Veterinary Medicine - August 2008 - (Page 437)

Copper-associated hepatopathies PEER-REVIEWED Much uncertainty exists about the relevance of copper concentrations in liver samples with or without evidence of disease, and it may be necessary to develop breed-speci c reference ranges. This controversy highlights the need for careful interpretation of laboratory data, biopsy results, and quantitative liver copper concentrations in light of a patient’s breed and clinical condition. CLINICAL PRESENTATION 1. A laparoscopic photograph showing a nodular and discolored liver. (Photo courtesy of Dr. Mike Willard of Texas A&M University’s College of Veterinary Medicine.) Genetically predisposed Bedlington terriers accumulate hepatotoxic copper concentrations and manifest clinical signs by 2 to 4 years of age. Other breeds may develop clinical disease at any age depending on the severity and nature of their hepatic dysfunction. Some dogs may present without clinical signs but with persistent blood work abnormalities, such as elevations in liver enzyme activities and other indicators of liver dysfunction. Dogs with chronic liver disease may present with weight loss, decreased appetite, polyuria and polydipsia, diarrhea, or intermittent vomiting. Jaundice, ascites, or hepatic encephalopathy may also occur in severely affected patients. Dogs may also present in acute crisis, which may re ect a sudden decompensation of occult chronic liver disease. Clinical signs may include anorexia, melena, vomiting, jaundice, or lethargy. Rarely, severe acute hepatic necrosis may result in the release of stored copper into the blood. This release causes hemolysis, probably from direct oxidative damage to erythrocyte membranes. Affected dogs may present with pallor, jaundice, lethargy, inappetence, or pigmenturia. Hemolysis secondary to copper toxicosis has only been reported in Bedlington terriers.5,6 (nonregenerative) or gastrointestinal blood loss (regenerative or nonregenerative). Liver disease predisposes patients to gastrointestinal ulceration because of impaired mucosal blood ow, which is a result of dehydration and portal hypertension and decreased clearance of histamine and gastrin.6 Evidence of gastrointestinal bleeding may include melena, hematochezia, or an increased serum BUN to creatinine ratio. Urinalysis results may reveal bilirubinuria, dilute urine (isosthenuria), or glucosuria. CLINICOPATHOLOGIC FINDINGS The most consistent laboratory nding is increased alanine transaminase (ALT) activity. Other liver enzyme activities may be increased concurrently, including alkaline phosphatase (ALP), aspartate transaminase (AST), and gammaglutamyltransferase (GGT). The relative increase in ALT activity is often much higher than the relative increase in ALP activity, suggesting predominantly hepatocellular rather than cholestatic liver disease. Even mild increases in ALT activity are important and merit more attention than changes in ALP activity. In addition, consider nonhepatic causes of increased ALP activity, particularly if it is the only abnormal parameter. Hyperbilirubinemia, hypoalbuminemia, hypoglycemia, low blood urea nitrogen (BUN) concentration, or hypocholesterolemia suggests considerable compromise to hepatic function. Elevated bile acid concentrations, ammonia tolerance testing results, or ammonia concentrations can con rm liver dysfunction and may provide prognostic information. However, they do not obviate the need for liver biopsy. Since copper accumulation in the liver occurs slowly, substantial increase of ALT or AST activity in a previously healthy patient is most suggestive of an acute injury by a noncopper hepatotoxin. Hepatoprotectants, supportive care, and periodic monitoring (every two weeks) of serum chemistry pro le results are indicated before liver biopsy is pursued. Other laboratory abnormalities may include anemia from chronic disease ULTRASONOGRAPHY Abdominal ultrasonography is indicated to rule out primary biliary tract disease, especially extrahepatic biliary obstruction, and can provide useful clues about the duration of a patient’s liver disease. If the liver appears mottled (mixed echogenicity), small, cirrhotic, or nodular, the liver disease is probably chronic. If the liver appears unremarkable in terms of size and echogenicity in a patient with a one-time-only increase in liver enzyme activities, acute liver injury is more probable. DEFINITIVE DIAGNOSIS Definitively diagnosing a copperassociated hepatopathy requires obtaining a liver biopsy sample surgically or laparoscopically (Figure 1) for histologic examination and copper quanti cation. Special stains (rubeanic acid, rhodanine, Timm’s) can be used as a qualitative indicator of copper accumulation. Copper-loaded lysosomes can be identi ed with these stains when hepatic copper concentrations exceed 400 ppm on a dry weight basis (Figure 2).6 Atomic absorption analysis of liver tissue is the only way to accurately assess the hepatic copper concentration. Most laboratories require fresh or freshly frozen liver samples (Table 1). Copper concentrations are reported as µg/g of dry weight, which is the same as parts per million per dry weight (ppm dw). VETERINARY MEDICINE August 2008 437

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Veterinary Medicine - August 2008 Contents Editors' Note Leading Off ClinQuiz Idea Exchange Practical Matters Diagnosing and Treating Canine Copper-Associated Hepatopathies Canine and Feline Demodicosis CE Form Advertiser Index Product Preview Marketplace/Classifieds Mind Over Miller

Veterinary Medicine - August 2008

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