COMMENTARY

Evaluating the Patient With Abnormal Liver Tests

Rowen K. Zetterman, MD

Disclosures

October 08, 2009

In This Article

Abnormal Liver Test Results

Most laboratory liver tests are not actual tests of liver function, although hepatic function can be inferred from prothrombin times (international normalized ratio), albumin levels, bilirubin, and other tests that result from synthesis (eg, factor V levels) within the liver. Aminotransferases, alkaline phosphatase, and GGT are enzymes that are released during injury to liver cells or bile ducts. Lactate dehydrogenase (LDH) is not a reliable liver test but can be significantly elevated during ischemic injury, Epstein-Barr virus infection (infectious mononucleosis), liver disease associated with hemolysis, and solid tumors or rapidly growing lymphomas.[14,15]

Liver tests can be used to screen for liver disease, confirm suspected liver disease, assist in differential diagnosis of liver disease, monitor the progression of liver disease, and monitor the progress of specific therapies. Other tests that may be helpful in diagnosis include mean corpuscular volume and serum uric acid levels because both can be elevated by alcohol consumption. Leukopenia and thrombocytopenia (which may result from hypersplenism associated with portal hypertension), and peripheral eosinophilia occur in some patients with autoimmune hepatitis and drug-induced hepatitis. Table 2 summarizes liver test abnormalities and possible associated conditions. (All liver tests except albumin are abnormal when elevated.)

Table 2. Common Liver Tests and Associated Conditions

Liver Test Abnormal in...
Albumin Cirrhosis, severe hepatocellular injury
Alkaline phosphatase Cholestasis, hepatocellular enzyme induction, canalicular injury, children during bone growth, bone disease, pregnancy (placenta origin)
Aminotransferases (AST, ALT) Hepatocellular injury (ethanol, drug-induced hepatitis, hepatitis B and C, ischemic injury, chronic liver disease, NAFLD, chronic viral hepatitis, alcoholism, nonspecific viral injury, and cholestatic or replacement disease); acute biliary obstruction; rarely in hyperthyroidism, celiac disease, skeletal muscle disease
Bilirubin Any acute or chronic liver disease; congenital disorders of bilirubin metabolism.
5′ nucleotidase Cholestasis
GGT Cholestasis; medications, ethanol; rarely anorexia nervosa, hyperthyroidism, myotonic dystrophy
INR Impaired synthesis of vitamin K-dependent coagulation factors
Lactate dehydrogenase Ischemic injury, Epstein-Barr virus infection, hemolysis, solid tumor
MCV Alcohol consumption, folic acid and B12 deficiency
Uric acid Alcohol consumption, gout
ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma glutamyltransferase; INR = international normalized ratio; MCV = mean corpuscular volume; NAFLD = nonalcoholic fatty liver disease
All liver tests except albumin are abnormal when elevated.

Aminotransferases

Aminotransferases are used to detect and monitor the progression and resolution of hepatocellular injury.[16] Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels may be elevated in 8%-21% of patients.[1,3] Elevations are more common in non-Hispanic blacks and Mexican Americans than in non-Hispanic whites, are more common in persons 30-40 years of age, decrease in likelihood after age 60 years, and are associated with hepatocellular injury from ethanol, medications, hepatitis B or C viruses, and, occasionally, chronic underlying liver diseases such as hemochromatosis.[17]

In most patients, an isolated aminotransferase elevation will be unexplained. Marked elevations of aminotransferases occur from viral infection, ischemic liver injury, and drug-induced liver disease, and a careful history and physical examination should assist in making a diagnosis. Moderate elevations occur in patients with autoimmune hepatitis and some patients with cirrhosis. Minimal elevations of aminotransferases are more frequent in NAFLD, chronic viral hepatitis, alcoholism, nonspecific viral injury, and cholestatic or replacement disease.[18]

The ratio of AST to ALT may indicate alcoholic liver disease when greater than 2:1.[19] Other considerations for aminotransferase elevation include Wilson's disease, celiac disease, and hyperthyroidism. Injury to other tissues containing aminotransferases, such as skeletal muscle, can cause an elevation of AST.

Cholestasis

Laboratory tests for cholestasis include GGT, alkaline phosphatase, and 5′ nucleotidase, of which GGT and alkaline phosphatase are most widely used.[16] These enzymes are elevated in hepatobiliary diseases, including abnormalities of either the canaliculus or the intrahepatic and extrahepatic bile ducts and in replacement disease from hepatic tumors or granulomas.[20] Hepatobiliary diseases include partial biliary tract obstruction from stones, pancreatitis, parasitic disease, acute cholecystitis, and papillary dysfunction. With biliary disorders, the tests may fluctuate in value, suggesting intermittent or partial blockage.

Acute biliary tract obstruction from stones can be associated with aminotransferase levels > 500 U/L with normal or mildly elevated alkaline phosphatase levels.[21] Medications such as ethanol, phenytoin, anabolic steroids, and major tranquilizers can also increase GGT and alkaline phosphatase levels due to hepatocellular enzyme induction or canalicular injury and cholestasis. Other considerations include primary biliary cirrhosis, sclerosing cholangitis, alcoholic liver disease, ductopenic syndromes, AIDS cholangiopathy, parenteral nutrition, and postoperative cholestasis. GGT may also be elevated with anorexia nervosa, hyperthyroidism, myotonic dystrophy, obesity, and diabetes mellitus.[22]

Isolated GGT elevations occur, and if other liver test results are normal and no ethanol or medication use is evident, additional workup can generally be delayed. Isolated alkaline phosphatase elevation occurs from bone disease, bone growth in children, and the placenta during pregnancy. GGT levels should be normal in these conditions. Additional evaluation of patients suspected of having cholestasis should include a careful history and physical examination and ultrasonography of the biliary tree or magnetic resonance cholangiography, and endoscopic retrograde cholangiography or liver biopsy when needed.

Hyperbilirubinemia

Bilirubin elevation can develop in any acute or chronic liver disease. Congenital disorders of hyperbilirubinemia are generally classified as unconjugated or conjugated depending on whether the indirect fraction or direct fraction of bilirubin is dominant.[18] Unconjugated syndromes include Gilbert's (a hepatocyte bilirubin uptake alteration) and Crigler-Najjar's (glucuronyl transferase deficiency). Conjugated syndromes include Dubin-Johnson's and Rotor's, both related to impairment of hepatocyte bilirubin secretion. Unconjugated hyperbilirubinemia also occurs with hemolysis and ineffective erythropoiesis. A direct bilirubin fraction >0.4 mg/dL should prompt an evaluation for hepatobiliary disease, hemolysis, or a congenital disorder of bilirubin metabolism.

Hemolysis may be identified by unconjugated hyperbilirubinemia coupled with reticulocytosis and can occur with acute and chronic liver diseases, such as Wilson's disease, autoimmune hepatitis, alcoholic hepatitis, and drug-induced liver disease. Abnormal liver tests will develop in 3%-7% of women during pregnancy and are seen in all pregnancy-related liver disorders.[23] Hyperemesis gravidarum is most frequently associated with abnormal liver test results. Elevated liver test results may also be associated with preeclampsia, including the HELLP syndrome (hemolysis, elevated liver tests, and thrombocytopenia), acute fatty liver of pregnancy (liver failure with coagulopathy and encephalopathy), and cholestasis of pregnancy.[24]

Additional laboratory evaluation depends on suspected underlying causes, such as hepatitis viruses (most commonly hepatitis B or C virus), iron overload syndromes (transferrin saturation and HFE testing), Wilson's disease (ceruloplasmin), autoimmune disorders (antinuclear and smooth muscle antibodies), alpha-1 antitrypsin deficiency (protease inhibitor type), or hepatocellular carcinoma (alpha-fetoprotein).

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