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The diagnostic approach to asymptomatic dogs with elevated liver enzyme activities
This review provides general guidelines for the diagnostic approach to an asymptomatic dog with elevated liver enzyme activities so that needless tests are not performed and clinically important liver disease is not missed.
Veterinarians perform blood tests in healthy animals for many reasons, including assessing metabolic function in geriatric patients or patients in need of procedures that require anesthesia, monitoring for drug toxicity, and screening for breed-related diseases. Increases in hepatobiliary enzyme activities-alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), and alkaline phosphatase (ALP)-are commonly encountered on serum chemistry profiles in these animals. In a study of dogs with a variety of ailments, serum ALP and ALT activities were elevated in 32% and 47% of cases, respectively.1 In another study of both healthy and ill dogs, elevations in ALP, ALT, GGT, and AST activities were found in 39%, 17%, 19%, and 11% of cases, respectively.2
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Although elevated serum hepatobiliary enzyme activities are frequently identified, they do not necessarily indicate clinically important hepatic disease. There are several reasons for this discordance. First, increased serum hepatobiliary enzyme activity can originate from nonhepatic tissues. Second, the liver's dual blood supply and large blood flow make it uniquely sensitive to injury due to systemic disorders and diseases in organ systems drained by the portal circulation, particularly the gastrointestinal tract and the pancreas. Finally, drugs can induce excess hepatobiliary enzyme production in the absence of liver damage (see boxed text titled "Drugs that affect liver enzyme interpretation").
Drugs that affect liver enzyme interpretation
This review provides general guidelines for the diagnostic approach to an asymptomatic dog with elevated liver enzyme activities so that needless tests are not performed and clinically important liver disease is not missed.
FACTORS AFFECTING HEPATOBILIARY ENZYME ACTIVITY
Three principal factors contribute to normal serum hepatobiliary enzyme activity. The first determinant is the normal concentration of that enzyme in tissues. Enzymes must be present in a high enough concentration for some spillover into the circulation to occur. The second determinant is the serum enzyme's half-life. An enzyme must have a serum half-life of sufficient duration to permit accumulation. The final determinant is intracellular localization, since enzymes must have access to the vascular compartment to be measured in serum.3 In general, cytosolic enzymes gain access to the serum easier than do enzymes that are within organelles or that are membrane-bound.3
Serum hepatobiliary enzyme activity increases because of leakage from damaged hepatobiliary cells, elution from damaged membranes, or increased synthesis.3 Serum hepatobiliary enzyme activity measurements are useful screening tests for liver damage. They have a high sensitivity (a measure of a test's ability to detect animals with hepatobiliary disease), so few patients with liver disease are missed (the false negative result rate is low). However, they have a lower specificity (a measure of a test's ability to exclude individuals without hepatobiliary disease), so some animals without liver disease will have elevations (false positive results). Thus, once an elevation in serum hepatobiliary enzyme activity is noted, confirmation of hepatobiliary disease requires performing tests with higher specificity. Such tests include hepatic function tests (measuring serum bilirubin, blood ammonia, and total serum bile acid concentrations), hepatobiliary histologic examination, or interpreting hepatobiliary enzyme activities in concert.
Increases in serum ALT activity are considered liver-specific in dogs. ALT activity can increase with severe muscle necrosis, but simultaneous evaluation of serum creatine kinase activity can rule out a muscle source.3,4 ALT is a cytosolic enzyme, and leakage occurs with damage to hepatobiliary membranes. The magnitude of serum ALT activity elevation is roughly proportional to the number of injured hepatocytes.3 Serum ALT activity may also increase because of induction of enzyme synthesis by corticosteroid use and, possibly to a lesser extent, by phenobarbital therapy.3,5 Serum ALT half-life is 2.5 days.6
Increases in serum ALT activity have the highest sensitivity (80% to 100%) for hepatic inflammation and necrosis, vacuolar hepatopathy, and primary neoplasia (hepatocellular carcinoma, cholangiocarcinoma) but have less sensitivity (50% to 60%) in cases of hepatic congestion, metastatic neoplasia, and portosystemic vascular anomalies.3
The highest tissue concentrations of AST are present in the liver, skeletal muscle, and cardiac muscle. Both cytosolic and mitochondrial liver isoenzymes have been found in people, and presumably both isoenzymes occur in dogs as well.3
Serum AST activity increases from leakage secondary to hepatocyte membrane injury, so it typically parallels serum ALT activity increases. Increased serum AST activity, in the absence of increased ALT activity, indicates an extrahepatic source, most likely muscle injury.4 Marked elevations in AST activity are suggestive of irreversible hepatocyte injury with release of mitochondrial AST stores. AST half-life is 22 hours.6
Measuring AST activity is somewhat more sensitive but less specific for detecting hepatic disease than is measuring ALT activity.3 Typically, there is little to no induction of serum AST with corticosteroid or phenobarbital treatment.3,5,7
Serum alkaline phosphatase
Alkaline phosphatase is a membrane-bound enzyme present in many tissues. Three major isoenzymes contribute to total serum ALP: bone, liver, and corticosteroid isoenzymes.1,3,8
Bone ALP accounts for about one-third of the total serum ALP and is elevated with conditions associated with increased osteoblastic activity such as bone growth, osteomyelitis, osteosarcoma, and secondary renal hyperparathyroidism.3
Liver ALP is a membrane-bound enzyme present on biliary epithelial cells and hepatocytes. Liver ALP half-life is 70 hours.3,8 The largest increases in liver ALP activities are associated with focal or diffuse cholestatic disorders and primary hepatic neoplasms (hepatocellular and bile duct carcinoma). Less dramatic increases are found in cases of hepatic necrosis, hepatitis, and nodular hyperplasia. Liver ALP can also be induced by corticosteroid or phenobarbital administration.3,5,7,9
Corticosteroid ALP isoenzyme is produced in the liver and is located on the hepatocyte plasma membranes lining the bile canaliculi and sinusoids.3 Corticosteroid ALP has a similar half-life to liver ALP. Corticosteroid ALP contributes to total serum ALP in dogs exposed to exogenous corticosteroids or in cases of spontaneous hyperadrenocorticism.3 However, increased corticosteroid ALP activity has also been associated with chronic illness, possibly secondary to stress and concomitant increases in endogenous glucocorticoid secretion.1,3,8
Increased ALP activity is one of the most common abnormalities detected on serum chemistry profiles in ill dogs. ALP activity measurement has a high sensitivity (80%) for hepatobiliary disease, but its specificity is low (51%). If elevated ALP activity is noted with a concurrent increase in serum GGT activity, specificity for liver disease increases to 94%.8
Serum GGT activity is largely derived from the hepatobiliary system. In dogs, hepatic GGT is located on the hepatocyte canalicular membrane. GGT activity appears to have a lower sensitivity but higher specificity (87%) for detecting hepatobiliary disease than ALP activity does.8
The most marked elevations of GGT activity result from diseases of the biliary epithelium such as bile duct obstruction and cholecystitis.3 Moderate elevations can also be found with primary hepatic neoplasia (hepatocellular and biliary carcinoma) and corticosteroid induction.1,3,7,8 Mild elevations are found in cases of hepatic necrosis and anticonvulsant administration.3,5,9
THE FIRST STEPS IN PATIENT EVALUATION
Asymptomatic dogs with increases in serum hepatobiliary enzyme activities may have either extrahepatic disease or primary hepatobiliary disease (Table 1). The first steps in evaluating these dogs are to get a thorough history and perform a physical examination. In addition, a minimum database (including a complete blood count, full serum chemistry profile, and urinalysis) should be obtained in all cases.
Table 1: Disorders Associated with Elevated Serum Hepatobiliary Enzyme Activity in Asymptomatic Dogs
Pertinent historical information includes the administration of any potentially hepatotoxic drugs, supplements, or nutraceuticals; exposure to any environmental toxins or infectious agents; recent anesthetic events; and details on housing, supervision outdoors, travel, and vaccination status. Carefully question owners about any possible vague signs of underlying disease such as intermittent gastrointestinal signs (e.g. vomiting, diarrhea, weight loss), behavioral changes, polyuria or polydipsia, or exercise intolerance. In the case of primary hepatobiliary disease, clinical signs may not be apparent until the disease process is advanced because of the liver's large regenerative capacity and functional reserve.
Several drugs have been associated with hepatotoxicity in dogs (Table 2).12 If a potentially hepatotoxic drug or supplement is being administered, discontinue it; if abrupt cessation is not possible, taper the drug and add another drug of a different class. Liver enzyme activities should be reevaluated two weeks after discontinuation of the suspected hepatotoxic agent. Persistent or progressive increases in liver enzyme activity indicate the need for further diagnostic testing.
Table 2: Drugs Associated with Acute Liver Disease in Dogs
Physical examination findings may include coat changes and hepatomegaly (due to hyperadrenocorticism), a stunted or pot-bellied appearance and poor body condition (due to a portosystemic vascular anomaly), mild abdominal discomfort (due to chronic pancreatitis), or thickened intestines (due to inflammatory bowel disease).
Signalment may be helpful since several breed-associated hepatopathies that are inflammatory, fibrotic, or both exist (Bedlington terriers, cocker spaniels, dalmatians, Doberman pinschers, Labrador retrievers, Skye terriers, West Highland white terriers) and portosystemic vascular anomalies have strong breed associations.10,11
IS FURTHER DIAGNOSTIC TESTING NEEDED?
Any elevation in liver enzyme activity in dogs of breeds predisposed to a hepatopathy or associated with portosystemic vascular anomalies requires further diagnostic evaluation. In breeds predisposed to inflammatory hepatopathies, a hepatic ultrasonographic examination with biopsy, culture, and quantitative copper analysis is recommended. In breeds predisposed to portosystemic vascular anomalies, look for a shunt by performing an ultrasonographic study. If a shunt cannot be confirmed but is still suspected, scintigraphy (colorectal or transplenic) can be considered. If a shunt is not identified by either ultrasonography or scintigraphy, a wedge biopsy may be necessary to identify cases of microvascular dysplasia.
Further diagnostic testing is also indicated if the patient in question is not of a breed predisposed to a hepatopathy, has no history of drug exposure, and has any of the following: An elevation of greater than three times the upper reference range limit in more than one enzyme activity A progressive increase in enzyme activities A single enzyme activity elevation and an increased bilirubin or decreased albumin concentration
In cases in which only a single liver enzyme activity is increased and the increase is less than three times the upper reference range limit, you may choose to perform a bile acid assay or repeat the serum chemistry profile in four weeks.
Finding an abnormal total serum bile acid concentration at any point necessitates further evaluation. However, a normal total serum bile acid concentration does not rule out liver disease.
Persistent and progressive increases in serum liver enzyme activities also require further evaluation.
FURTHER PATIENT EVALUATION
Once you decide to pursue additional diagnostic testing, the next step is diagnostic imaging. If diagnostic imaging fails to show any abnormalities that dictate a specific diagnostic or therapeutic approach (e.g. surgery in the case of gallbladder mucoceles, choleliths, or portosystemic vascular anomaly), then consider obtaining a hepatic biopsy sample.
Abdominal radiographs allow assessment of liver size and abdominal detail and may reveal choleliths (50% are visible radiographically). Hepatomegaly is typically associated with any vacuolar hepatopathy (e.g. hyperadrenocorticism, adrenal hyperplasia syndromes, and hypothyroidism), phenobarbital hepatopathy, and acute and chronic inflammatory hepatobiliary disease. Microhepatia may be seen with portosystemic vascular anomalies (with the exception of microvascular dysplasia) or cirrhosis. Choleliths can be associated with cholecystitis and may indicate a subclinical hepatobiliary infection.
Ultrasonography is helpful in differentiating focal (abscess, hepatobiliary neoplasia), multifocal (nodular hyperplasia, metastatic disease), or diffuse lesions. In cases of nodular hyperplasia, homogenous hypoechoic masses or mixed hypoechoic to hyperechoic lesions may be noted but cannot be differentiated from primary or secondary neoplasia.13 Ultrasonography can also reveal changes in liver echogenicity; unfortunately, no change is classic for a specific disease. Both a corticosteroid hepatopathy and hepatic lipidosis are characterized by a diffusely hyperechoic liver. Normal liver parenchyma does not rule out hepatic disease.
The gallbladder and biliary tree can also be evaluated ultrasonographically. Gallbladder mucoceles, choleliths, and intrahepatic or extrahepatic bile duct dilatation can be identified ultrasonographically. Hepatic portal vasculature can also be evaluated to identify small, single or multiple acquired shunts. Extrahepatic causes for liver enzyme elevations may also be evaluated, including pancreatitis, hyperadrenocorticism (assessment of adrenal glands), and gastrointestinal tract disease.
Before the hepatic biopsy, perform a coagulation profile to assess the prothrombin time, partial thromboplastin time, and platelet count. Hepatic biopsy samples can be obtained with ultrasound guidance (Tru-Cut biopsy) or exploratory surgery (see the article) or laparoscopy (wedge biopsy). A wedge biopsy is the gold standard, and studies suggest that discordance occurs on histopathologic assessment of wedge vs. Tru-Cut biopsy samples from the same liver.14 The results of any hepatic biopsy, however, need to be interpreted in light of sampling error.
The method by which to obtain a biopsy sample may be influenced by the suspected diagnosis. In some diseases, such as microvascular dysplasia and nodular hyperplasia, a wedge biopsy is often necessary to obtain a definitive diagnosis. In other cases, such as with a diffuse vacuolar hepatopathy, inflammatory disease, or neoplasia, a diagnostic sample can likely be obtained by performing a Tru-Cut biopsy. In the case of focal or diffuse neoplasia, a fine-needle aspiration biopsy may yield diagnostic samples. In most cases, however, fine-needle aspiration biopsy is inadequate for diagnostic purposes.
Cholecystocentesis can also be performed to obtain bile for culture in cases in which subclinical infection is suspected. This procedure should be performed with ultrasonographic guidance by an experienced ultrasonographer.
DIAGNOSTIC FINDINGS FOR SPECIFIC CAUSES OF ELEVATED HEPATIC ENZYME ACTIVITIES
Causes of elevated liver enzyme activity in asymptomatic dogs can generally be divided into extrahepatic and hepatobiliary diseases.
Your diagnostic test findings may point to three extrahepatic causes-hyperadrenocorticism, hypothyroidism, and gastrointestinal disorders.
Hyperadrenocorticism is associated with mild to moderate increases in total serum ALP activity in about 85% of cases. Similar degrees of elevation may be seen with GGT activity, and in 50% to 80% of dogs a mild increase in ALT activity is noted.15 Other clinicopathologic changes that might provide clues to the presence of hyperadrenocorticism are mild polycythemia, a stress leukogram, mild thrombocytosis, hypercholesterolemia, hypertriglyceridemia, and isosthenuria.15
Dogs with adrenal hyperplasia syndromes secondary to excess sex hormone production exhibit similar liver enzyme activity elevations as dogs with hyperadrenocorticism do but are frequently asymptomatic (lacking the typical signs of hyperadrenocorticism). Consider testing for hyperadrenocorticism (endogenous ACTH concentration, low-dose dexamethasone suppression test) in dogs with suggestive signs. If the test results for hyperadrenocorticism are negative, consider testing for atypical hyperadrenocorticism (sex hormone panel before and after ACTH stimulation).
Hypothyroidism may result in mild increases in ALP and ALT activities, but these occur less commonly than other clinicopathologic changes including a mild nonregenerative anemia, fasting hypercholesterolemia, and hypertriglyceridemia. Consider testing for hypothyroidism (free T4 concentration, thyroid-stimulating hormone test) in dogs that are of breeds prone to this condition and that exhibit concurrent weight gain, decreased exercise tolerance, or skin and coat changes.
Gastrointestinal disorders such as inflammatory bowel disease and pancreatitis may cause mild to moderate elevations in ALP and ALT activities.16,17 These conditions may give rise to what has been called a reactive hepatopathy. The histologic features include mild to moderate mononuclear periportal inflammatory infiltrates, lipidosis, and focal hepatocellular necrosis.17 These changes are likely secondary to inappropriate gastrointestinal absorption of toxic bacterial products such as endotoxin. Additional clinicopathologic changes that might be seen with inflammatory bowel disease include a peripheral eosinophilia and mild hypoalbuminemia, hypoglobulinemia, and hypocholesterolemia.17 With chronic pancreatitis, hyperlipidemia, hypertriglyceridemia, or mild hyperglycemia may be noted.16 Further work-up should include an abdominal ultrasonographic examination followed by endoscopy with intestinal biopsy or evaluation of serum canine pancreatic lipase immunoreactivity in suspected cases of inflammatory bowel disease and pancreatitis, respectively.
Hepatobiliary system disorders to consider include nodular hyperplasia, hepatic tumors, vascular anomalies, and gallbladder mucoceles.
Nodular hyperplasia is a common cause of mild to moderate increases in total serum ALP activity in asymptomatic dogs older than 8 years of age. In patients with nodular hyperplasia, other serum liver enzymes activities (transaminases) may be elevated, but hepatic function test results are usually normal.
Grossly, nodular hyperplasia can resemble macronodular cirrhosis or neoplasia. On histologic examination, variable degrees of vacuolar change are seen within hepatocytes, and lipogranulomas are common.13 In more advanced cases, there may be varying degrees of mixed inflammatory cells. In biopsy samples with adequate amounts of tissue, the pathologist should be able to identify normal hepatic tissue surrounding the nodule. Examination of a small needle biopsy sample may yield an inappropriate diagnosis of a vacuolar hepatopathy or chronic inflammatory disease.13
Any primary or metastatic tumor of the liver may result in elevations in ALP, ALT, or AST activities. The most common primary liver neoplasms are hepatocellular adenomas, hepatocellular carcinomas, and bile duct carcinomas.18 The most commonly reported metastatic liver neoplasms are those arising from the mammary glands, spleen, adrenal glands, pancreas, gastrointestinal tract, bone, and lungs.18 The liver can also be involved in other malignant processes including malignant histiocytosis, lymphoma, and systemic mastocytosis. Hepatic wedge, needle, or fine-needle aspiration biopsies are necessary to confirm the diagnosis.
Vascular anomalies within the portal venous system include microscopic (microvascular dysplasia) and macroscopic (congenital extrahepatic or intrahepatic portosystemic shunts) defects in vascular development. Clinical signs are directly related to the degree of diversion of portal blood flow around the liver, so patients with vascular anomalies may be asymptomatic in cases of mild shunting.19 Similar breed predisposition is noted in cases of portosystemic shunts and microvascular dysplasia, and both conditions may be present simultaneously. Typically, portosystemic shunts will be identified in young dogs (less than 2 years of age) while dogs with microvascular dysplasia may not be identified until they are somewhat older.20 In the absence of a concurrent portosystemic shunt, animals with microvascular dysplasia may remain asymptomatic for life; however, others may progress to develop signs of hepatic insufficiency.
In patients with portosystemic shunts, twofold to threefold increases in serum ALP, ALT, and AST activities have been recorded while patients with microvascular dysplasia may have normal to mild increases in these enzyme activities.20 Microcytic red blood cells are commonly noted in cases of portosystemic shunts but are not seen in cases of microvascular dysplasia.
Gallbladder mucoceles have been associated with mild to marked increases in serum activities of ALP, AST, ALT, and GGT.21 In a retrospective study examining gallbladder mucoceles, seven of 30 cases had no clinical signs of illness.21 In the 23 symptomatic cases, clinical signs were nonspecific and included vomiting, lethargy, and anorexia. The diagnosis was made on abdominal ultrasonographic examination, which revealed immobile, echogenic bile with a striated or stellate pattern within the lumen of the gallbladder (Figure 1).21 Cholecystectomy is recommended in these cases to prevent sequelae including cholecystitis, extrahepatic bile duct obstruction, and gallbladder rupture.21
1. On this ultrasonogram, organized, striated, and immobile echogenic sediment can be seen within the gallbladder, consistent with a gallbladder mucocele. The possibility of perforation should be considered given the surrounding effusion.
Increases in serum liver enzyme activities are sensitive indicators of hepatobiliary disease, but these activities can be elevated secondary to various endocrinopathies, gastrointestinal disease, pancreatic disease, systemic disease, and enzyme induction. In asymptomatic patients, a systematic approach is required to obtain a definitive diagnosis. A careful review of the patient's history is essential to uncover vague clinical signs that the owner may have missed and to identify any potential exposure to hepatotoxic agents. A complete minimum database, including a complete blood count and urinalysis, is required to rule out an underlying extrahepatic disease. In some cases, sequential monitoring may be elected; however, persistent elevation, marked elevations, concurrent increases in serum bilirubin concentrations, or concurrent decreases in albumin concentrations warrant further investigation, including diagnostic imaging and, in many cases, hepatic biopsy.
Johanna Cooper, DVM
Cynthia R.L. Webster, DVM, DACVIM
Department of Clinical Sciences Cummings
School of Veterinary Medicine
North Grafton, MA 01536
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