Increased Liver Enzyme Activity in a Dog
A 9-year-old neutered male Labrador retriever was referred for increased serum alanine aminotransferase (ALT) activity.
History. The increased ALT activity (4 times the upper limit of the reference interval) was noticed incidentally by the dog’s primary care veterinarian 4 weeks earlier. A repeat serum biochemical profile obtained 2 weeks ago showed a similar elevation in ALT activity. The owner reported that the dog was not displaying any clinical signs of disease. Other than heartworm preventive, the dog was not receiving any medications and had no known exposure to toxins.
Physical Examination. The patient was judged to be overweight (body condition score of 7/9). Moderate dental calculus was noted on oral examination and bilaterial ceruminous discharge was noted on otic examination. No other abnormalities were found.
Laboratory Results. The results of a complete blood count and blood smear examination were unremarkable. A serum biochemical profile (Table 1) showed an ALT activity of 584 U/L (reference interval, 10–130 U/L). Urinalysis results were within normal limits.
Diagnostic Imaging. An abdominal ultrasound examination showed gastric distension but no other significant findings. No changes of the liver or biliary system were observed.
Ask Yourself ...
Based on the history, physical examination, and laboratory and diagnostic imaging findings, which of the following would be your next step?
A. No further diagnostics at this time, but repeat a serum biochemical profile in 2 monthsB. Measure pre- and postprandial serum bile acid concentrationsC. Test for leptospirosis, hyperadrenocorticism, and hypothyroidismD. Perform a hepatic biopsyE. Start treatment with hepatoprotectants and a commercial “hepatic support” diet
Correct Answer:D. Perform a hepatic biopsy
ALT activity is a marker for hepatocellular damage (Table 2). While serum alkaline phosphatase activity may be increased due to a number of extrahepatic conditions, increased serum ALT activity is considered to be a more specific marker for hepatobiliary disease.1 This patient had ALT activity level greater than 4 times the upper limit of the reference interval, and this elevation persisted for more than 4 weeks. This finding suggested clinically important hepatobiliary disease and warranted further investigation.
Diagnostics. Because the liver has a considerable reserve capacity, patients with liver disease can have normal liver function test results.2 The results of the dog’s serum biochemical profile did not suggest hepatic insufficiency. Paired pre- and postprandial serum bile acid measurement is sensitive and specific for detecting hepatic insufficiency in dogs. However, in this case, serum bile acid measurement would not have aided in diagnosis or therapy selection.
Abdominal ultrasound is a useful imaging modality for evaluation of the hepatobiliary system. However, clinicians must recognize that patients may have clinically important hepatic parenchymal disease despite an apparently normal liver and biliary tract on abdominal ultrasonography.3
Extrahepatic Disease. Because of the liver’s central role in metabolism and its unique dual blood supply, it is often affected by extrahepatic disease. Hepatopathies can be the primary disease process or can be secondary to extrahepatic disease, drugs, or toxins.4 The diagnostic and therapeutic approach for patients with primary and secondary hepatopathies differs greatly. Based on the signalment, history, physical examination, and clinicopathologic findings, there was no evidence that this dog had extrahepatic disease or exposure to xenobiotics. Consequently, extensive testing for extrahepatic disease was not indicated.
Hepatic Biopsy. Collection of a hepatic biopsy was indicated due to the strong suspicion of a chronic primary hepatopathy. No evidence of a coagulopathy was found on a coagulation profile (including prothrombin time and activated partial thromboplastin time) or a buccal mucosal bleeding time.
Seven hepatic wedge biopsies were collected laparoscopically (Figure 1). Six of these were submitted for histopathology, and one specimen was immediately frozen. In addition, bile was submitted for aerobic and anaerobic culture.
Figure 1: Laparoscopic view of the liver; biopsy sites are visible on the margin of the liver
The frozen specimen was submitted for copper quantification by flame atomic absorption spectrometry (Colorado State University Veterinary Diagnostic Laboratories; dlab.colostate.edu).
Diagnosis. Histopathologic evaluation of the liver biopsy specimens showed chronic periportal hepatitis with bridging fibrosis. Copper-staining showed accumulation of copper in hepatocytes (Figure 2). The hepatic copper concentration was 1651 ppm dry weight (reference interval, 120–400 ppm). The final diagnosis was copper-associated chronic hepatitis.
Figure 2: Copper-associated chronic hepatitis; this histopathologic section shows abundant copper granules in the cytoplasm of periportal hepatocytes and in some hepatocytes Rhodamine stain; original magnification, 40x
Treatment. The patient was switched to a commercial hepatic support diet with a vegetable protein source, restricted copper content, and increased zinc content.5 Supportive treatment with ursodiol and SAMe was initiated. The patient’s hepatic copper accumulation was treated with D-penicillamine.6
Take-Home Messages
Depending on magnitude and duration, increases of serum ALT activity are clinically important and warrant further investigation.*
Hepatic function tests can be normal in patients with early chronic hepatitis.
Abdominal ultrasound examination can be unremarkable in patients with chronic hepatic parenchymal disease.
Increases in serum hepatic enzyme activities can be from extrahepatic sources (eg, alkaline phosphatase can be of hepatic or bone origin) or due to primary or secondary hepatopathies.
Biopsy is indicated in patients that are suspected of having chronic primary hepatopathy.
* In our opinion, further investigation is warranted when a single ALT activity determination is greater than 5 times the upper limit of the reference interval, or when multiple determinations demonstrate activity greater than 2 times the upper limit of the reference interval for more than 4 weeks.
TX at a Glance
Treatment should be started as early as possible in the course of chronic hepatitis.
Treatment should be guided by hepatic histopathology, hepatic copper quantification, and bile/liver culture.
Chelating agents and reduced dietary copper intake are the main treatments for copper-associated chronic hepatitis.
Hepatoprotectants have a place in the treatment of copper-associated chronic hepatitis.
The use of corticosteroids and other antiinflammatory drugs in the treatment of copper-associated chronic hepatitis is controversial.
Assessment of the patient’s response to treatment is crucial.
INCREASED LIVER ENZYME ACTIVITY • Jonathan A. Lidbury & Jörg M. Steiner
References
Interpretation of liver enzymes. Center S. Vet Clin North Am Small Anim Pract 37:297-333, 2007.2. Primary hepatitis in dogs: A retrospective review (2002-2006). Poldervaart JH, Favier RP, Penning LC, et al. J Vet Intern Med 23:72-80, 2009.3. Statistical relevance of ultrasonographic criteria in the assessment of diffuse liver disease in dogs and cats. Feeney DA, Anderson KL, Ziegler LE, et al. Amer J Vet Res 69:212-221, 2008.
The diagnostic approach to asymptomatic dogs with elevated liver enzyme activities. Cooper J, Webster CRL. Vet Med May: 279-288, 2006.5. Dietary management of hepatic copper accumulation in Labrador retrievers. Hoffmann G, Jones PG, Biourge V, et al. J Vet Intern Med 23:957-963, 2009.6. Randomized, double blind, placebo-controlled treatment with D-penicillamine against copper accumulation in Labrador retrievers. Hoffman G, Jones PG, Mesu S, et al. J Vet Intern Med 20:752 (abstract).
Suggested Reading1. General principles in the treatment of liver disease. Rothuizen J. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, 7th ed—St Louis: Elsevier, 2010, pp 1629-1637.2. Heritabilities of copper-accumulating traits in Labrador retrievers. Hoffman G, Heuven H, Leegwater P, et al. Anim Genet 39:454, 2008.3. Inflammatory canine hepatic disease. Willard MD. In Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, 7th ed—St Louis: Elsevier, 2010, pp 1637-1642.4. Laboratory tests for the diagnosis of liver disease. Williams DA, Rothuizen J. In Steiner JM (ed): Small Animal Gastroenterology—Hannover: Schlütersche, 2008, pp 56-63.5. Update on hepatobiliary imaging. Gaschen L. Vet Clin North Am Small Anim Pract 39:439-467, 2009.