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Subject: Enzyme Tests that Detect Cholestasis (ALP, 5'-Nucleotidase, GGT, LAP)
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ALP refers to a group of enzymes that catalyze the hydrolysis of a large number of organic phosphate esters at an alkaline pH optimum. The major value of the serum ALP in the diagnosis of liver disorders is in the recognition of cholestatic disease. However, an elevation in the ALP concentration is a relatively common finding and does not always indicate the presence of hepatobiliary disease. The degree of elevation does not distinguish between intra- and extrahepatic cholestasis. Elevations in serum 5ʹ-nucleotidase are seen in the same types of hepatobiliary diseases associated with an increased serum ALP. Most studies suggest that serum ALP and 5ʹ-nucleotidase are equally valuable in demonstrating biliary obstruction or hepatic infiltrative and space-occupying lesions. Elevated serum levels of gamma-glutamyl transpeptidase (GGT) are found in diseases of the liver, biliary tract, and pancreas, and reflect the same spectrum of hepatobiliary disease as ALP, 5ʹ-nucleotidase, and leucine aminopeptidase. Serum GGT and ALP correlate reasonably well. There are conflicting data as to whether serum GGT has better sensitivity for hepatobiliary disease than ALP or leucine aminopeptidase.
Increased ALP in liver diseases (due to increased synthesis from proliferating bile duct epithelium) is the best indicator of biliary obstruction but does not differentiate intrahepatic cholestasis from extrahepatic obstruction. In cholestasis, ALP level is increased out of proportion to other liver function tests.
Increases before jaundice occurs.
High values (greater than five times normal) favor obstruction and normal levels virtually exclude this diagnosis.
Markedly increased in infants with congenital intrahepatic bile duct atresia but is much lower in extrahepatic atresia.
Increased 10 times normal: carcinoma of the head of the pancreas, choledocholithiasis, and drug cholestatic hepatitis.
Fifteen to twenty times increase: primary biliary cirrhosis, primary or metastatic carcinoma.
Increase (3–10 times normal) with only slightly increased transaminases may be seen in biliary obstruction and converse in liver parenchymal disease (e.g., cirrhosis, hepatitis); increased greater than three times normal in <5% of acute hepatitis.
Increased (2–10 times normal; usually 1.5–3 times increase) serum ALP and LD in early infiltrative (e.g., amyloid) and space-occupying diseases of the liver (e.g., tumor, granuloma, abscess).
Increase less than three to four times normal is nonspecific and may occur in all types of liver diseases (e.g., congestive heart failure, infiltrative liver diseases, cirrhosis, acute [viral, toxic, alcoholic] or chronic hepatitis, acute fatty liver).
Increased five times normal: infectious mononucleosis, postnecrotic cirrhosis.
Increased ALP (of liver origin) and LD with normal serum bilirubin, AST, and ALT suggest obstruction of one hepatic duct or metastatic or infiltrative disease of the liver.
GGT/ALP ratio >5 favors alcoholic liver disease.
Isolated increase of GGT is a sensitive screening and monitoring test for alcoholism. Increased GGT due to alcohol or anticonvulsant drugs is not accompanied by increased ALP.
Serum 5′-nucleotidase (5′-N) and LAP parallel the increase in ALP in obstructive type of hepatobiliary disease, but the 5′-N is increased only in the latter and is normal in pregnancy and bone disease, whereas the LAP is increased in pregnancy but is usually normal in bone disease. GGT is normal in bone disease and pregnancy. Therefore, these enzymes are useful in determining the source of increased serum ALP. Although serum 5′-N usually parallels ALP in liver disease, it may not increase proportionately in individual patients.
Bilirubin (“bile”) in urine implies increased serum conjugated bilirubin and excludes hemolysis as the cause. Often precedes clinical icterus. May occur without jaundice in anicteric or early hepatitis, early obstruction, or liver metastases. (Tablets detect 0.05–0.1 mg/dL; dipsticks are less sensitive; test is negative in normal persons.)
Complete absence of urine urobilinogen strongly suggests complete bile duct obstruction; is normal in incomplete obstruction and decreased in some phases of hepatic jaundice. Increased in hemolytic jaundice and subsiding hepatitis. Increase may evidence hepatic damage even without clinical jaundice (e.g., some patients with cirrhosis, metastatic liver disease, congestive heart failure). Presence in viral hepatitis depends on the phase of disease (normal is <1 mg or 1 Ehrlich U/2-hour specimen).