Liver Enzyme Elevations in Dogs: Diagnostic Approach*

3 CE CREDITS CE Article 2

❯❯ Lucia Alvarez, DVM Abstract: Increased liver enzyme activities are sensitive indicators of hepatic disease, but their ❯❯ Jacqueline C. Whittemore, limited specificity can make their interpretation a challenge. A stepwise approach to diagnosing the a DVM, PhD, DACVIM source of increased liver enzyme activity involves characterization of the clinical picture, identifica- University of Tennessee tion of the predominant enzyme activity pattern, elimination of common extrahepatic diseases, and a systematic diagnostic workup for hepatobiliary disease. Comprehensive hepatobiliary testing includes a complete blood count, biochemical profile, and urinalysis; coagulation and liver function tests; abdominal imaging; bile cytology and culture; and liver biopsy for histopathology, culture, and metal analysis.

At a Glance lterations in circulating liver en- atocellular injury and cholestasis and may zyme activities may present a be caused by concurrent disease pro- Signalment, History, and Adiagnostic challenge because they cesses or progressive disorders. Physical Examination are common, often nonspecific biochemi- The magnitude and duration of increase Page 416 cal findings. A systematic approach to in liver enzyme activities should be con- Laboratory Screening interpretation of increased liver enzyme sidered in addition to the pattern. Mildly Page 418 activities is outlined in Figure 1. The first increased activity of a single liver enzyme Additional Testing step is to develop an integrated clinical in a clinically asymptomatic dog may be Page 420 picture based on the patient’s signalment, spurious and should be rechecked. Lipemia Diagnostic Imaging history, clinical signs, and concurrent lab- and hemolysis may falsely increase activi- Page 422 oratory abnormalities. Careful evaluation ties of serum liver enzymes and should be of this picture aids in ranking diagnostic considered when interpreting laboratory Liver Sampling Techniques Page 422 differentials. data. Because increases in hepatocellular Increases in liver enzyme activities are leakage enzyme activity are proportional Diagnostic Sampling categorized as cholestatic, hepatocellular to the severity of damage, increases greater Page 422 leakage, or mixed. A cholestatic or induc- than twice the reference interval warrant ible pattern is characterized by predomi- further scrutiny. Increased activity of mul- nant increases in alkaline phosphatase tiple liver enzymes, particularly if a hepato- (ALP) and γ-glutamyl transpeptidase (GGT) cellular or mixed pattern of injury is present, activities. A hepatocellular leakage pat- also warrants close attention because of an *A companion article, “Liver En- tern has predominant increases in the increased likelihood of severe disease. zyme Elevations in Dogs: Physi- activities of alanine aminotransferase ology and Pathophysiology,” be- (ALT) and aspartate aminotransferase Signalment, History, and gins on page 408. (AST) secondary to hepatocyte injury or Physical Examination aDr. Whittemore discloses that she has received financial sup- necrosis. A mixed pattern of liver enzyme Once spurious or self-limiting increases port from Heska Corporation. activity increase suggests concurrent hep of liver enzyme activities have been ruled

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FIGURE 1

Vascular anomalies

Intrahepatic cholestasis

Inflammatory/immune disorders Metal storage disorders Amyloidosis Neoplasia Vascular anomalies

Step 2:

Step 3: Step 3:

Step 4:

Flowchart demonstrating a stepwise approach to the evaluation of increased activities of liver enzymes. Blue differentials are etiologies that may require a comprehensive hepatobiliary evaluation for diagnosis.

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Box 1 the onset of injury.1 Liver injury may worsen Breeds Associated With for days or weeks following withdrawal of the medication before improvement is seen. Increased Activities of Repeat challenge with a suspected hepato- Liver Enzymesa toxin may greatly exacerbate hepatotoxicosis. Alternatively, a patient may develop tolerance Hepatocellular leakage pattern for a hepatotoxin and have negative challenge Idiopathic hepatitis results. If potential hepatotoxins are identified, ❯ American and English cocker spaniels they should be discontinued and liver enzyme ❯ Labrador retriever activities reassessed in 2 to 3 weeks. ❯ Standard poodle The patient’s vaccination history and poten- Copper-associated hepatitis tial exposure to infectious agents should be ❯ Bedlington terrier determined. Hepatopathies have been docu- ❯ Dalmatian mented with Leptospira interrogans serovars ❯ Doberman pinscher Icterohaemorrhagiae and Pomona and Lepto ❯ Labrador retriever spira kirschneri serovar Grippotyphosa2; addi- ❯ Skye terrier tional associations may be identified with ❯ West Highland white terrier increased molecular testing. Canine adenovi- Amyloidosis rus 1 infection, heartworm disease, ehrlichio- QuickNotes ❯ Chinese shar-pei sis, leishmaniasis, neosporosis, toxoplasmosis, Supplements, and systemic mycoses should be considered Cholestatic pattern as potential causes of hepatocellular disease.3,4 nutraceuticals, and Benign hyperphosphatasemia In dogs, bacterial infections arise primarily topical medications ❯ Scottish terrier from hematogenous routes and breaks in host are easily over- ❯ Siberian husky defenses, such as periodontal disease.5 Hyperlipidemia looked as potential Lethargy, inappetence, vomiting, and diar- ❯ Miniature schnauzer hepatotoxins. rhea are common clinical signs. Icterus, ascites, Gallbladder disease acholic feces, or hepatic encephalopathy may ❯ Shetland sheepdog occur with acute liver failure or progression a This list does not include breeds associated with congenital of chronic disease. Physical examination may vascular abnormalities, which commonly have mixed liver enzyme be unremarkable or may reveal abnormali- activity patterns. ties consistent with an extrahepatic disorder. Poor body condition, icterus, abdominal pain, out, the patient should be evaluated for breed hepatomegaly or microhepatia, and abdomi- associations (Box 1). A careful dietary history nal effusion may suggest hepatic dysfunc- may identify risk factors for infection (e.g., raw tion. The presence of clinical signs, physical or undercooked meat) or intoxication (e.g., examination abnormalities, or evidence of poor food storage practices, recalled diets). decreased liver function should prompt an Depending on the geographic location, access expeditious workup to maximize chances of to Amanita mushrooms and cycad palm plants obtaining a diagnosis and successful thera- should be determined. The owner should be peutic intervention. carefully questioned about medications to which the patient may have access, including Laboratory Screening supplements, nutraceuticals, and topical gluco- A minimum database of a complete blood corticoids. Owners may not notice a pet’s con- count (CBC), biochemical profile, and urinaly- sumption of prescription medications or know sis should be obtained for dogs with verified that common items for human use, such as increased activities of liver enzymes. those containing xylitol, can be hepatotoxic. Hepatobiliary disease can be associated Diagnosis of drug-related hepatotoxicity with a variety of CBC abnormalities. Although can be challenging. The time between initial gastrointestinal bleeding or coagulopathy sec- administration of a medication and detection ondary to hepatobiliary dysfunction may stim- of hepatic injury can vary greatly, which makes ulate a regenerative anemia, the chronicity of it difficult to establish exposure preceding many hepatic diseases often leads to anemia

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of chronic disease, which is nonregenerative. Additional Testing Microcytosis is common with acquired or con- Thorough evaluation of liver enzyme activity genital portosystemic shunts.6 Thrombocytosis increases may require additional testing for occurs with hyperadrenocorticism,7 chronic extrahepatic and hepatobiliary diseases after blood loss, and inflammatory disorders,8 and integration of the minimum database with the thrombocytopenia suggests ongoing vasculitis clinical presentation. Hyperadrenocorticism and or consumptive processes. hypothyroidism should be considered in dogs Biochemical changes may aid in the dif- with appropriate clinical findings and chole- ferentiation of extrahepatic and hepatobiliary static enzyme activity increases. Thyroid hor- disease. Concentrations of bilirubin, choles- mone testing should be interpreted carefully terol, blood urea nitrogen (BUN), albumin, because sick euthyroid syndrome is common and glucose provide information about liver in dogs with chronic disease. Dogs with gas- function despite low sensitivity and specificity. trointestinal signs should be evaluated for pan- In the absence of hemolysis or sepsis, hyper- creatitis and primary gastrointestinal disease. bilirubinemia indicates cholestasis due to Depending on risk assessment and vaccina- hepatobiliary disease or posthepatic obstruction history, infectious disease screening may tion. Cholesterol concentrations increase with be indicated. cholestatic disease and decrease with end- Liver function can be evaluated in a vari- QuickNotes stage liver disease.9 BUN concentration may ety of ways. Increased bile acids are extremely be increased secondary to gastrointestinal sensitive for detecting decreased functional Coagulation test- bleeding or decreased by shunting of por- hepatic mass or portosystemic shunting in non- ing should be tosystemic blood or decreased hepatic pro- icteric patients. Administration of ceruletide, a conducted no more duction.9 Creatinine concentration typically cholecystokinin analogue, instead of food may than 24 hours remains within the reference interval. With improve the reliability of results in anorectic the loss of approximately 70% of functional before liver biopsy. patients, facilitate standardization of serum bile hepatic parenchyma, hypoalbuminemia may acid evaluation, and be more sensitive for mild occur.10 Other causes of hypoalbuminemia hepatic dysfunction.16 Urine nonsulfated bile should be ruled out, including gastrointestinal acids have a specificity similar to that of serum disease, protein-losing nephropathy, hemor- bile acids but are less sensitive.17 Increased rhage, vasculitis, inflammation, and prolonged ammonia concentration occurs with portosys- anorexia. Hypoglycemia may occur after loss temic shunting, hepatic failure, and urea cycle of 75% of hepatic parenchymal function and is enzyme deficiencies and is a useful biomarker a poor prognostic indicator.9,11 Other causes of for hepatic encephalopathy.18 Protein C is a hypoglycemia should be excluded, including circulating anticoagulant protein that is syn- congenital portosystemic vascular anomalies, thesized by the liver. Decreased protein C activ- insulinoma, and sepsis.12 ity may be a useful biomarker for decreased A variety of abnormalities may be identified hepatic function or hepatoportal perfusion.19 on urinalysis. Hyposthenuria and isosthenuria Protein C activity may also be useful for thera- occur frequently with extrahepatic and hepato- peutic monitoring and differentiation between biliary diseases. Bilirubinuria with or without microvascular dysplasia and congenital porto- hyperbilirubinemia may be identified. A small systemic shunts.19 The liver synthesizes most amount of bilirubinuria can be normal, particu- clotting factors and is responsible for activation larly in male dogs.13 The presence of urobilino- of vitamin K–dependent clotting factors. In dogs gen can be normal or associated with hepatic with chronic hepatitis, prolonged prothrom- disease, while absence may suggest biliary bin time (PT) and partial thromboplastin time obstruction. Due to urobilinogen’s instability (PTT) have been associated with decreased and variable excretion, this test has question- survival times.20 Buccal mucosal bleeding time able clinical usefulness.14 Portosystemic shunting is used to assess risk of abnormal platelet func- and end-stage liver disease may result in ammo- tion. Because of the fragile balance between nium biurate crystal formation. Glucosuria and procoagulant and anticoagulant factors,21 we aminoaciduria, consistent with Fanconi syn- recommend that PT, PTT, and buccal mucosal drome, have been noted in dogs with copper- bleeding time tests be conducted no more than storage hepatopathy.15 24 hours before liver biopsy.

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Diagnostic Imaging of the time in one veterinary study.28 Accuracy Survey radiography allows assessment of may be improved by use of the largest appro- the size, shape, position, opacity, and mar- priate biopsy instrument and collection of gins of the liver. Mineralization of hepatic multiple samples. Keyhole surgical biopsies parenchyma or choleliths may be detected allow collection of large samples and good on survey films. Abdominal ultrasonography access for hemostatic control, but the sur- allows visualization of focal, multifocal, or dif- geon’s ability to evaluate all aspects of the fuse lesions within the hepatic parenchyma, liver, gallbladder, and other organs is limited. although it cannot distinguish pathologic from Laparoscopy offers excellent visualization and benign lesions.22 Ultrasonography also allows sampling of the liver, gallbladder, and other assessment of the biliary tract and provides abdominal organs; provides better hemostatic visualization for percutaneous cholecystocen- access than percutaneous sampling; and is tesis, a minimally invasive method of bile col- less invasive than laparotomy. Widespread lection.23,24 Gallbladder rupture and iatrogenic use of laparoscopy is limited by require- inoculation of bile with surface microbes are ments for specialized training and equipment. rare complications,23 but the procedure is gen- Laparotomy is recommended when surgical erally regarded as safe. Normal findings on cure may be possible and in cases for which abdominal imaging do not rule out primary full exploration of the abdominal cavity is QuickNotes hepatobiliary disease. desired. When a liver biopsy Liver Sampling Techniques Diagnostic Sampling is performed, The optimal time for liver biopsies is early in Histopathologic evaluation of liver biopsy samples should the disease course so that they yield useful samples remains the gold standard for the be obtained for information rather than demonstrate non- diagnosis of hepatobiliary disease, but it can specific end-stage changes. When selecting fail to provide a definitive diagnosis. Clinicians histopathology, a biopsy technique, clinicians should con- often must incorporate information regarding aerobic and anaero- sider the ability to obtain adequate samples the extent and type (inflammatory, neoplastic, bic cultures, and for histopathology, aerobic and anaerobic vascular, vacuolar) of pathology into the clini- copper and iron cultures, and copper and iron quantitation. cal picture to make a diagnosis. quantitation. Contraindications to biopsy include coagu Quantification of iron and copper concen- lopathy and liver failure. trations may aid in diagnosis, prognostica- Ultrasound-guided fine-needle aspiration t i o n , a n d t h e r ap e u t i c t a i lo r i ng. 29,30 Abnormally of the liver is easy to perform and minimally high hepatic copper levels cause oxidative invasive. Unfortunately, cytology has been stress and are associated with low hepatic demonstrated to have poor agreement (29% glutathione levels, which contribute to hepa- to 66%) with primary histopathologic diagno- tocellular damage.29 Both inborn errors of ses,25,26 including the diagnosis of neoplasia. In metabolism leading to decreased copper data from two recent studies, 3.6% (2 of 56)26 excretion and impaired copper excretion due and 3.9% (2 of 51)27 of cases were inappropri- to chronic hepatitis and cholestatic disease ately diagnosed with neoplasia on cytology; may occur in dogs.29 Abnormal accumulation 14% (2 of 14)26 and 50% (5 of 10)27 of cases of iron may be due to increased intestinal with histologically confirmed neoplasia were absorption or abnormalities of hemoglo- identified cytologically. The poor agreement bin metabolism and delivery of iron to the between liver cytology and histopathology liver.31 Accumulation of iron in Kupffer cells and the potential ramifications of misdiag- has been correlated with inflammation and noses should be kept in mind when consider- increased copper levels.30 ing fine-needle aspiration findings. Aerobic and anaerobic cultures of hepatic The least invasive method of liver biopsy tissue and bile complete a comprehensive is percutaneous ultrasound-guided needle hepatobiliary workup. In findings from one biopsy. One disadvantage of this technique study,32 biliary cultures were more commonly is the inability to directly monitor the liver for positive (30%) than hepatic cultures (7%) in hemostasis. Needle biopsy findings concurred dogs. It is unclear whether the biliary system with findings from wedge biopsies only 48% is more susceptible to infection or whether it

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is a more sensitive sampling site. Cytologic hepatobiliary disease includes a CBC, bio- evaluation of bile may aid in identification of chemical profile, and urinalysis; liver func- infectious organisms. tion tests, including coagulation parameters; abdominal radiography and ultrasonography; Conclusion bile cytology and culture; and hepatic biopsy Successful interpretation of liver enzyme for histopathology, culture, and metal analysis. abnormalities requires integrated evaluation Employing a systematic approach facilitates of the patient’s clinical picture and diagnos- diagnosis of hepatobiliary disease in a timely tic testing. A thorough diagnostic workup for fashion to improve patient outcome.

References 1. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J ease in dogs. JAVMA 2003;222:1368-1375. Med 2006;354:731-739. 18. Szatmari V, Rothiuzen J, van den Ingh TS, et al. Ultrasono- 2. Greene CE, Sykes JE, Brown CA, et al. Leptospirosis. In: Infec- graphic findings in dogs with hyperammonemia: 90 cases (2000- tious Diseases of the Dog and Cat. 3rd ed. Philadelphia: WB Saun- 2002). JAVMA 2004;224:717-727. ders; 2006:402-417. 19. Toulza O, Center SA, Brooks MB, et al. Evaluation of plasma 3. Decaro N, Martella V, Buonavoglia C. Canine adenoviruses and protein C activity for detection of hepatobiliary disease and porto- herpesvirus. Vet Clin North Am Small Anim Pract 2008;38:799- systemic shunting in dogs. JAVMA 2006;229:1761-1771. 814. 20. Shih JL, Keating JH, Freeman LM, et al. Chronic hepatitis in 4. Webster CRL, Cooper JC. Diagnostic approach to hepatobiliary Labrador retrievers: clinical presentation and prognostic factors. J disease. In: Kirk’s Current Veterinary Therapy XIV. St. Louis: Saun- Vet Intern Med 2007;21:33-39. ders Elsevier; 2009:543-549. 21. Senzolo M, Burra P, Cholongita E, et al. New insights into the 5. Pavlica Z, Petelin M, Juntes P, et al. Periodontal disease burden coagulopathy of liver disease and liver transplantation. World J and pathological changes in organs of dogs. J Vet Dent 2008;25:97- Gastroenterol 2006;12:7725-7736. 105. 22. Feeney DA, Anderson KL, Ziegler LE, et al. Statistical relevance 6. Simpson KW, Meyer DJ, Boswood A, et al. Iron status and of ultrasonographic criteria in the assessment of diffuse liver dis- erythrocyte volume in dogs with congenital portosystemic vascular ease in dogs and cats. Am J Vet Res 2008;69:212-221. anomalies. J Vet Intern Med 1997;11:14-19. 23. Vörös K, Sterczer A, Manczur F, Gaál T. Percutaneous ultra- 7. Bass MC, Schultze AE. Essential thrombocythemia in a dog: sound-guided cholecystocentesis in dogs. Acta Vet Hung 2002; case report and literature review. JAAHA 1998;34:197-203. 50:385-393. 8. Dunn JK, Heath MF, Jeffries AR, et al. Diagnostic and hemato- 24. Savary-Bataille KC, Bunch SE, Spaulding KA, et al. Percutane- logic features of probable essential thrombocythemia in two dogs. ous ultrasound-guided cholecystocentesis in healthy cats. J Vet In- Vet Clin Pathol 1999;28:131-138. tern Med 2003;17:298-303. 9. Center SA. Acute hepatic injury: hepatic necrosis and fulminant 25. Wang KY, Panciera DL, Al-Rukibat RK, et al. Accuracy of ul- hepatic failure. Small Animal Gastroenterology. 3rd ed. Philadel- trasound-guided fine-needle aspiration of the liver and cyto- phia: WB Saunders; 1996:654-704. logic findings in dogs and cats: 97 cases (1990-2000). JAVMA 10. Cooper J, Webster CRL. Acute liver failure. Compend Contin 2004;224:75-78. Educ Pract Vet 2006;28:498-512. 26. Cohen M, Bohling MW, Wright JC, et al. Evaluation of sensitiv- 11. Poldervaart JH, Favier RP, Penning LC, et al. Primary hepati- ity and specificity of cytologic examination: 269 cases (1999-2000). tis in dogs: a retrospective review (2002-2006). J Vet Intern Med JAVMA 2003;223:964-967. 2009;23:72-80. 27. Weiss DJ, Blauvelt M, Aird B. Cytologic evaluation of inflamma- 12. Holford AL, Tobias KM, Bartges JW, et al. Adrenal response to tion in canine liver aspirates. Vet Clin Pathol 2001;30:193-196. adrenocorticotropic hormone in dogs before and after surgical at- 28. Cole TL, Center SA, Flood SN, et al. Diagnostic comparison of tenuation of a single congenital portosystemic shunt. J Vet Intern needle and wedge biopsy specimens of the liver in dogs and cats. Med 2008;22:832-838. JAVMA 2002;220:1483-1490. 13. Webster CRL. History, clinical signs, and physical findings in 29. Spee B, Arends B, van den Ingh TS, et al. Copper metabolism hepatobiliary disease. In: Textbook of Veterinary Internal Medicine. and oxidative stress in chronic inflammatory and cholestatic liver 6th ed. St. Louis: Elsevier; 2008:1423-1434. diseases in dogs. J Vet Intern Med 2006;20:1085-1092. 14. Reine NJ, Langston CE. Urinalysis interpretation: how to 30. Schultheiss PC, Bedwell CL, Hamar DW, et al. Canine liver iron, squeeze out the maximum information from a small sample. Clin copper, and zinc concentrations and association with histologic le- Tech Small Anim Pract 2005;20:2-10. sions. J Vet Diagn Invest 2002;14:396-402. 15. Appleman EH, Ciancolo R, Mosenco AS, et al. Transient ac- 31. Alexander J, Tung BY, Croghan A, Kowdley KV. Effect of iron quired Fanconi syndrome associated with copper storage hepatop- depletion on serum markers of fibrogenesis, oxidative stress and athy in 3 dogs. J Vet Intern Med 2008;22:1038-1042. serum liver enzymes in chronic hepatitis C: results of a pilot study. 16. Bridger N, Glanemann, B, Neiger, R. Comparison of postpran- Liver Int 2007;27:268-273. dial and ceruletide serum bile acid stimulation in dogs. J Vet Intern 32. Wagner KA, Hartmann FA, Trepanier LA. Bacterial culture re- Med 2008;22:873-878. sults from liver, gallbladder, or bile in 248 dogs and cats evalu- 17. Balkman CE, Center SA, Randolph JF, et al. Evaluation of urine ated for hepatobiliary disease: 1998-2003. J Vet Intern Med 2007; sulfated and nonsulfated bile acids as a diagnostic test for liver dis- 21:417-424.

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1. The ______of liver enzyme activity b. Canine parvovirus a reliable and noninvasive means to increase is not a consideration when c. Leishmania infantum assess the gallbladder and biliary tree. evaluating a dog with increased liver d. Leptospira interrogans d. Seeding of the gallbladder with skin enzyme activities. bacteria is a frequent complication of a. magnitude c. pattern 5. ______is a poor prognostic indicator in ultrasound-guided cholecystocentesis. b. duration d. sequence patients with hepatic disease. a. Hyperbilirubinemia 8. Which is not a contraindication to liver 2. Which of the following may be associ- b. Decreased BUN concentration biopsy? ated with hepatotoxicosis? c. Hypercholesterolemia a. increased bile acids a. xylitol c. metaldehyde d. Hypoglycemia b. poor anesthetic risk b. ethylene glycol d. cannabis c. coagulopathy 6. ______can be used as a biomarker of d. liver failure 3. Which of the following regarding hepato- hepatic encephalopathy. toxins is incorrect? a. Serum bile acids 9. Which is not an advantage of fine-needle a. Pet owners may not consider human b. Urine nonsulfated bile acids aspiration of the liver? foods as potential hepatotoxins. c. Serum ammonia concentration a. It allows reliable diagnosis of neoplasia. b. Nutritional and herbal supplements are d. Protein C activity b. It is minimally invasive. often overlooked during the history. c. The risk of hemorrhage is limited. c. Plants and fungi do not contain 7. Which statement regarding abdominal d. It does not require anesthesia. hepatotoxins. imaging is correct? d. Timing between ingestion of a hepa- a. A lack of ultrasonographic abnor- 10. When performing a biopsy, samples of totoxin and liver injury can be highly malities rules out clinically significant liver parenchyma should be collected for variable. hepatic disease. all of the following except b. The ultrasonographic appearance of the a. histopathology. 4. ______has/have not been associated liver can be used to distinguish benign b. protein C activity. with hepatic disease. from pathologic changes. c. metal analysis. a. Canine adenovirus 1 c. Abdominal ultrasonography provides d. bacterial culture.

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