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Compendium September 2009 (Vol 31, No 9)

Liver Enzyme Elevations in Dogs: Physiology and Pathophysiology

by Lucia Alvarez, DVM, Jacqueline C. Whittemore, DVM, PhD, DACVIM (SAIM)

    CETEST This course is approved for 3.0 CE credits

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    Abstract

    Increased liver enzyme activities are sensitive indicators of primary hepatic disease, but they are also associated with extrahepatic diseases. The patient's signalment, clinical status, and pattern of liver enzyme activity can help in interpreting findings. The three basic liver enzyme patterns are (1) cholestatic, (2) hepatocellular leakage, and (3) mixed. Predominant increases in the activities of the cholestatic or inducible enzymes, alkaline phosphatase and γ-glutamyl transpeptidase, occur with endocrine disorders, cholestasis, neoplasia, benign nodular hepatic hyperplasia, and administration of certain drugs and occur idiopathically in certain breeds. Predominant increases in the activities of the hepatocellular leakage enzymes, alanine aminotransferase and aspartate aminotransferase, occur with circulatory disturbances, hepatotoxicities, infectious diseases, hepatitis, and neoplasia. A mixed pattern of increased liver enzyme activities may occur with hepatotoxicity or concurrent cholestasis and hepatocellular injury or necrosis.

    Primary liver disease is often diagnosed after hepatic damage is irreversible. Biochemical screening during routine wellness visits facilitates detection of hepatopathies in asymptomatic patients, when medical intervention is more likely to be successful.

    Increased liver enzyme activities are common in dogs. Serum biochemistry testing conducted on 1022 samples from dogs showed that 39.1% and 17.4% had increased alkaline phosphatase (ALP) and alanine aminotransferase (ALT) activities, respectively.1 Although liver enzyme activity increases are highly sensitive biomarkers of hepatobiliary disorders, interpretation of these increases is complicated by the fact that breed variations and extrahepatic diseases often cause similar laboratory findings. Discerning which abnormal findings warrant further investigation can be challenging.

    This article reviews the physiology of the inducible liver enzymes, ALP and γ-glutamyl transpeptidase (GGT), and the hepatocellular leakage enzymes, ALT and aspartate aminotransferase (AST). Breed-specific abnormalities and underlying etiologies associated with cholestatic, hepatocellular leakage, and mixed patterns of injury are presented.

    Inducible Liver Enzymes

    The activities of ALP and GGT, the inducible or cholestatic liver enzymes, increase with a variety of conditions (BOX 1). Both enzymes are found along the canalicular membrane of hepatocytes; their expression is increased with intrahepatic or extrahepatic cholestasis. Inducible ALP isoenzymes are found in intestine, kidney, liver, and bone tissue.2 Measured ALP activity in serum or plasma generally comprises liver (L-ALP), bone (B-ALP), and corticosteroid (C-ALP) isoenzymes.3 In healthy dogs, L-ALP accounts for the largest fraction of measured ALP activity. B-ALP activity is highest in growing animals and animals with osteolytic disorders. Little or no C-ALP activity is found in normal dogs. Because corticosteroids may increase the activity of multiple ALP isoenzymes,3,4 determination of the predominant isoenzyme increase rarely aids in identification of the underlying pathophysiologic disorder. There are no commercially available tests for the differentiation of ALP isoenzymes.2

    GGT is a membrane-bound protein found lining biliary surfaces and within periportal hepatocytes. Although high concentrations are present in the kidney and pancreas, circulating GGT activity principally originates from liver tissue. GGT has a lower sensitivity but higher specificity than ALP for primary hepatobiliary disease5 and is exquisitely sensitive to cholestasis. The specificity of concurrent increased activities of ALP and GGT for hepatobiliary disease is >90%, versus 51% for increased ALP activity alone and approximately 80% for GGT alone.6

    Increased cholestatic enzyme activity is associated with a number of breeds. Marked increases in ALP activity may occur with benign familial hyperphosphatasemia, described in Siberian huskies and Scottish terriers.7,8 Scottish terriers may have ALP activity that is five times higher than that in other breeds; ALP activity increases with age in this breed, independent of ALP-inducing disease.9 Other breed associations with increased ALP activity may reflect underlying disease. Moderate to severe hypertriglyceridemia in miniature schnauzers has been associated with moderate increases in ALP and mild increases in ALT activity.10 It is unknown whether these increases correlate with underlying primary diseases such as biliary mucoceles or secondary processes such as vacuolar hepatopathy. Activity increases greater than two times the reference interval in miniature schnauzers warrant further investigation.10 Shetland sheepdogs may have increased concentrations of triglycerides and cholesterol and increased cholestatic liver enzyme activities due to clinically silent gallbladder disorders.11

    Cholestatic enzyme activity may be increased by numerous extrahepatic conditions. Increased activities of ALP and GGT secondary to hepatic lipid or glycogen accumulation have been reported with hyperadrenocorticism, diabetes mellitus, and hypothyroidism.12,13 Increased concentrations of progesterone and 17-hydroxyprogesterone may cause similar enzyme changes.13 ALP and GGT activities increase with altered bile flow secondary to pancreatitis, inflammatory bowel disease, cholangitis, cholecystitis, and biliary obstruction. Sepsis can cause cholestasis through multifactorial mechanisms, including altered hepatocyte function.14 Benign nodular hepatic hyperplasia may stimulate inducible enzyme activity increases. Canine hepatocellular carcinoma cells have been demonstrated to express a unique thermostable isoenzyme of ALP, resulting in increased serum ALP activity.15 Pancreatic neoplasia may also induce ALP and GGT expression. Persistently increased ALP activity is a negative prognostic indicator for dogs with osteosarcoma16 and is common in dogs with mammary carcinoma17 and lymphosarcoma.

    Exogenous substances may also induce cholestatic enzyme increases. Glucocorticoid administration in dogs causes moderate to marked increases in serum GGT and ALP activities and mild increases in ALT and AST activities.3 Phenobarbital can increase ALP activity without causing liver injury.18 Infrequently, phenobarbital causes idiosyncratic hepatotoxicity with attendant clinical signs.18

    Hepatocellular Leakage Enzymes

    ALT and AST are hepatocellular leakage enzymes. Found primarily in the cytosol of hepatocytes, ALT is released into circulation after hepatocellular membrane disruption. The magnitude of ALT activity increase approximates the degree of hepatocyte damage. Because the liver has a remarkable regenerative capacity, the degree of ALT increase should not be used as a prognostic indicator. In dogs, ALT generally has a circulating half-life of 2 to 3 days.5 Decreases in serum ALT activity of 50% every 2 to 3 days suggest that hepatocyte damage is resolving.5 Normalization of ALT activity with the concurrent appearance of biomarkers for hepatobiliary dysfunction, such as hypoalbuminemia, hypoglycemia, or hypocholesterolemia, suggests loss of functional hepatic parenchyma.

    AST is found in the cytosol and mitochondria of hepatocytes and myocytes. Given the presence of AST in myocytes, increased AST activity is less specific for hepatic damage than ALT. When increased AST activity is secondary to hepatic damage, it generally increases proportionally to ALT activity. If AST activity is increased disproportionately, especially when creatine kinase (CK) activity is increased, primary muscle damage should be suspected. Because increased AST activity is more sensitive than ALT activity for some types of liver damage, hepatocellular membrane disruption should be considered when AST activity is increased and CK and ALT activities are within their reference intervals.5

    A variety of extrahepatic and hepatic disorders can cause increased hepatocellular leakage enzyme activity (BOX 2). Because the portal circulation provides at least half of the hepatic blood flow, the liver is particularly vulnerable to vascular compromise.19 Anemia, congestive heart failure, and shock can moderately increase ALT and AST activities. Mild to moderate increases may occur with strenous exercise and should resolve consistent with their half-lives after exertion is discontinued. Hepatotoxicity and hepatitis result in hepatocellular membrane disruption. Underlying etiologies for hepatitis include infectious agents, inborn errors of metabolism, immune-mediated inflammation, and reactive hepatopathies. Copper-associated hepatopathy occurs as an autosomal recessive disorder in Bedlington terriers and has been described in West Highland white terriers, Skye terriers, dalmatians, Doberman pinschers, and Labrador retrievers.20,21 Heritability of copper-associated hepatopathy has recently been demonstrated for Labrador retrievers,22 which also have an increased prevalence of idiopathic chronic hepatitis.23 Rarely, liver lobe torsion has been described in large-breed dogs presenting with nonspecific clinical signs (vomiting, anorexia, lethargy) and increased hepatocellular leakage enzyme activities.24 Hepatic abscesses and primary or metastatic neoplasia are also associated with increased hepatocellular leakage enzyme activities.

    Mixed Liver Enzyme Patterns

    A mixed pattern of increased cholestatic and hepatocellular leakage enzyme activities suggests concurrent disorders, hepatocellular inflammation and necrosis with secondary cholestasis, or drug induction resulting in concomitant mild cholestatic and hepatocellular leakage enzyme activity increases. Serial monitoring may aid in identification of the primary pattern, and a comprehensive diagnostic workup is often warranted. Portosystemic vascular anomalies and microvascular dysplasia may cause hepatocellular, cholestatic, or mixed patterns of injury.25

    Hepatotoxins (BOX 3) can cause hepatocellular, cholestatic, or mixed patterns of injury. Because nutrients, bacteria, drugs, and other xenobiotic agents are delivered hematogenously from the gastrointestinal tract to the liver, the liver is at higher risk than other organs for toxic insult.19 A drug may cause dose-dependent (predictable), idiosyncratic (unpredictable), or both types of toxicity. Dogs with low glutathione transferase activity or decreased inherent protective mechanisms may be predisposed to liver injury.26

    Conclusion

    Given their high sensitivity and limited specificity for hepatic disease, liver enzyme activity increases may be difficult to interpret. The patient's signalment, clinical status, and pattern of liver enzyme activity increase may aid practitioners in ranking diagnostic differentials. Predominant increases in ALP and GGT activities characterize a cholestatic liver enzyme pattern. Causes include breed-specific abnormalities, endocrine disorders, hepatic and posthepatic cholestasis, neoplasia, benign nodular hepatic hyperplasia, and induction by drugs. A hepatocellular leakage pattern is characterized by increases in ALT and AST activities. Etiologies include circulatory disturbances, hepatotoxins, hepatic infection and inflammation, and primary hepatic neoplasia. Mixed patterns occur with hepatotoxicity, progressive hepatic disease, and concurrent disorders.

    Read the companion article, "Liver Enzyme Elevations in Dogs: Diagnostic Approach".

    Downloadable PDF

    Dr. Whittemore discloses that she has received financial support from Heska Corporation.

    1. Comazzi S, Pierlasi C, Bertazzolo W. Haematological and biochemical abnormalities in canine blood: frequency and associations in 1022 samples. J Small Anim Pract 2004;45:343-349.

    2. Itoh H, Kakuta T, Genda G, et al. Canine serum alkaline phosphatase isoenzymes detected by polyacrylamide gel disk electrophoresis. J Vet Med Sci 2002;64:35-39.

    3. Wiedmeyer CE, Solter PF, Hoffman WE. Kinetics of mRNA expression of alkaline phosphatase isoenzymes in hepatic tissues from glucocorticoid-treated dogs. Am J Vet Res 2002;63:1089-1095.

    4. Wiedmeyer CE, Solter PF, Hoffman WE. Alkaline phosphatase expression in tissues from glucocorticoid-treated dogs. Am J Vet Res 2002;63:1083-1088.

    5. Center SA. Interpretation of liver enzymes. Vet Clin North Am Small Anim Pract 2007;37:297-333.

    6. Center SA, Slater MR, Manwarren T, et al. Diagnostic efficacy of serum alkaline phosphatase and γ-glutamyltransferase in dogs with histologically confirmed hepatobiliary disease: 270 cases (1980-1990). JAVMA 1992;201:1258-1264.

    7. Lawler DF, Keltner DG, Hoffman WE, et al. Benign familial hyperphosphatasemia in Siberian huskies. Am J Vet Res 1996;57: 612-617.

    8. Gallagher AA, Panciera DL, Panciera RJ. Hyperphosphata-semia in Scottish terriers: 7 cases. J Vet Intern Med 2006;20: 418-421.

    9. Nestor D, Holan K, Johnson CA, et al. Serum alkaline phosphatase activity in Scottish terriers versus dogs of other breeds. JAVMA 2006;228:222-224.

    10. Xenoulis PG, Suchodolski JS, Levinski MD, et al. Serum liver enzyme activities in healthy miniature schnauzers with and without hypertriglyceridemia. JAVMA 2008;232:63-67.

    11. Aguirre AL, Center SA, Randolph JF, et al. Gallbladder disease in Shetland sheepdogs: 38 cases (1995-2005). JAVMA 2007; 231:79-88.

    12. Hess RS, Saunders HM, Van Winkle TJ, et al. Concurrent disorders in dogs with diabetes mellitus: 221 cases (1993-1998). JAVMA 2000;217:1166-1173.

    13. Webster CRL, Cooper JC. Diagnostic approach to hepatobiliary disease. In: Kirk's Current Veterinary Therapy XIV. St. Louis: Saunders Elsevier; 2009:543-549.

    14. Chand N, Sanyal AJ. Sepsis-induced cholestasis. Hepatology 2007;45:230-241.

    15. Fukui Y, Sato J, Sato R, et al. Canine serum thermostable alkaline phosphatase isoenzyme from a dog with hepatocellular carcinoma. J Vet Med Sci 2006;68:1129-1132.

    16. Ehrhart N, Dernell WS, Hoffmann WE, et al. Prognostic importance of alkaline phosphatase activity in serum from dogs with appendicular osteosarcoma: 75 cases (1990-1996). JAVMA 1998;213:1002-1006.

    17. Karayannopoulou M, Polizopoulou ZS, Koutinas AF, et al. Serum alkaline phosphatase isoenzyme activities in canine malignant mammary neoplasms with and without osseous transformation. Vet Clin Pathol 2006;35:287-290.

    18. Gaskill CL, Hoffmann WE, Cribb AE. Serum alkaline phosphatase isoenzyme profiles in phenobarbital-treated epileptic dogs. Vet Clin Pathol 2004;33:215-222.

    19. Webster C. Hepatocyte survival signaling. 26th Proc Am College Vet Intern Med 2008;26:675-677.

    20. Spee B, Arends B, van den Ingh TS, et al. Copper metabolism and oxidative stress in chronic inflammatory and cholestatic liver diseases in dogs. J Vet Intern Med 2006;20:1085-1092.

    21. Smedley R, Mullaney T, Rumbeiha W. Copper-associated hepatitis in Labrador retrievers. Vet Pathol 2009;46:484-490.

    22. Hoffmann G, Heuven HC, Leegwater PA, et al. Heritabilities of copper-accumulating traits in Labrador retrievers. Anim Genet 2008;39:454.

    23. Shih JL, Keating JH, Freeman LM, et al. Chronic hepatitis in Labrador retrievers: clinical presentation and prognostic factors. J Vet Intern Med 2007;21:33-39.

    24. Schwartz SG, Mitchell SL, Keating JH, et al. Liver lobe torsion in dogs: 13 cases (1995-2004). JAVMA 2006;228:242-247.

    25. Simpson KW, Meyer DJ, Boswood A, et al. Iron status and erythrocyte volume in dogs with congenital portosystemic vascular anomalies. J Vet Intern Med 1997;11:14-19.

    26. Watanabe T, Sugiura T, Manabe S, et al. Low glutathione S-transferase dogs. Arch Toxicol 2004;
    78:218-225.

    References »

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    CETEST This course is approved for 3.0 CE credits

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