From Medscape Gastroenterology
Evaluating the Patient With Abnormal Liver Tests
Rowen K. Zetterman, MD
The signs and symptoms of potential liver disease are often encountered in clinical practice. The 42-year-old asymptomatic man with an aspartate aminotransferase level of 96 U/L, the 35-year-old woman with itching and an alkaline phosphatase level of 182 U/L, and the obese woman with right-upper-quadrant pain and minimal aminotransferase elevation may all show up in the busy office of the primary care physician. These patients require further evaluation, and some may need a gastroenterology consultation.
Abnormal liver test results are also common, with or without further evidence of liver disease. Aminotransferase elevation occurs in approximately 8% of Americans, with men (9.3%) more likely to have abnormalities than women (6.6%).[1-3] Men (especially Native American men) are also more likely to have underlying chronic liver disease, including hepatitis C with or without alcoholic liver disease, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), and hepatitis B.[5,6] NAFLD is often the most likely diagnosis when abnormal liver tests are encountered in adults in the absence of overt signs of advanced liver disease.
Patients with abnormal liver tests pose clinical challenges in diagnosis. The presence of elevated aminotransferase and gamma glutamyltranspeptidase (GGT) serum levels can indicate a greater likelihood of finding a cause for the liver injury. In the absence of signs of chronic liver disease, factors such as ethanol, medications, nutritional issues, female sex, or NAFLD will account for most causes of abnormal liver test results.[9,10]
If there are no physical signs of chronic liver disease in patients with mild increases of aminotransferase or alkaline phosphatase, it may be best to simply retest the patient in 3-5 months. If more than 1 liver test result is abnormal or test values are moderately or markedly elevated, the patient should be evaluated immediately. A careful history and physical examination coupled with a thoughtful laboratory and radiologic evaluation will often provide a likely diagnosis.
History and Physical Examination
The symptoms of liver disease are nonspecific. Anorexia, nausea and vomiting, fever and chills, right-upper-quadrant pain, dark urine and light-colored stools, or alteration of taste for cigarettes (suggesting acute hepatitis) may be present. Dry mouth and dry eyes are associated with autoimmune disorders such as primary biliary cirrhosis, and pruritus develops with intrahepatic cholestasis or extrahepatic biliary blockage. In advanced liver disease, symptoms of confusion and disorientation may indicate hepatic encephalopathy. A history of illicit or prescribed medications, ethanol use, tattoos (especially self-administered), multiple sexual partners, and travel to endemic areas can raise questions of drug-induced or chronic viral hepatitis. The presence of type 2 diabetes mellitus, hypertension, or hyperlipidemia can suggest NAFLD.
Table 1 summarizes signs that may suggest underlying liver disease and associated conditions.
Table 1. Signs of Liver Disease and Related Conditions
Physical Sign Possible Condition
Jaundice, spider angiomata Cirrhosis
Hyperpigmentation Primary biliary cirrhosis
Cutaneous excoriations Cholestasis
Dupuytren's contractures Alcoholism
White nails, clubbing Cirrhosis
Xanthomata, xanthelasma Primary biliary cirrhosis
Obesity, increased waist circumference Nonalcoholic fatty liver disease
Kayser-Fleischer corneal rings Wilson's disease
Parotid enlargement Alcoholic liver disease
Signs of congestive heart failure: jugular venous distention, right pleural effusion, S3 gallop Cardiac cirrhosis
Gynecomastia, testicular atrophy Cirrhosis
Peripheral edema, signs of ascites, hepatosplenomegaly, caput medusa Cirrhosis
Arterial bruit heard over the liver Hepatocellular carcinoma, alcoholic hepatitis, arteriovenous malformation (rare)
Age and Chronic Liver Disorders in Adults
Chronic liver disorders tend to group within specific age ranges. In the teenage years, Wilson's disease and autoimmune hepatitis are the most prevalent chronic liver diseases. During the twenties, Wilson's disease continues to present as liver disease up to the age of 25 years, and autoimmune hepatitis and chronic viral hepatitis also occur. In the 30-year age group, chronic viral hepatitis and primary biliary cirrhosis (90% are women) are likely. During the forties and fifties, primary biliary cirrhosis remains prevalent in women and alcoholic hepatitis, chronic viral hepatitis, and hemochromatosis occur in men.
After age 60 years, hemochromatosis will also be found in women and alpha-1 antitrypsin deficiency and cryptogenic cirrhosis become more common in both sexes. Drug-induced liver disease can be found at any age, although it is more common in older adults. Primary sclerosing cholangitis may also occur at any age, although it tends to occur in men in their twenties and thirties. NAFLD coupled with metabolic syndrome and occasionally alpha-1 antitrypsin deficiency occurs at any age.
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 are used to detect and monitor the progression and resolution of hepatocellular injury. 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.
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.
The ratio of AST to ALT may indicate alcoholic liver disease when greater than 2:1. 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.
Laboratory tests for cholestasis include GGT, alkaline phosphatase, and 5′ nucleotidase, of which GGT and alkaline phosphatase are most widely used. 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. 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. 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.
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.
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. 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. 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.
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).
Abnormal Liver Test Results: Points for Clinical Practice
1. Abnormal liver test results will be identified in 8%-20% of patients during clinical care.
2. Most patients with abnormal liver test results should have additional evaluation. A referral to the gastroenterologist may be needed.
3. A careful history and physical examination frequently provide the diagnosis, obviating the need for invasive testing.
4. If there are signs or symptoms of chronic liver disease, considering the patient's age may assist in the diagnosis.
5. Isolated elevation of GGT occurs and a cause may not be identified.
6. The presence of multiple abnormal test results makes significant liver disease more likely.
7. Aminotransferase, alkaline phosphatase, and GGT levels can be elevated from causes other than liver disease.
8. Persisting abnormalities of aminotransferases or enzymes of cholestasis should be further evaluated because up to two thirds will have a diagnosis requiring follow-up or intervention.
9. Supplemental testing with additional laboratory tests, ultrasonography, or magnetic resonance cholangiography should be considered when the diagnosis is unclear or confirmation of liver disease diagnosis is required.
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Authors and Disclosures
Rowen K. Zetterman, MD
Professor of Internal Medicine, University of Nebraska, Omaha; Clinical Professor of Medicine, Creighton University, Omaha, Nebraska
Disclosure: Rowen K. Zetterman, MD, has disclosed no relevant financial relationships.
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