Liver Enzymes and Tests
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ALANINE TRANSFERASE
ALT was formerly known as serum glutamic-pyruvic transaminase (SGPT).
Common Indications
Systemic disease including weight loss, hepatomegaly, vomiting, diarrhea, icterus, ascites, depression, and anorexia; also, as a screening procedure for hepatic disease in any patient with undiagnosed illness. Most patients with known chronic hepatitis should undergo periodic ALT determinations to monitor the problem.
Advantages
Specificity for the liver.
Disadvantages
Lack of sensitivity (i.e., patients with significant hepatic disease such as cirrhosis or hepatic neoplasia may have normal ALT) and inability to distinguish among different hepatic diseases or when there is secondary nonhepatic disease involvement.
Analysis
Measured in serum (heparinized plasma in selected assays) by spectrophotometric and dry reagent methods. ALT is stable in separated serum for approximately 1 (at 22°C) to 7 (at 4°C) days.
Normal Values
Serum enzyme activity may vary markedly among laboratories, depending on the technique and the units used.
Danger Values
Despite correlation between ALT and active hepatic damage, no correlation exists between ALT and hepatic function; hence, no danger values exist.
Artifacts
See Introduction to Serum Chemistries.
Drug Therapy That May Alter Serum ALT
Any drug causing hepatocellular damage (i.e., drug-induced hepatopathy) may cause increased ALT. The list of all drugs suspected to cause increased ALT is extensive and includes many that are safe in the majority of patients. A list of selected drugs documented to cause increased ALT in human beings, dogs, and cats is given in Table 9-6. Administration of one of these drugs does not automatically explain an increased ALT, however.
NOTE:
A patient can have an idiosyncratic reaction to almost any drug, causing an increased ALT.
Causes of Decreased ALT
Not significant.
Causes of Increased ALT
Increase in ALT is principally caused by hepatocellular damage from any cause (Table 9-9 ). RBCs and striated muscle cells contain small amounts of ALT, and damage to these may cause relatively minor increases (i.e., less than two to three times normal) in serum ALT, as may exercise. Dogs with muscular dystrophy may have major increases in ALT, but should also have increases in AST and creatine kinase (CK) values.
TABLE 9-9
Selected Causes of Increased Serum Alanine Aminotransferase Levels
| DOGS | CATS |
|---|---|
| Hepatic Parenchymal Disease | Hepatic Parenchymal Disease |
| Cholangitis | Cholangitis |
| Cholangiohepatitis | Cholangiohepatitis |
| Cirrhosis | Feline infectious peritonitis (FIP) |
| Copper storage disease | Hepatic lymphoma |
| Hepatic malignancy | Cirrhosis |
| Chronic hepatitis | Hepatic toxin |
| Hepatic toxin | Trauma |
| Trauma | Pancreatitis |
| Pancreatitis | Hyperthyroidism |
| Other Disorders | Other Disorders |
| Anoxia because of anemia/shock | Anoxia because of anemia/shock |
| Iatrogenic (see Table 9-6) | Iatrogenic (see Table 9-6) |
NOTE: Almost any disease affecting the liver can cause increased ALT levels. The disorders listed are those that may be more likely to cause a significant increase. However, any of these diseases can exist with minor or no increase in ALT values.
Hepatocytes contain substantial amounts of ALT in the cytosol, and major increases in serum ALT (i.e., three or more times normal) indicate hepatocellular leakage of the enzyme but do not always signify primary or irreversible hepatic disease. Hepatic disease may have normal to significantly increased serum ALT activity. The magnitude of the increase in ALT does not correlate with the seriousness of the hepatic disease and is not a prognostic indicator unless a specific disease is being considered. The serum ALT half-life is approximately 1 to 2 days or less, and serum ALT is expected to decrease over 1 to 2 weeks once active hepatic damage ceases. It is thought that ALT remains elevated during hepatic regeneration.
After increased serum ALT is identified, many factors must be considered (Figure 9-7 ). If no other evidence of disease is found, the increased ALT indicates the need for periodic monitoring because it may be the first detectable sign of significant hepatic disease. If other abnormalities consistent with hepatic disease are found, the approach is like that in any other patient with hepatic disease. Common causes of serum ALT more than three times normal include hepatic anoxia, poor hepatic perfusion, spontaneous and surgical trauma (e.g., hit by a car, surgery), chronic hepatitis, cirrhosis, cholangitis and cholangiohepatitis, acute biliary obstruction, hepatic necrosis as the result of any cause, acute pancreatitis, hepatic neoplasia, sepsis, and certain drugs. Sepsis, especially septicemia and toxemia, may secondarily damage hepatocytes. Abdominal inflammation may do the same. The pancreas is close to the liver, and inflammation in the pancreas may cause mechanical damage to the liver. In Doberman pinschers, Bedlington terriers, Dalmatians, and West Highland white terriers, a persistently increased serum ALT suggests chronic hepatitis that may or may not be associated with increased hepatic copper concentrations.
Diagnostic approach to increased alanine aminotransferase (ALT) in dogs and cats. BUN, Blood urea nitrogen; CBC, complete blood count; SAP, serum alkaline phosphatase.
ASPARTATE TRANSFERASE
AST was formerly known as serum glutamic-oxaloacetic transaminase (SGOT).
Occasional Indications
Same as for ALT.
Disadvantages
Not as specific for the liver as ALT.
Analysis
Same as for ALT.
Drug Therapy That May Alter AST
Decreased AST may be caused by metronidazole therapy. Hepatotoxic drugs may cause increased AST (see Table 9-6).
Causes of Decreased AST
None.
Causes of Increased AST
Like ALT, AST is present in significant quantities in hepatocytes. Although ALT is present in the cytosol, AST is present in the mitochondria. Increased serum ALT reflects cell membrane damage and leakage; significant AST increases tend to reflect more serious hepatic damage because the mitochondria are not damaged as readily as is the cell membrane. AST is, however, present in significant quantities in many other tissues, including muscle and RBCs; therefore, increased AST is not as specific for hepatic injury as is increased ALT. Exercise and intramuscular (IM) injections may increase serum AST. The most common causes of increased AST include hepatic disease, muscle disease (inflammation or necrosis), or hemolysis (spontaneous or artifactual). Increased AST is an indication to check for ongoing hemolysis by measuring the hematocrit and observing the color of the plasma and serum on a centrifuged blood sample. If no hemolysis is found, the next step is to measure serum ALT to determine whether the increased AST is from the liver (significant increases in both ALT and AST suggest that AST increases are of hepatic origin).
SERUM ALKALINE PHOSPHATASE
Common Indications
Systemic disease, including weight loss, hepatomegaly, vomiting, diarrhea, ascites, icterus, depression, or anorexia; also as a screen for hepatic disease and hyperadrenocorticism.
Advantages
Useful in evaluating the liver for subtle cholestatic disease.
Disadvantages
Affected by corticosteroids, bone lesions, and osteoblastic activity in young growing dogs.
Analysis
Measured in serum or heparinized plasma by spectrophotometric methods. Stability in heat (55°C) has been used to attempt to differentiate SAP of bone origin (i.e., heat sensitive) from SAP of hepatic origin (i.e., heat stable). It is difficult to obtain reproducible results with the heat-inactivation test; however, L-phenylalanine inhibits steroid-induced SAP and can be used to help determine if increased SAP is due to corticosteroids. Alternatively, cellulose acetate electrophoresis can separate the isoenzymes more definitively. The diagnostic usefulness of determining the percentage of steroid fraction is questionable, because dogs with various types of hepatic disease often have considerable steroid involvement.
Normal Values
May vary markedly from laboratory to laboratory. Immature dogs characteristically have SAP (bone origin) activities up to twice that of sexually mature dogs.
Danger Values
Because of the lack of correlation with hepatic function, no danger values exist for SAP.
Artifacts
See Introduction to Serum Chemistries.
Drug Therapy That May Increase SAP
Any drug that causes hepatic enzyme induction or cholestasis (see Table 9-7) may increase SAP. Glucocorticoids, primidone, and barbiturates typically increase SAP in dogs, but other drugs are less consistent. Although glucocorticoids can cause marked SAP increases in dogs, cats are almost never affected.
Causes of Decreased SAP
Not significant.
Causes of Increased SAP
SAP of bone origin is commonly increased (SAP less than three times normal) in dogs less than 6 to 8 months old. Bone disease (e.g., osteosarcoma, osteomyelitis) may increase SAP (usually a minor increase) and generally denotes a guarded prognosis from presumed metastatic disease in the bones.
Increased SAP is interpreted differently in dogs and cats (Table 9-10 ). Cats have less hepatocellular SAP, which is readily excreted by their kidneys. Therefore, any increase in feline SAP is considered significant, indicating further tests. Not all cats with hepatic disease have increased SAP. The major causes of increased SAP in cats are hepatic lipidosis, cholangitis and cholangiohepatitis, hyperthyroidism, and diabetes mellitus. SAP increases are generally more specific than GGT in cats with hepatic lipidosis (cats with lipidosis classically have very high SAP with little to no increase in GGT; however, this finding is not consistent enough to make a diagnosis). Hyperadrenocorticism (spontaneous and iatrogenic) very, very rarely increases SAP in cats. Increased SAP in a cat is an indication for serum thyroid hormone determination, urinalysis, blood glucose and serum ALT measurement, and perhaps a hepatic function test (e.g., bile acid). If hepatic disease is the apparent cause of the increased SAP, one must determine if hepatic biopsy is indicated (see the later discussion under Bile Acids).
TABLE 9-10
Causes of Increased Serum Alkaline Phosphatase Levels
| DOGS | CATS | |
|---|---|---|
| Biliary Tract Abnormalities | Biliary Tract Abnormalities | |
| Pancreatitis | Same as for dogs | |
| Bile duct neoplasia | ||
| Cholelithiasis | ||
| Cholecystitis | ||
| Ruptured gallbladder | ||
| Hepatic Parenchymal Disease | Hepatic Parenchymal Disease | |
| Cholangiohepatitis | Cholangiohepatitis | |
| Chronic hepatitis | Hepatic lipidosis | |
| Copper storage disease | Hepatic lymphoma | |
| Cirrhosis/fibrosis | Feline infectious peritonitis (FIP) | |
| Hepatic neoplasia | ||
| Lymphoma | ||
| Hemangiosarcoma | ||
| Hepatocellular carcinoma | ||
| Metastatic carcinoma | ||
| Toxic hepatitis | ||
| Aflatoxin | ||
| Other Disorders | Other Disorders | |
| Diabetes mellitus | Diabetes mellitus | |
| Hyperadrenocorticism | Hyperthyroidism | |
| Chronic passive congestion because of right heart failure | ||
| Diaphragmatic hernia | ||
| Septicemia | ||
| Ehrlichiosis* | ||
| Young dog with bone growth | ||
| Osteomyelitis* | ||
| Iatrogenic (see Table 9-7) | Iatrogenic (see Table 9-7)* | |
NOTE: Almost any disease affecting the liver can cause increased SAP levels. The disorders listed are those that may be more likely to cause a significant increase. However, any of these can exist with minor or no increase in SAP values.
*Rarely of importance.
The major causes of SAP values more than three times normal in dogs are hepatobiliary disease, hyperadrenocorticism, and therapy with glucocorticoids or anticonvulsants. Hepatic disease with increased SAP usually has a cholestatic component; however, this does not imply icterus or gross obstruction of the biliary tract. Intrahepatic cholestasis caused by diffuse or focal compression of bile canaliculi may occur in various hepatopathies, even those secondary to septicemia, toxemia, and chronic stress-induced vacuolar (i.e., hydropic change) hepatopathy. Acute hepatocellular necrosis can transiently increase SAP (usually less than five times normal). Extrahepatic biliary tract obstruction and enzyme induction caused by endogenous or exogenous glucocorticoids or drug administration may increase SAP more than 10 times normal. As with ALT, the magnitude of the increase in SAP does not correlate with the seriousness or prognosis of the disease.
In dogs it is important first to rule out young age, drug therapy, and hyperadrenocorticism to avoid performing an unnecessary hepatic biopsy (Figure 9-8 ). Hyperadrenocorticism can easily be confused with primary hepatic disease because it typically causes hepatomegaly, pu-pd, increased ALT, and sometimes increased serum bile acids. Unless a patient has signs of hepatic failure (i.e., icterus, hepatic encephalopathy, hypoglycemia, weight loss, vomiting, hypoalbuminemia, ascites, microhepatia), hyperadrenocorticism must be precluded by adrenal gland function testing. If a hepatic biopsy specimen is obtained from a patient with hyperadrenocorticism, vacuolar hepatopathy is documented.
Diagnostic approach to increased serum alkaline phosphatase (SAP) in dogs. CBC, Complete blood count.
GAMMA-GLUTAMYL TRANSPEPTIDASE
Occasional Indications
Same as for SAP. SAP appears to be more sensitive for hepatobiliary disease in dogs; however, in cats, GGT has slightly greater sensitivity and perhaps greater specificity for hepatic disease except hepatic lipidosis. Therefore, it is more frequently indicated in cats than in dogs. GGT is less influenced than SAP by secondary hepatic disease conditions or enzyme-inducing drugs. The use of SAP and GGT together has a higher predictive value of hepatic disease.
Analysis
Measured in serum, urine, and body fluids by spectrophotometric methods. GGT is stable in serum at 4°C for at least 3 days and at 20°C for up to 1 year.
Normal Values and Danger Values
Same as for SAP.
Artifacts
See Introduction to Serum Chemistries.
Drug Therapy That May Affect GGT
Same as for SAP.
Causes of Decreased GGT
Not significant.
Causes of Increased GGT
Causes are similar to increased SAP and tend to parallel the magnitude of the rise in SAP, but bone lesions are not recognized to increase GGT. It is induced by glucocorticoid therapy and certain drugs, as is SAP. In cats, GGT may increase more than SAP, except in hepatic lipidosis (where classically the SAP is usually quite high, but GGT values show only a mild [or no] increase). GGT does not tend to increase after acute hepatic necrosis, as does SAP. Increased GGT should be pursued as for increased SAP (see Figure 9-8). Increased GGT may suggest pancreatitis obstructing the bile duct, as for SAP.
Causes of Increased Urine GGT
Increased 24-hour urinary excretion of GGT can be caused by various nephrotoxins (e.g., gentamicin).
LACTIC DEHYDROGENASE
Rare Indications
Disadvantages
Lack of specificity. The lactic dehydrogenase (LDH) test is not recommended.
Analysis
Measured in serum, heparinized plasma, or cerebrospinal fluid (CSF) by spectrophotometric methods.
Normal Values and Danger Values
Same as for ALT and SAP.
Causes of Decreased LDH
Not significant.
Causes of Increased LDH
LDH is found in so many body tissues that serum LDH is of questionable diagnostic value. Inexplicable increases of small to great magnitude are not uncommon.
BILE ACIDS
Frequent Indications
Suspected occult hepatic disease, chronic weight loss, abnormal CNS signs, icterus, hepatomegaly, and microhepatia; also to monitor hepatic function in patients with known hepatic diseases. Because of the ease of this test compared with BSP, ICG, and ammonia, serum bile acids are used routinely as a screening test for hepatic dysfunction.
Advantages
Ease of use, few extrahepatic factors affect it.
Disadvantages
Does not reliably distinguish among different hepatobiliary diseases. Values may change enough from day to day that it can be difficult to use the serum bile acid concentrations to determine if a change in hepatic function has or is occurring.
Analysis
Measured in serum by either a direct enzymatic method that quantifies total serum 3-alpha-hydroxylated bile acids or uses an RIA procedure that measures specific bile acids. It is important that a validated assay for dogs and cats be used because some methods are not accurate. Values for enzymatic and RIA procedures cannot be compared.
Maximum information is obtained by determining a 12-hour fasting preprandial and 2-hour postprandial concentration. Dogs and cats should be fed canned food containing moderate fat content, causing the gallbladder to contract. Preprandial and postprandial concentrations together improve the sensitivity of the test, making it more sensitive than other function tests (e.g., resting serum ammonia concentrations).
Normal Values
Because of different techniques and assays (μmol/L or μg/ml), normal values must be established for each laboratory.
Danger Values
None.
Artifacts
Very increased serum dehydrogenase activities may require modification of the spectrophotometric technique. Severe lipemia (i.e., chylomicronemia) and hemolysis may falsely decrease bile acid measurements, and hypertriglyceridemia may falsely increase concentrations when spectrophotometric techniques are used, but they do not affect RIA. This test is not indicated in icteric patients.
Drug Therapy and Other Factors That May Alter Serum Bile Acid Concentration
Cholestyramine lowers serum concentrations by binding to bile acids in the intestinal lumen, preventing their reabsorption. Ursodeoxycholic acid (a synthetic bile acid) therapy may increase total serum bile acid concentrations. Resection of the ileum (the principal site of bile acid reabsorption), severe ileal disease, or cholecystectomy may also cause serum bile acids to inaccurately reflect hepatic function. Prolonged anorexia (>1 to 2 days) may cause fasting serum bile acid concentrations to be less than would be found if the patient were eating normally. Intestinal hypomotility may cause the 2-hour postprandial sample to be a less sensitive indicator of hepatic disease because of failure to deliver the bile acids to the ileum in a timely fashion. ARE may increase total serum bile acid concentrations because of bacterial deconjugation of bile acids with subsequent increased small intestinal uptake. Hepatic insufficiency does not decrease serum bile acid concentrations.
Causes of Decreased Serum Bile Acid Concentration
Delayed gastric emptying, rapid intestinal transit, malabsorption disorders, and ileal resection may cause subnormal values. With ARE, total measurable moieties may or may not decrease, but it is expected that unconjugated serum bile acid concentrations may increase.
Causes of Increased Serum Bile Acid Concentration
Serum bile acid concentrations are increased because of hepatocellular disease, cholestatic disease, or portosystemic shunting. When both fasting and 2-hour postprandial serum bile acid levels are determined, the sensitivity of these tests becomes greater than with other hepatic function tests. Because of the ease of performing and wide availability of the test, it has replaced other clinical hepatic function tests. Serum bile acids offer no additional information in icteric patients with hepatic or extrahepatic biliary tract disease. In nonicteric patients suspected of having hepatic disease, serum bile acids are a good screening test to support further diagnostic evaluations. Not all patients with hepatic disease have increased serum bile acid concentrations, and the relative increase in bile acids is not diagnostic for the type of disease or the prognosis. Reported fasting serum bile acids that are increased greater than 20 μmol/L or postprandial values of greater than 25 μmol/L suggest significant hepatic disease or portosystemic shunting and dictate further hepatic evaluation and possibly hepatic biopsy. Generally, preprandial and postprandial bile acids are determined simultaneously; however, if only fasted values are determined and found to be normal, postprandial measurements are required. The magnitude of the rise or the percent increase from preprandial to postprandial values does not imply a specific diagnosis or prognosis. Most animals with chronic hepatitis, marked hepatic necrosis, cholestasis, and hepatic neoplasia have abnormal values. Bile acids are usually not markedly altered by secondary hepatic disease from nonhepatic disorders or with glucocorticoid or anticonvulsant therapy; however, in rare cases they may be.
Increased serum bile acids are possibly the most sensitive biochemical indicator of congenital portosystemic shunts. Almost all animals with congenital portal vascular anomalies have increased postprandial bile acids; some of the highest concentrations occur in these cases.
AMMONIA AND AMMONIA TOLERANCE TESTING (ATT)
Rare Indications
Same as for bile acids (i.e., when a sensitive function test is needed to prove hepatic disease in an animal in which easier tests do not allow diagnosis).
Advantages
Good sensitivity and specificity.
Disadvantages
Procedural requirements for submitting the samples, and the likelihood of vomiting or CNS signs with ATT.
Analysis
Measured in blood, serum, plasma (heparinized is recommended), CSF, or urine by enzymatic, selective electrode, dry reagent, and resin absorption methods. There does not appear to be any advantage of arterial over venous blood. Blood must be drawn into an ice-chilled tube, which is stoppered tightly after filling, immediately put back on ice, and promptly taken to the laboratory. A control sample should be taken at the same time using the same technique. The test must be performed within 20 minutes, or the plasma must be frozen at −20° C, which stabilizes the ammonia concentration for at least 2 days. If an ATT is to be performed, samples for ammonia determination should be taken before and 30 or 45 minutes after administration of NH4Cl, 100 mg/kg of body weight. The NH4Cl may be administered orally as a solution in 20 to 50 ml of water, as a 5% solution, as a dry powder in gelatin capsules, or rectally as a 5% solution. The use of orally administered gelatin capsules is the easiest and the least likely to result in expulsion (i.e., vomiting or defecation of the NH4Cl).
Warning: Administration of NH4Cl to patients with increased resting blood ammonia concentrations may cause encephalopathy. The clinician should not perform ATT if the patient is showing obvious encephalopathic signs. Lack of obvious encephalopathic signs does not guarantee that blood ammonia levels are normal.
Normal Values
Resting ammonia: dogs, 45 to 120 μg/dl; cats, 30 to 100 μg/dl. ATT, ammonia at 30 minutes: dogs, minimal change from normal values; cats, no change from normal values.
Danger Values
Dogs, greater than 1000 μg/dl (hepatic encephalopathy may be imminent, although poor correlation exists between clinical signs of encephalopathy and plasma ammonia concentrations); cats, unknown.
Artifacts
Falsely increased: allowing the blood to stand, strenuous exercise. See Introduction to Serum Chemistries.
Drug Therapy That May Alter Ammonia
Decreased serum ammonia may be the result of intestinal antibiotics (e.g., aminoglycosides), lactulose, Lactobacillus acidophilus cultures, enemas, and diphenhydramine. Increased serum ammonia may be the result of valproic acid, asparaginase, narcotics, diuretics causing hypokalemia or alkalosis, hyperalimentation, ammonium salts, and high-protein meals (including blood from spontaneous GI bleeding).
Causes of Hypoammonemia
Not significant.
Causes of Hyperammonemia
Urea cycle disorders (extremely rare) and hepatic insufficiency (especially congenital or acquired portosystemic shunting). Resting blood ammonia concentrations are probably less sensitive than fasting serum bile acids in detecting hepatic dysfunction, whereas the ATT is possibly as sensitive as preprandial and postprandial bile acids in detecting portosystemic shunting. A significantly increased fasting blood ammonia concentration renders an ATT unnecessary. Clinical signs are not well correlated with blood ammonia concentrations. An abnormal ATT result or resting ammonia value in a patient with hepatic disease is generally an indication for hepatic biopsy or a portogram. Rarely, plasma ammonia is increased because of urinary tract obstruction, especially if complicated by infection with urease-producing bacteria. Some young dogs (notably Scottish deerhounds in Great Britain) have been found to have elevated resting blood ammonia values that spontaneously return to normal as the dog ages. Therefore, caution must be used when diagnosing congenital portosystemic shunting in at least some breeds solely by evaluating the resting serum ammonia concentration.
CHOLESTEROL
See Chapter 8.
Go to: Regurgitation and vomiting
Go to: Weight loss, anorexia, abdominal pain
Go to: Liver enzyme interpretation Part II
Reference:
Published online 2009 May 15. doi: 10.1016/B0-72-168903-5/50014-8
Gastrointestinal, Pancreatic, and Hepatic Disorders
Michael D. Willard and David C. Twedt