Accurate clinical evaluation of liver function can be accomplished by a series of diagnostic procedures.
Physical examination and a complete history of the patient are important in the diagnosis of liver failure - most signs are relatively non-specific. Important in differentiating acute from chronic disease.
Therefore, examination of urine and blood samples is essential in the diagnostic process.
Tests can be divided into two categories, ie those indicating hepatocellular damage and those measuring hepatic function.
This approach is a guide to the investigation of liver disease and, although examples of tests are quoted, the lists are by no means complete.
Remember both primary liver disease (cirrhosis , toxic hepatitis ) occur as does secondary disorders (Cushing's disease, heart disease).
Adult: most likely to be inflammatory or infectious disease. Consider toxic insult , or drug damage, eg steroid hepatopathy.
Geriatric: may have chronic degenerative changes, eg cirrhosis .
Breed
Some breeds have congenital/familial liver disease, eg PSS in Yorkshire Terrier, Irish Wolfhound and others; or copper toxicosis in Bedlington Terrier , Doberman Pinscher , West Highland White Terrier .
Chronic active hepatitis also predominantly affects some breeds, eg Doberman Pinscher and others.
Pacing, hyperexcitability, seizures (hepatic encephalopathy in advanced liver failure).
Icterus.
Ascites.
Acholic feces.
Intolerance to sedation and anesthesia.
Gastrointestinal ulceration.
Hepatocutaneous syndrome.
Coagulopathies.
Clinical examination
Palpation of liver size and shape:
Small liver may indicate cirrhosis or PSS.
Large liver may indicate acute inflammation , amyloidosis , hypertrophy or infiltration, extramedullary hematopoiesis, passive congestion or neoplasia .
Hepatic pain is associated with acute inflammation.
Where history and clinical signs are suggestive of liver disease, or in a particular breed with a predisposition to congenital liver disease, or a general health screen suggests liver involvement, further evaluation of liver function is necessary.
Try to answer the following questions:
Is there evidence of liver damage?
Is the damage affecting primarily the hepatocellular or biliary system?
Is there evidence of liver dysfunction?
What is the prognosis?
Is there evidence of liver failure?
Do the laboratory screening tests support hepatic involvement?
Ascitic fluid analysis
If ascitic fluid is present a sample should be collected for analysis.
True transudate associated with failure to produce albumin.
Modified transudate associated with portal hypertension.
Blood sample analysis Serum protein
Liver is important for synthesis of albumin and globulins .
In severe hepatic disease synthesis of these is reduced and hypoproteinemia as a result of hypoalbuminemia or occasionally hypoglobulinemia (or both) may result. In fact, in most cases of severe liver disease hypergammaglobulinemia is present.
In inflammatory conditions, protein production in the liver switches from albumin to acute phase proteins and this can cause a transient decrease in albumin concentrations.
This hypoproteinemia may contribute to ascites in cases with portal hypertension.
Ammonia
Ammonia absorbed from the gut is detoxified in the liver.
Increasing ammonia concentrations in peripheral circulation can result in signs of hepatic encephalopathy .
Ammonia is difficult to measure accurately in blood as it is volatile and analysis must be done soon after sampling.
Urea
Urea is synthesized in the liver as a method of detoxifying ammonia absorbed from the gut.
In severe liver disease urea concentrations may be reduced. Do not rely on low urea levels to indicate liver dysfunction - it is not specific.
Glucose
Glycogen is synthesized in the liver as a storage mechanism for glucose and, in prolonged starvation, the liver is the main site of gluconeogenesis.
In severe liver failure hypoglycemia may develop.
Is the liver involvement primary or secondary?
Many diseases can cause secondary hepatic changes:
Steroid hepatopathy (or simply hepatomegaly and sALP increase) in hyperadrenocorticism .
Hepatic hypoxia due to poor perfusion in severe cardiac disease.
Hepatomegaly and damage due to right sided heart failure and hepatic congestion.
Hepatocyte damage is assessed by measurement of enzymes released from damaged hepatocytes:
Alanine aminotransferase (ALT) .
Aspartate aminotransferase (AST) .
These enzymes are only released while damage is ongoing.
These enzymes are not liver function tests.
Animals with fibrotic livers may have severly impaired liver function but no active cellular destruction. Therefore, liver enzymes may be normal.
Alanine aminotransferase (ALT)
ALT is found within the cytoplasm of hepatocytes.
After a one-off insult, levels peak in 3-4 h and return to normal in 14 days.
If levels remain high ongoing damage is likely.
Elevations in ALT crudely correlate with numbers of hepatocytes damaged.
Aspartate aminotransferase (AST)
AST is found in many cells.
Not specific for liver damage so elevated levels may be seen in other diseases.
The elevation of AST crudely correlates with hepatocyte damage.
Assessment of biliary damage
Cholestasis is the stagnation of bile flow and can be caused by intra- or extra-hepatic factors.
Alkaline phosphatase (ALP)
Serum ALP is a good indicator of cholestasis as it is readily released from bile duct before plasma bilirubin elevated.
Lag between injury and rise in ALP of 2-3 days.
Takes 10 days to return to normal after insult.
ALP may also elevate following use of steroids, Cushing's disease and in young growing animals.
Gamma glutamyltransferase (GGT)
GGT is found on surface of hepatocytes and bile duct epithelium.
GGT has a longer half-life than ALP.
Elevations seen in hepatocellular damage and biliary disease.
Cholesterol
The liver is the site of cholesterol regulation.
Cholesterol concentrations may be reduced in severe hepatic failure and portosystemic shunts.
Biliary disease may result in increased cholesterol concentrations due to reflux from bile into blood and increased synthesis.
Assessment of hepatic function Bilirubin
Hyperbilirubinemia is associated with bile duct obstruction and liver disease. Remember in hemolysis the liver's ability to conjugate bilirubin may be overwhelmed and icterus can develop without liver dysfunction.
Low levels of bilirubin (1+ on a dipstick) in the urine of a dog can be normal.
Bilirubinuria of 2+ or 3+ is an indication of hyperbilirubinemia.
Do not use the ratio of congugated to uncongugated bilirubin to differentiate liver disease from cholestasis.
Bile acid stimulation test
Bile acids are synthesized in the liver and released through the bile ducts to the intestine and then taken up in the portal circulation and recycled.
They should not appear in the circulation in significant concentrations.
Sensitive indicators of hepatic function and biliary and portal circulation.
Elevations in a fasted serum sample indicate abnormal liver function.
The stimulation test is performed by measuring peripheral blood concentration pre- and post-prandially - rising bile acids is a more sensitive indiction of abnormal hepatic function.
Scintigraphy
Primarily used in the investigation of portosystemic shunts .
Can also give indication of hepatic function .
Radioactive material put into intestine and liver uptake monitored.
Clotting parameters
Liver has important role in synthesis of particular clotting factors.
Spontaneous bleeding is rare in animals with liver disease. Clotting parameters should always be checked prior to biopsy.
Prolonged activated partial thromboplastin time (APPT) .
Prolonged prothrombin time (PT) .
Both indicative of severe hepatic dysfunction.
Platelet dysfunction may also occur in liver disease.
Focal enlargement may be seen with lobar neoplasia or cysts.
Hepatoportal angiography
Invasive as requires general anesthesia but allows good visualization of portal vein abnormalities.
Largely been superceded by hepatic ultrasonography.
Ultrasonography
Used to examine liver architecture .
This is an essential modality in the presence of ascitic fluid.
Ultrasound can be used to guide biopsy and, since the type of lesion cannot be differentiated by the use of ultrasound alone, it is essential to perform a biopsy if lesions are visible ultrasonographically.
May also be used to detect presence of portosystemic shunts.
Fine needle aspirate (FNA)
FNA can be used to collect a tissue sample for cytological examination.
This is most useful in cases of diffuse disease or in conjunction with ultrasound guidance where the chance of obtaining a representative sample is greater.
Rarely provides a definitive diagnosis.
Liver biopsy
May provide information about pathogenesis of disease and etiology, except in cases of 'end stage' liver failure.
Can be performed percutaneously (usually with ultrasound guidance) and a biopsy gun technique.
Surgical biopsy allows visualization of the whole organ and careful sample site selection which may improve diagnostic success.
Prognostic indicators
Many authors have looked for prognostic indicators in liver disease.
The most reliable seem to be acute phase protein concentrations:
Reduced albumin and alpha-globulin gives poor prognosis.
Reduced albumin, normal alpha-1 antitrypsin and slight increase in hepatoglobin indicates chronic progressive hepatitis.
Acute hepatitis is characterized by acute phase increase in alpha-globulins.
Roth L (2001) Comparison of liver cytology and biopsy diagnoses in dogs and cats: 56 cases.Vet Clin Pathol30 (1), 35-38.
Center S (1999) Chronic liver disease: current concepts of disease mechanisms.JSAP40 , 106-114.
Other sources of information
Center S, Schermerhorn T, Lyman R, Phillips L (2000) Hepatoportal Microvascular Dysplasia. In: Current Veterinary Therapy XIII. Bonagura J (ed), W B Saunders, Philadelphia. pp 682-686.
Hess P R & Bunch S E (2000) Diagnostic Approach to Hepatobiliary Disease. In: Current Veterinary Therapy XIII. Bonagura J (ed), W B Saunders, Philadelphia. pp 659-664.
Vetstream contributor(s)
Dr Kyle Braund BVSc MVSc PhD FRCVS DipACVIM , Veterinary Neurological Consulting Services, 1476 Lakeview Ridge, Dadeville, AL 36853, USA.
Dr James W Simpson SDA BVM&S MPhil MRCVS , Department of Veterinary Clinical Studies, Royal (Dick) School of Veterinary Studies, Easter Bush Veterinary Hospital, Nr Roslin, Midlothian EH25 9RG, UK.
Important in differentiating acute from chronic disease.
Do not rely on low urea levels to indicate liver dysfunction - it is not specific.