V158 Common Canine Liver Diseases David C. Twedt, DVM, DACVIM Colorado State University Fort Collins, CO, USA OBJECTIVES OF THE PRESENTATION To present the most common types of liver disease seen in a clinical practice. To provide key points important to the diagnosis of common liver diseases. To present reactive hepatopathies, vacuolar hepatopathies and chronic hepatitis. KEY POINTS The most common cause of abnormal liver enzymes are the reactive hepatopathies. Idiopathic vacuolar hepatopathy is an emerging and common condition observed in dogs. Chronic hepatitis to be successful in therapy must be diagnosed early. OVERVIEW OF THE ISSUE Reactive Hepatopathies The so-called “reactive hepatopathies” which occur secondary to extrahepatic disease can result in both serum hepatic test and histomorphologic abnormalities. Most of the reactive hepatopathies cause increases in laboratory tests that evaluate hepatocellular integrity (ALT, AST) and tests of hepatic cholestasis (ALP, GGT). In most cases there is little if any changes in tests that evaluate hepatic function (bilirubin, albumin, glucose and BUN). Most of the animals with secondary liver disease also have normal serum bile acid concentrations, which again support a concept that there is generally minimal hepatocellular dysfunction in most of these disease conditions. This group is characterized by nonspecific hepatocellular degeneration or necrotic changes without evidence of chronic progressive inflammation. These changes are usually secondary to manifestations of a primary non-hepatic disease. The reason the liver often undergoes these changes is that the liver is involved in many metabolic and detoxification functions and is very dependent on adequate oxygenation. Endogenous toxins, anoxia, metabolic changes, nutritional changes and endogenous stress related glucocorticoid release might be responsible for the majority of these changes. We have also found that secondary liver changes routinely occur following general anesthesia. Histologic findings often include descriptors such as vacuolar degeneration, hydropic degeneration, swollen hepatocytes, lipidosis, intracellular or intrahepatic cholestasis, and periportal or variable hepatic necrosis. These changes are devoid of typical chronic inflammatory cell infiltrates characteristic of chronic hepatitis. We were able to identify associated disease and the probable cause for the hepatic enzyme and histologic changes in most cases. Concurrent diseases included neoplasia, gastrointestinal, renal, autoimmune, dermatologic, dental, infectious and cardiac disease as a few examples. In some cases an underlying disease is not identified. The ALT values on the average are 1–2 X normal and the ALP values 1–3 X normal. It is interesting to note that in a series of 32 dogs having reactive hepatopathies, 8/8 cases in which serum bile acids were run, all were within the normal reference range suggesting hepatic function remains intact. This category is the most common histologic change to occur in dogs and is by far the most common cause of elevated liver enzymes. Based on this fact, dogs presented with elevations in ALT and ALP should always have primary non-hepatic disease ruled out first. These changes are usually very reversible and no specific hepatic therapy is required short of treating the primary disease. The liver changes resolve once the primary etiology is successfully treated. Vacuolar Hepatopathies The histological reports of vacuolar hepatopathy are often very frustrating in determining the underlying etiology. Hepatocellular vacuoles distending the cytosolic compartment may contain, fat, glycogen, intracellular water (edema) or other metabolic wastes or intermediates. Vacuolar hepatopathies may occur in conjunction with hydropic degeneration in which there is cytosolic swelling but devoid of distinct vacuoles. A number of conditions discussed above causing reactive hepatopathies can be responsible for vacuolar hepatopathies or lesions may develop as a result of secondary chronic stress (endogenous steroid induced) resulting from concurrent disease. Steroid hepatopathy occurs in dogs but not cats due to endogenous or exogenous glucocorticoids. A history of steroid administration or clinical signs referable to Cushing’s disease supports the diagnosis. Steroids cause hepatic glycogen accumulation and hepatomegaly. The ALP with will be increased, often dramatically with variable increases in GGT and ALT. The liver changes can result in some decrease in liver function demonstrated by mild increases in serum bile acids. Withdrawing steroids or successful treatment of Cushing’s disease will result in reversible changes in the liver. Idiopathic vacuolar hepatopathy is a frustrating diagnosis frequently observed in older dog. In all intense purposes they appear typical of steroid hepatopathies based on histology and abnormal ALP but without clinical or laboratory evidence of Cushing’s disease. The liver of these dogs contains excess glycogen and they have laboratory finding predominately G-ALP isoenzymes. One is unable to make the diagnosis of Cushing’s disease based on lack of typical clinical signs and normal conventional adrenal testing (i.e., ACTH stimulation or LDDS). We have recently investigated several dogs having vacuolar hepatopathy and increased ALP without overt Cushing’s disease to have abnormal concentrations in some of the other adrenal steroids (i.e., sex hormones such as progesterone, estradiol, DHEAS-S or 17a- Hydroxy-progesterone). There is now speculation that increases in some of these steroid hormones may result in the hepatic changes and ALP increase. It appears those most if not all of these dogs live a normal life with out adverse consequences from their liver disease. Obviously further investigation is required into this syndrome. We have observed several dogs following empirical ketoconazole therapy have decreases in ALP supporting there may be adrenal hyperplasia producing some aberrant type of adrenal steroid. We have recently observed a vacuolar hepatopathy syndrome specific to Scottish Terriers. Chronic Hepatitis Copper associated chronic hepatitis has been documented and is discussed below. Drug-induced hepatitis specifically primidone, Phenobarbital and diethylcarbamazine oxibendazole has been reported to produce chronic hepatitis in some dogs. Recently we have also observed dogs receiving chronic carprofen to have changes representing chronic hepatitis. Infectious agents such as leptospirosis and infectious canine hepatitis are also a cause of chronic hepatitis. Possibly other infectious agents may be responsible as well. Alpha1-antitrypsin (AAT- also referred to as alpha one protease inhibitor) deficiency in the serum leading to accumulation of AAT in the hepatocytes, is known to cause chronic hepatitis and cirrhosis in man. Recent investigation by researchers in Sweden using immunostaining for AAT in hepatocytes found many dogs with chronic hepatitis to be positive. The breed most often associated with AAT accumulation was the cocker spaniel. Circulating autoantibodies are important diagnostic markers used to identify autoimmune liver disease in humans. It appears that autoantibodies (ANA, antimitochondrial antibodies [AMA], smooth muscle antibodies [SMA], liver membrane autoantibodies [LMA]) are of a minor importance in classifying canine chronic hepatitis and thought to occur in most cases secondary to the liver damage. Nonetheless, immune mediated mechanisms are thought to be associated with certain cases of chronic hepatitis and are supported by the fact that some dogs respond favorably to immunosuppressive therapy. Secondary immune hepatitis may result from non-specific damage to hepatocytes that result in release of liver antigens. Antibodies are then formed against these liver specific antigens with continued damage intact hepatocytes. Breed Predisposition There are a number of breeds that have an increased incidence of chronic hepatitis, which suggests a genetic basis. Chronic hepatitis in Doberman Pinschers is more common in young to middle-aged female dogs. The CH is characterized by cholestasis, hypoalbuminemia with increased concentrations of copper and iron in the liver tissue. CH has been reported that Cocker Spaniels as an inherited liver disease that is specific but not associated with copper accumulation. These dogs have marked hypoalbuminemia, ascites and hepatic encephalopathy and generally have a grave prognosis. Other breeds that appear to have increased incidence include Labrador Retrievers and Standard Poodles. Copper Associated Hepatitis Abnormal hepatic copper accumulation may be the result of either a primary metabolic defect in copper metabolism or as a secondary event as the result of abnormal hepatic function causing decreased copper excretion. When we reviewed a number of dogs having chronic hepatitis and not associated with known breed associated copper accumulation we found many dogs had increases in both copper and iron hepatic concentrations. A number of these dogs were also deficient in hepatic zinc. The interrelationship of the heavy metals and liver disease needs further investigation. The diagnosis of abnormal Cu accumulation requires a liver biopsy. Excess Cu within the liver can be demonstrated using histochemical staining for hepatic Cu using rhodanine or rubeanic acid stain. Definitive determination of excess hepatic Cu requires a quantitative analysis of tissue Cu measured on the biopsy sample. Normal canine hepatic Cu concentrations are less than 400 µg/g dry weight liver. Hepatic Cu concentrations in dogs with secondary Cu accumulation generally fall in the range less than 1,000 µg/g dry weight while breed associated hepatotoxicities generally have much higher concentrations. Hepatic copper toxicity was first identified in Bedlington Terriers. It was subsequently shown that affected Bedlington terriers have an inherited autosomal recessive defect, which results in reduced biliary excretion of copper due to hepatic metallothionein sequestration of the metal in hepatic lysosomes. Clinically there is a progressive hepatic Cu accumulation with age ranging from 1,000 to 12,000 µg/g per dry weight of liver. The extent of hepatic damage tends to parallel the increasing hepatic Cu concentrations. During the last decade an increasing number of breeds other than the Bedlington terrier have been identified with concurrent chronic hepatitis and increases in the hepatic Cu content. Liver disease with concurrent Cu accumulation is reported in the Doberman Pinscher, West Highland White Terrier, Skye Terrier as well as many other pure breed and mixed-breed dogs. Recently we have identified a number of Dalmatians having a suspected inherited copper associated liver disease. Clinical Findings The incidence of chronic hepatitis makes up approximately one fourth of the cases having liver biopsies at Colorado State University (based on a review of 150 consecutive liver biopsies). Chronic hepatitis is more common in female dogs and the average age at presentation ranges from 4 to 10 years. It is interesting to note that in both our series and in studies by others it is uncommon to observe chronic hepatitis/cirrhosis in dogs older than 10 years of age. The clinical signs parallel the extent of hepatic damage. Early in the disease there are usually no or only minimal clinical signs. Only after the disease progresses do the clinical signs specific for liver disease becomes evident. Frequent early signs are gastrointestinal associated with vomiting, diarrhea and poor appetite or anorexia. Ascites, jaundice and hepatic encephalopathy may then occur as the disease progresses. With development of these late signs the long-term prognosis is generally poor. The laboratory findings include consistently elevated ALT, ALP and GGT. The magnitude of rise need not be marked however. One report found 75% of the cases of chronic hepatitis to have abnormal bilirubin increases (mean value of 2.6 mg/dl). Hyperbilirubinemia is however considered to be a later laboratory finding. Serum proteins are variable and as chronic hepatitis lesions become more severe albumin levels decline. We found serum bile acids concentrations to be abnormal in most all cases having chronic hepatitis. Early in the disease the fasted bile acids may be normal but postprandial bile acid concentrations are abnormal. We believe that identifying abnormal bile acid concentrations in the dog having abnormal liver enzymes to be a good predictor of significant liver disease which includes chronic hepatitis. In our study all dogs evaluated with chronic hepatitis had abnormal bile acid concentrations. In a second study only 8/26 dogs with chronic hepatitis had normal fasting bile acids. However in theses cases postprandial samples were not determined. Determining postprandial bile acids has been shown to increase the sensitivity of this test. Diagnosis A presumptive diagnosis is made based on the clinical features and persistent increases of ALP and ALT values. The diagnosis is supported by abnormal bile acid concentrations, radiographic or ultrasound findings. A definitive diagnosis however requires a hepatic biopsy showing characteristic morphological patterns. Fine needle aspirates with cytology are not helpful in making the diagnosis of chronic hepatitis because it is important to see the architecture of the liver and location and extent of the inflammation. Recent evidence also suggests that a needle biopsy may not provide enough portal triads to absolutely make the diagnosis of hepatitis. One must work with the pathologist when making the diagnosis of chronic hepatitis and to be certain that characteristic abnormalities found in chronic hepatitis are present. That there is still considerable confusion in nomenclature and description of histological changes and terminology varies with pathologists. I believe that all cases suspected of having chronic hepatitis should also have hepatic copper, zinc and iron content determined. Finding abnormalities in metal content will help direct a course of therapy. SUMMARY Common liver conditions in the dog include reactive hepatopathies, vacuolar hepatopathies and chronic hepatitis. Breed predisposition, clinical and laboratory presentation are important is directing the work up and possible diagnosis. A liver biopsy may be the only definitive means of making the diagnosis of chronic hepatitis.
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