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.
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 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?
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.
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.
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
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 examination of the liver may assist in differentiating homogeneous enlargement from cellular infiltration and in differentiating hepatic from post-hepatic cholestasis.
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.
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
Chronic progressive hepatitis-idiopathic, immune mediated?
Bedlington Terriers, WHW Terriers—copper toxicity
Lobular dissecting hepatitis
Drug induced- primidone, phenytoin
Non-suppurative (lymphocytic) cholangiohepatitis
Toxins e.g., thiacetarsamide, anticonvulsants
Aflatoxin, bacterial endotoxin, blue green algae
Bacterial- Leptospira, Salmonella, Clostridia
Viral- adenovirus I (ICH), canine herpes
Acute haemolytic anaemia
Surgical hypotension or hypoxia
End-stage fibrosis of many inflammatory hepatic diseases. Aetiology undetermined in majority of cases.
The canine liver is uniquely sensitive to the effects of exogenous or endogenous corticosteroids.
The liver is a frequent site for both primary and metastatic neoplasia.
Lymphosarcoma (may also be multi-focal)
Portosystemic or hepatic encephalopathy