surface
enzymes are then regulated in production. These enzymes can also become
markedly increased as a result of drug induction.
ALP is present in the dog as multiple isoenzymes in the liver, bone, intestine,
kidney and placenta; however the principal ones are ALPl (in the liver), ALPb
(bone) and ALPs (steroids) in the dog and the key causes of increased serum
ALP are cholestasis, drug/hormone induction and increased osteoblastic
activity. ALP has higher specificity for cholestasis in cats than in dogs as there
are no steroid-induced isoenzymes. The plasma half-life for ALP in the dog is
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66 h in contrast to 6 h in the cat and the magnitude of enzyme increase is
typically greater for the dog than the cat.
Bone source from osteoblasts is elevated in young growing dogs before their
epiphysial plates close or in some bone tumours (i.e osteosarcoma where
increased ALP is a poor prognosis factor suggesting diffuse bone metastasis).
Hepatic ALP is released into the blood as a result of extra- or intra-hepatic
cholestasis and drug/hormone induction. After hepatic insult ALP release is
delayed compared with that of ALT. This result from the fact that the increase
is due not only to the solubilisation of ALP from membranes by accumulated
bile salts but also to induction of de novo synthesis. ALP is also the last
enzyme to return to the reference range after an acute insult as impairment of
bile flow is usually the last to return to normal.
Steroid induced ALP (ALPs) is less than 15% of the total ALP in normal dogs
but can increase to 85% after glucocorticoid administration. However
increased ALPs has also been found in primary hepatobiliary disease,
diabetes mellitus, hypothyroidism and pancreatitis and synthesis can also be
induced by anticonvulsants. Most dogs with hypeadrenocorticism have
marked elevation of ALPs and therefore the absence of raised ALPs may help
to rule out hyperadrenocorticism.
Primary liver disease
Cholestasis (intra-, extra-hepatic)
Hepatic inflammation
Nodular hyperplasia
Neoplasia
Extrahepatic conditions
Bone metabolism
GI disease
Hyperthyroidism
Pregnancy
Right sided heart failure
Sepsis
Urological disease (nephritis, cystic
calculi)
Drug induced
Corticosteroids (iatrogenic,
hyperadrenocorticism, endogenous
with stress)
Anticonvulsants (pimidone,
phenobarbital, Phenytoin)
Azathioprine
Table 2- Causes of increased ALP in dogs.
GGT is another microsomal membrane-bound glycoprotein associated with
the biliary tree. It generally parallels the activity of ALP. There are GGT
isoenzymes in other tissues (kidney, pancreas, intestines, heart, lung,
muscles, RBCs) but most circulating GGT is considered hepatic in origin).
There is no bone isoenzyme and therefore GGT increase in not seen in
growth or bone disease. However milk and colostrums contain GGT and may
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cause an increase in nursing animals up to 10 days of age. As with ALP a
steroid induced isoenzyme exists but synthesis is less likely to be induced by
anticonvulsants.
In dogs it is probably more specific and less sensitive than ALP, but in cats
the converse is true. In cats, most cholestatic disease will cause greater
increases of GGT than ALP, except in idiopathic hepatic lipidosis where ALP
increases may occur in the absence of a significant rise in GGT.
Evaluation of Liver function: when I suspect a liver problem, what other
parameters can I measure in house to guide my interpretation of liver
enzyme serum activities?
On a routine biochemistry panel it is important to note the liver function tests
including bilirubin (in the serum and in the urine), albumin, glucose, urea and
cholesterol.
Bilirubin results from degradation of haemoglobin and other haemoproteins
in the reticulo-endothelial system (spleen), it then undergoes a conjugation in
the liver in order to be modified into a conjugated form that can be eliminated
via the biliary system into the intestines. Intestinal flora modifies bilirubin into
other pigments which give their characteristic brown colour to the faeces.
Albumin is exclusively made in the liver and if not lost, sequestered or
diluted, a low concentration would suggest significant hepatic dysfunction.
However the reserve capacities of the liver with regard to albumin secretion
are high and it may take greater than 60 % hepatic dysfunction for albumin
concentrations to decline. Albumin is a negative acute phase reactant and its
synthesis is down regulated proportionally to the up regulation of globulin
synthesis.
The liver intervenes in the regulation of glucose homeostasis, however
significant hypoglycaemia is only seen in severe hepatic compromise
(massive hepatic necrosis, end-stage liver disease, PSS). Sepsis or large
diffuse tumours may also cause hypoglycaemia through excessive utilisation
or secretion of insulin like factors.
Urea is produced by hepatic conversion of ammonia. In case of significant
liver disease a low urea is therefore to be expected. However, in some cases
azotaemia may be seen. This indicates decreased glomerular filtration which
can be a consequence of primary hepatic disease. Urea production is also
increased in case of GI bleeding, as degradation of proteins from the blood
generates a large amount of ammonia.
Cholesterol is derived from the diet and hepatic synthesis, and undergoes
enterohepatic recycling. However the usefulness of serum cholesterol
concentration as a marker of liver disease is limited as its concentration may
be decreased, normal or increased, depending on the type of liver disease,
the dietary intake and the intestinal and pancreatic functions.
Urinalysis can provide essential information when interpreting biochemical
results panel. In chronic liver disease the urine specific gravity is almost
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always decreased. In the normal dog small quantities of bilirubin are common
in urine samples. There are 3 potential explanations:
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a small amount of conjugated bilirubin escapes from the liver and
passes into the circulation and readily passes through the glomeruli
•
bound to albumin unconjugated bilirubin may be filtered where there is
mild proteinuria
•
in dogs the normal kidney may have a minor role in processing effete
haemoglobin.
In cats, bilirubinuria should ALWAYS be considered significant.
Urate crystalluria can be found in almost 2/3 of dogs with congenital PSS and
their presence can reinforce a suspicion of PSS.
2. Are those raised liver enzymes significant in my
asymptomatic patient?
In the asymptomatic patient with an increased liver biochemical test, the
increased value should be confirmed at least once to exclude spurious results
from laboratory error and to avoid unnecessary and costly additional testing. A
careful history is essential to exclude drug associated enzyme elevations. The
signalment of the patient may also provide an insight to the possible aetiology
of the enzyme increase. For example old dogs frequently have nodular
hyperplasia, neoplasia or systemic disease while younger to middle aged
dogs more commonly have chronic hepatitis. A careful physical examination
may also provide clues to the diagnosis. The most common cause of
abnormal liver enzymes is not primary liver disease but rather reactive hepatic
changes occurring secondary to other non hepatic diseases. These would
include such conditions as intra-abdominal disorders (IBD, nutritional
abnormalities), cardiovascular disease or metabolic derangements
(endocrinopathy). Generally these changes are reversible once the primary
disease is treated. Successful resolution of the non-hepatic disease and
continued abnormal liver enzymes would be a strong indication for further
investigation of the liver.
If no likely explanation for the laboratory abnormalities can be found there are
2 courses of action that one can take:
• Either begin a diagnostic evaluation of the patient starting with bile
acid determinations.
• Or re-evaluate the patient’s liver enzymes at a later date. A rational
wait period for re-evaluation is 4-6 weeks giving consideration to the
half life of the liver enzymes and the time needed for recovery from
an acute occult hepatic injury. It is best not to delay retesting
beyond 6 weeks in the event that an active disease process may
progress.
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3. Are those raised liver enzymes significant in a patient
with clinical signs consistent with hepatic disease?
⇒ Ascites
Definition: Ascites is the accumulation of free fluid in the peritoneum. Ascites
can be caused by hypoalbuminaemia or portal hypertension, which can be
classified as pre-hepatic (portal obstruction by a mass, clot), hepatic or posthepatic (heart disease, pericardial disease).
Cardiac disease and extra-hepatic disease that can cause hypoalbuminaemia
should also be considered as prognosis and treatment will be very different.
Careful history and physical examination will certainly help in differentiating
between the different conditions.
⇒ Jaundice:
Definition: jaundice is a syndrome characterised by hyperbilirubinaemia and
deposition of bile pigment in the skin, mucous membranes, and sclera with
resulting yellow appearance. Visually detectable jaundice occurs when serum
bilirubin exceeds 1.5 mg/dL. The differential diagnosis of jaundice includes:
- Pre-hepatic conditions such as haemolytic anaemia
- Hepatic diseases causing intra-hepatic cholestasis
- Post-hepatic causes such as biliary obstructive disease
Haematology usually helps to differentiate between pre-hepatic jaundice
(severe anaemia, PCV<20%) and the other causes. If the anaemia is only
mild or absent, further testing is indicated: full biochemistry, UA, abdominal
radiographs and ultrasonography.
⇒ Neurological signs:
Waxing and waning bizarre, unpredictable behaviour, dementia, progressive
loss of arousability, myoclonus and seizures can all be signs of hepatic
encephalopathy. Sometimes clinical signs worsen after a meal with a high
protein content.
History is important as these animals often have a chronic history of
intermittent digestive signs and onset on neurological signs is rarely acute.
Physical examination: small size for age in PSS, concurrent abnormalities for
patient with end-stage liver disease such as ascites, jaundice.
General blood panel usually gives a good index of suspicion as neurological
signs occur in end-stage liver disease or congenital porto-systemic shunts
and typical abnormalities of liver dysfunction are evident on biochemistry
panel: low urea, low albumin, low or high cholesterol
⇒ PUPD
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Endocrinopathies should always be considered in the differential diagnosis of
an animal with reported PUPD and elevated liver enzymes.
Hyperadrenocorticism, hyperthyroidism, diabetes mellitus can all cause
elevations in liver enzyme activities and PUPD. These diseases should be
ruled out.
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