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Diagnostic approach to increased liver enzyme activities in dogs (Proceedings)


Elevations of in one or more serum liver enzyme activities (LEA) are a common finding on serum biochemical analysis. Liver enzyme measurements do not reflect liver function but rather hepatocyte membrane integrity, cholestasis and enzyme induction.

Elevations of in one or more serum liver enzyme activities (LEA) are a common finding on serum biochemical analysis. Liver enzyme measurements do not reflect liver function but rather hepatocyte membrane integrity, cholestasis and enzyme induction1. Increased LEA is highly sensitive but not specific for liver disease; extrahepatic disorders and normal breed variation can also cause abnormally increased LEA2. Interpretation of abnormal LEA requires consideration of the pattern and magnitude of abnormal LEA, patient factors such as age, breed, medication history, clinical signs, results of routine laboratory testing and whether or not there is evidence to suggest the abnormal LEA may be secondary to a non-hepatic condition1,3. Considered together, these factors will determine whether or not a specific evaluation for hepatobiliary disease is warranted.

Increased serum alkaline phosphatase (ALP) activity is the most common and least specific liver enzyme abnormality in the dog1. Multiple forms, or isoenzymes, of ALP exist. The three main ALP iosenzymes in canine serum are liver-ALP (L-ALP), glucocorticoid- ALP (G-ALP) and bone-ALP (B-ALP)1. L-ALP, G-ALP and B-ALP do not leak from damaged cells; rather their expression is induced by intra- or extrahepatic cholestasis, endogenous or exogenous corticosteroids and osteoblast activity, respectively1,4. In healthy, adult dogs, L-ALP accounts for the majority of ALP measured2. Because glucocorticoids can induce G-ALP and L-ALP expression and because G-ALP can be induced by chronic stress and inflammatory mediators associated with systemic illness (including liver disease), identification of the predominant isoenzyme is of little clinical utility1,2. The half-life of ALP in the dog is approximately 70 hours1.

Increased serum ALP activity is expected under the following non-hepatobiliary conditions: (1) Breed related increases in ALP activity have been documented in Scottish Terriers (up to 5x higher than other breeds, increases with age), Siberian Huskies and Miniature Schnauzers with hypertriglyceridemia (<2-3 x normal); (2) Mild increase (<2x normal) due to induction of B-ALP may be observed in young, growing animals1,5 ; (3) Induction of B-ALP due to increased osteoblastic activity may also be observed in bone tumours (namely osteosarcoma), secondary renal hyperparathyroidism and osteomyelitis1,6,7 ; (4) Large increases (up to 100 times normal or greater) in serum ALP activity are expected in dogs administered exogenous glucocorticoids1. Topical and ocular steroid formulations may also induce ALP5 , although to a lesser degree; (5) Phenobarbital therapy (2-6 x normal)1 ; (6) Endogenous glucocorticoids (i.e. hyperadrenocorticism); (7) Diabetes mellitus (2-5 x normal mildly increased ALT activity); (8) Hypothyroidism; (9) Mammary neoplasia; and (10) sepsis1,2,7.

Increased serum ALP activity is expected under the following hepatobiliary conditions: (1) Marked increases occur in intra- or extrahepatic cholestatic disorders (see below); (2) Marked increases occur in primary or metastatic hepatic neoplasia1,7 ; and (3) Extension of pancreatic inflammation to the liver parenchyma can result in mild to moderate increases in serum ALP and ALT activities. Alternatively, moderate to marked increases in serum ALP activity may result from common bile duct obstruction due to pancreatic inflammation and swelling.

Similar to L-ALP, gamma-glutamyl transferase (GGT) cholestatic disorders promote release of GGT from its hepatocellular membrane location into the serum1. Although high tissue concentrations of GGT can be identified in the kidney and pancreas, serum GGT activity is mainly derived from the liver1,2. Increased GGT activity is less sensitive but more specific for intra- or extrahepatic cholestasis than ALP2,4. Increased serum GGT activity generally parallels serum ALP activity and is expected to be induced by cholestatic disorders, glucocorticoid administration and pancreatitis7. Assuming the patient is not being treated with glucocorticoids or anticonvulsants, concurrent increases in ALP and GGT activities are strongly suggestive of cholestatic hepatobiliary disease2. Both ALP and GGT lack specificity for differentiation between intra- and extrahepatic cholestasis1.

Common intrahepatic cholestatic conditions include vacuolar hepatopathy, nodular hyperplasia, chronic hepatitis, acute hepatic necrosis or inflammation and neoplasia2. Common extrahepatic cholestatic conditions include gallbladder mucocele, cholecystitis, cholelithiasis, neoplasia, biliary obstruction secondary to pancreatic disease and intestinal obstruction at the level of the major duodenal papilla, obstructing the common bile duct2.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are present in high concentration within the liver but also in other tissues such as skeletal muscle, kidney and heart1. ALT and AST are found primarily in the cytosol of hepatocytes, resulting in immediate leakage into the systemic circulation upon damage to the hepatocyte membrane1,2 . The magnitude of increase in ALT or AST does not predict the reversibility of hepatocellular injury but does correlate with the number of hepatocytes affected1,4,7. Serum AST and ALT activities can increase following muscle injury in the dog4 ; concurrent elevations in AST, ALT and creatinine kinase activities are suggestive of muscle injury. The plasma half-lives of ALT and AST in the dog are 60 and12 hours respectively4. Increased serum ALT activity is indicative of hepatocellular damage but is not specific for primary hepatocellular disease7. Primary hepatocellular diseases characterized by increased serum ALT activity include chronic hepatitis, copper-associated hepatitis, hepatotoxicity, infection (e.g. leptospirosis, canine adenovirus 1, etc.), neoplasia (primary or metastatic), amyloidosis, liver lobe torsion, hepatic abscess, etc.2. Disease conditions that secondarily result in hepatocellular damage thereby increasing serum ALT activity include decreased hepatic perfusion with subsequent hepatocellular hypoxia (e.g. shock, anemia, cardiac disease (CHF, heartworm infection, etc.), endotoxemia/septicemia, diabetes mellitus, hyperthermia, etc.2,7. Serum ALT activity increased 2-3 times above the normal range is a significant finding7. However, more subtle elevations in ALT activity may be significant in breeds predisposed to chronic hepatopathies (see below), even if the patient is asymptomatic.

It is essential to remember the pattern of LEA is describes the predominantpattern of enzyme change (i.e. cholestatic / inducible versus hepatocellular leakage). For example, even in markedly cholestatic conditions such as extrahepatic biliary obstruction, some increase in serum ALT activity is expected as hepatocellular membrane damage can occur secondary to severe cholestasis. However, the degree of change in cholestatic enzyme activity is expected to be greater than the degree of change in hepatocellular leakage enzyme activity and may be accompanied by other biochemical indictors of cholestasis (e.g. hyperbilirubinemia, hypercholesterolemia, etc). Similarly, mild to moderate cholestasis may be a feature of disorders primarily characterized by hepatocellular damage (e.g. canine chronic hepatitis). Occasionally, cholestatic/inducible and hepatocellular leakage LEA are elevated to similar proportions. In such cases, conditions to consider include congenital vascular anomalies, hepatocellular damage with secondary cholestasis, drug induction with concomitant hepatocellular membrane injury or concomitant hepatic and extrahepatic conditions2.

Breed related increases in serum ALP activity have been reported and are described above. Breed predispositions to hepatobiliary disease are helpful for narrowing the list of differential diagnoses, thereby guiding the type and urgency of the diagnostic evaluation. Breeds in which a predisposition to chronic hepatitis has been described include Cocker Spaniel, Labrador Retriever, Standard Poodle and German Shepherd dog, among others3,8. Breeds in which a predisposition to copper-associated chronic hepatitis has been described include Doberman Pinscher, Beddlington Terrier, Labrador Retriever, West Highland White Terrier, Dalmation and Skye Terrier2,8. Chinese Sharpei's are predisposed to development of amyloidosis2. Shetland sheepdogs and seemingly Cocker Spaniels and Miniature Schnauzers are predisposed to development of gallbladder mucoceles. Congenital extrahepatic shunts are most common in toy breed dogs including the Yorkshire Terrier, Havanese, Maltese, Dandie Dinmont Terrier, Pug and Miniature Schanuzer9. Congenital intrahepatic shunts are most common in large breed dogs including Irish Wolfhound, Labrador Retriever, Golden Retriever, Australian Cattle dog and Australian Shepherd9. Age: Mild (<2x normal) due to induction of B-ALP may be observed in young, growing animals1,5. Recent ingestion of colustrum has also been associated with increased serum ALP and GGT activities in dogs1,10. Decreased blood urea nitrogen, protein, albumin, glucose and cholesterol as well as increased ALP and ALT activities may be identified in young dogs with congenital portosystemic shunting10. Increasing AST activity within 24 hours of birth has been suggested to be due to muscle trauma associated with birth1. Increased ALP due to induction of B-ALP may be observed as a paraneoplastic phenomenon in dogs with appendicular osteosarcoma; a disease typically of large or giant breed, middle age to older dogs6. Hepatic nodular hyperplasia and neoplasia are most common in middle age to older dogs. A careful medication and herbal supplement history is important to evaluate for exposure to drugs that can result in enzyme induction or hepatotoxicity. Glucocorticoids and phenobarbital are common inducers of ALP and GGT activity. Drugs (e.g. acetaminophen, lomustine, azathioprine, TMS, carprofen, griseofulvin, mitotane) herbal supplements (e.g. pennyroyal oil), natural products (e.g. sago palm, blue green algae, aflatoxin, Amanita mushroom, etc.) and synthetic chemicals (e.g. xylitol) are all known canine hepatotoxins2.

The patient must be carefully evaluated for clinical signs consistent with the non-hepatobiliary conditions previously discussed. Clinical signs of hepatobiliary disease range form non-specific (e.g. lethargy, weight loss, anorexia, vomiting, diarrhea) to more specific signs such as icterus, polyuria, polydipsia, gastrointestinal ulceration, ascites and hepatomegaly11. Spontaneous hemorrhage due to coagulopathy is rare; excessive bleeding from a gastrointestinal ulcer or following an invasive procedure such as liver biopsy is more common11. Signs of extrahepatic biliary obstruction include lethargy, anorexia, vomiting, rapid development of icterus and cranial abdominal pain12. Abdominal pain, icterus, tachycardia, tachypnea and fever are suggestive of gallbladder rupture12. Behavioural changes, ataxia, unresponsiveness, pacing, circling, blindness, seizures, and coma are potentially consistent with hepatic encephalopathy9. Animals with congenital portosystemic shunts may display stunted growth, prolonged recovery from sedation or general anesthesia, gastrointestinal signs or lower urinary tract signs (ammonium biurate urolithiasis)9.

Because increased LEA indicate cholestasis, enzyme induction or hepatocyte membrane integrity but are not reflective of liver function1 , the remainder of the patient's routine clinicopathological testing must be carefully evaluated for evidence supporting hepatobiliary disease. Complete blood count abnormalities potentially consistent with hepatobiliary disease include regenerative anemia due to blood loss (e.g. gastrointestinal ulceration, coagulopathy, bleeding mass, etc), microcytic, hypochromic non-regenerative anemia (chronic gastrointestinal blood loss), microcytosis (congenital portosystemic shunt), target cells or poikilocytes11. Neutrophilic leukocytosis may be noted in cases of bile peritonitis, cholecystitis, leptospirosis or other infectious causes. Albumin is synthesized entirely by the liver. The relatively long-half life of albumin means that hypoalbuminemia is most commonly associated with chronic conditions such as chronic hepatitis, cirrhosis or portosystemic shunting11. Decreased conversion of ammonia to urea due to decreased hepatic blood flow (e.g. congenital or acquired portosystemic shunting) or severe parenchymal disease can result in decreased blood urea nitrogen (BUN) concentration. Hypoglycemia may occur due to impaired glucose production or loss of glycogen stores and is most commonly a feature of congenital portosystemic shunts in small breed dogs, acute hepatic failure, xylitol toxicosis or end stage chronic hepatitis (less common, poor prognostic indicator)11. Hypercholesterolemia may be a feature of severe cholestasis, potentially due to decreased excretion of cholesterol in bile11. Hypocholesterolemia due to decreased hepatic synthesis may be a feature of end stage chronic hepatitis. In the absence of hemolysis, hyperbilirubinemia is less sensitive but more specific for hepatobiliary disease then LEA11. Hyperbilirubinemia of hepatic origin is expected in hepatobiliary conditions characterized by failure of hepatocytes to process and excrete bilirubin with subsequent intrahepatic cholestasis. Hyperbilirubinemia of post-hepatic origin arises from obstruction of bile flow through the extrahepatic ducts (see "extrahepatic cholestatic conditions" above).

With the exception of Factor VIII, the liver is the site of synthesis of all coagulation proteins and the site of activation of the vitamin-K dependent factors3,11. Prolonged clotting time (prothrombin time or partial thromboplastin time) or a specific factor deficiency is identified in up to 75% and 90% of dogs with hepatobiliary disease, respectively11. Coagulation abnormalities may reflect failure of hepatic protein synthesis due to severe parenchymal disease (e.g. chronic or acute hepatitis), vitamin-K deficiency (e.g. extrahepatic biliary obstruction) or disseminated intravascular coagulation.

The magnitude of LEA elevation (fold increase above normal) is an important consideration when determining whether the biochemical abnormalities noted are consistent with the suspected etiology or disorder or whether additional diagnostic investigation is warranted. The highest serum ALP activities are seen in dogs with cholestatic disorders, chronic hepatitis, hepatic necrosis (2-5x normal), massive hepatocellular carcinoma, bile duct carcinoma and in dogs treated with corticosteroids (5x normal)1,11. Median increases of 6-10x the normal range are reported but increases up to 100x or greater the normal range are possible1,11. Marked increases in serum ALP activity have also been observed in dogs with malignant or benign mammary neoplasia1. Drug induction of GGT is generally minimal compared to ALP induction1,7. GGT activity can increase to 4-7 times the normal range within 2 weeks in dogs treated with glucocorticoids and 2-3 times the normal range in dogs treated with phenobarbital1. Increases in serum GGT activity are mild (1-3x normal) or moderate to marked (10-50x normal) in dogs with acute hepatic necrosis or extrahepatic cholestasis, respectively1,11. The largest increases in serum ALT activity are expected in dogs with hepatocellular necrosis and/or inflammation11. Serum ALT activity rises sharply within 24-48 hours of acute hepatocellular injury and may peak as high as 100x the normal range during the first 5 days, while serum AST activity may peak at values 10-30x the normal range11.

The ultimate goal of careful interpretation of abnormal LEA is determining which patients warrant additional evaluation for hepatobiliary disease. The specifics of the investigation will depend on the differential diagnoses generated through consideration of patient signalment, clinical presentation and the pattern of abnormal LEA (see above). Common tests for evaluation of the hepatobiliary system include pre and post prandial serum bile acid concentrations, fasting plasma ammonia concentration, antibody titres to Leptospirainterrogans serovars, abdominal ultrasound, nuclear scintigraphy study, liver biopsy (histopathology, heavy metal analysis, aerobic and anaerobic bacterial culture) and cholecystocentesis (cytology, aerobic and anaerobic bacterial culture). Dogs with clinical signs of hepatobiliary disease, clinical signs of possible hepatic encephalopathy, clinicopathological markers of hepatic dysfunction and/or LEA elevations of a magnitude that is consistent with hepatobiliary disease or inconsistent with the suspected non-hepatobiliary disorder, warrant further investigation. Mild asymptomatic elevations in ALT are indication for abdominal ultrasound and liver biopsy (with copper quantification) in breeds predisposed to chronic hepatopathies. Because most post-hepatic causes of hyperbilirubinemia warrant surgical correction, abdominal ultrasound is indicated in patients with hyperbilirubinemia without evidence of hemolysis in order to differentiate between hepatic and post-hepatic disorders and in breeds predisposed to gallbladder disorders with consistent clinical signs or laboratory abnormalities. Pre and post prandial serum bile acid concentrations, fasting plasma ammonia concentration, abdominal ultrasound and/or nuclear scintigraphy study are indicated in breeds predisposed to congenital portosystemic shunts with consistent clinical signs or laboratory markers. Depending on the magnitude and pattern of abnormal LEA, evaluation for hepatobiliary disease should also be considered in a dog where abnormal LEA persists despite appropriate treatment of an underlying non-hepatobiliary condition or an underlying non-hepatobiliary condition can not be identified despite an appropriate diagnostic investigation.


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