Liver Enzyme Elevations in Dogs: Diagnostic Approach*
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3 CE CREDITS CE Article 2 Liver Enzyme Elevations in Dogs: Diagnostic Approach* ❯❯ 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 history, clinical signs, and concurrent lab- and hemolysis may falsely increase activi- Diagnostic Imaging 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 416 Compendium: Continuing Education for Veterinarians® | September 2009 | CompendiumVet.com FREE Liver Enzyme Elevations in Dogs: Diagnostic Approach CE 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 differen- tials are etiologies that may require a comprehensive hepatobiliary evaluation for diagnosis. CompendiumVet.com | September 2009 | Compendium: Continuing Education for Veterinarians® 417 FREE CE Liver Enzyme Elevations in Dogs: Diagnostic Approach 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 418 Compendium: Continuing Education for Veterinarians® | September 2009 | CompendiumVet.com FREE CE Liver Enzyme Elevations in Dogs: Diagnostic Approach 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 obstruc- tion history, infectious disease screening may tion. Cholesterol concentrations