The New England Journal of Medicine Primary Care recommend adjusting aminotransferase values for sex and body-mass index,2 but these adjustments are rare- ly made. Aspartate aminotransferase is found, in de- creasing order of concentration, in the liver, cardiac EVALUATION OF ABNORMAL muscle, skeletal muscle, kidneys, brain, pancreas, lungs, LIVER-ENZYME RESULTS IN leukocytes, and erythrocytes. The highest level of ASYMPTOMATIC PATIENTS alanine aminotransferase is in the liver, and levels of this enzyme are accordingly more specific indicators of liver injury. Both enzymes are released into the DANIEL S. PRATT, M.D., AND MARSHALL M. KAPLAN, M.D. blood in increasing amounts when the liver cell mem- brane is damaged. Necrosis of liver cells is not re- quired for the release of the aminotransferases. In OW that routine laboratory testing is auto- fact, there is poor correlation between the degree of mated and is frequently part of an annual liver-cell damage and the level of the aminotransfer- checkup, physicians are often faced with the ases.1 If the aminotransferase levels are normal on re- N testing, no further evaluation is necessary. If the results problem of a patient with one abnormal result on measurement of serum aminotransferases or alkaline of repeated tests remain abnormal, further evaluation phosphatase but no symptoms. Many batteries of is indicated. screening tests now include measurement of serum The first step in the evaluation is to obtain a com- alanine aminotransferase, aspartate aminotransferase, plete history in an effort to identify the most com- alkaline phosphatase, and g-glutamyltransferase. Al- mon causes of elevated aminotransferase levels: alco- though these enzymes are present in tissues through- hol-related liver injury, chronic hepatitis B and C, out the body, they are most often elevated in pa- autoimmune hepatitis, hepatic steatosis (fatty infiltra- tients with liver disease and may reflect liver injury. tion of the liver), nonalcoholic steatohepatitis, hemo- The first step in the evaluation of a patient with chromatosis, Wilson’s disease, alpha1-antitrypsin de- elevated liver-enzyme levels but no symptoms is to ficiency, and a recently recognized cause, celiac sprue repeat the test to confirm the result. If the result is (Table 1). Table 2 lists the blood tests that can be still abnormal, the physician should evaluate the de- used to identify many of these disorders. It is more gree of the elevation. A minor elevation (less than efficient to order all the blood tests in the first group twice the normal value) may be of no clinical impor- initially, unless the history strongly suggests a defi- tance if the disorders listed in Table 1 have been nite diagnosis, such as alcohol abuse. The cause of ruled out and, in fact, may not even be abnormal. the aminotransferase elevation can usually be identi- The normal range for any laboratory test is the mean fied on assessment of the pattern of the results of liv- value in a group of healthy persons ±2 SD. Thus, er-enzyme tests and additional testing. 5 percent of the results obtained from these normal The cause of an elevated alanine aminotransferase persons fall outside the defined normal range, 2.5 level varies greatly depending on the population stud- percent of which may be above the upper limit of ied. Among 19,877 Air Force trainees who volun- normal. There are also circumstances in which ele- teered to donate blood, 99 (0.5 percent) had elevat- vations in liver-enzyme levels are physiologic; for ex- ed alanine aminotransferase levels.3 A cause for the ample, alkaline phosphatase levels are increased in elevation was found in only 12: 4 had hepatitis B, healthy women during the third trimester of preg- 4 had hepatitis C, 2 had autoimmune hepatitis, 1 had nancy. The evaluation of the patient with an isolated cholelithiasis, and 1 had acute appendicitis. In a group elevation of an aminotransferase differs from that for of 100 consecutive blood donors with elevated ala- a patient with an isolated elevation of alkaline phos- nine aminotransferase levels, 48 percent had changes phatase or g-glutamyltransferase. related to alcohol use, 22 percent had fatty liver, 17 percent had hepatitis C, 4 percent had another iden- AMINOTRANSFERASE LEVELS tified problem, and in the remaining 9 percent, no Aminotransferase levels are sensitive indicators of specific diagnosis was made.4 In another study of liver-cell injury and are helpful in recognizing hepa- 149 asymptomatic patients with elevated alanine ami- tocellular diseases such as hepatitis.1 Both aminotrans- notransferase levels who underwent liver biopsy, 56 ferases are normally present in serum at low levels, usu- percent had fatty liver, 20 percent had non-A, non- ally less than 30 to 40 U per liter. The normal range B hepatitis, 11 percent had changes related to alco- varies widely among laboratories. Some researchers hol use, 3 percent had hepatitis B, 8 percent had other causes, and in 2 percent, no cause was identi- fied.5 A recent study assessed 1124 consecutive pa- tients who were referred for chronic elevations in ami- From New England Medical Center, Box 217, 750 Washington St., Bos- 6 ton, MA 02111, where reprint requests should be addressed to Dr. Pratt. notransferase levels. Eighty-one of these patients had ©2000, Massachusetts Medical Society. no definable cause of the elevation and underwent a 1266 · April 27, 2000 Downloaded from www.nejm.org at COLUMBIA UNIV HEALTH SCIENCES LIB on August 3, 2009 . Copyright © 2000 Massachusetts Medical Society. All rights reserved. PRIMARY CARE CAUSES OF ELEVATED TABLE 1. CAUSES OF CHRONICALLY ELEVATED AMINOTRANSFERASE LEVELS AMINOTRANSFERASE LEVELS. Alcohol Abuse Hepatic causes The diagnosis of alcohol abuse can be difficult be- Alcohol abuse Medication cause many patients conceal information about their Chronic hepatitis B and C alcohol use. The diagnosis is supported by the find- Steatosis and nonalcoholic steatohepatitis Autoimmune hepatitis ing of a ratio of aspartate aminotransferase to alanine Hemochromatosis aminotransferase of at least 2:1. In a study of hun- Wilson’s disease (in patients «40 years old) dreds of patients who had histologically confirmed Alpha -antitrypsin deficiency 1 liver disorders, more than 90 percent of the patients Nonhepatic causes who had an aspartate aminotransferase:alanine ami- Celiac sprue Inherited disorders of muscle metabolism notransferase ratio of at least 2:1 had alcoholic liver Acquired muscle diseases disease.7 The percentage increased to more than 96 Strenuous exercise percent when the ratio was greater than 3:1. The in- creased ratio reflects primarily the low serum activity of alanine aminotransferase in patients with alcohol- ic liver disease. This decrease is due to an alcohol- related deficiency of pyridoxal 5-phosphate.8 Measurement of g-glutamyltransferase may also be helpful in diagnosing alcohol abuse. A g-glutamyl- TABLE 2. LABORATORY TESTS THAT MAY IDENTIFY THE CAUSE OF ELEVATED AMINOTRANSFERASE LEVELS IN A PATIENT transferase level that is twice the normal level in pa- WITH NO SYMPTOMS. tients with an aspartate aminotransferase:alanine ami- notransferase ratio of at least 2:1 strongly suggests the diagnosis of alcohol abuse. However, the lack of TEST DIAGNOSIS specificity of the g-glutamyltransferase level precludes Initial tests its use as a single test to diagnose alcohol abuse. Test for hepatitis C antibody in Presence of hepatitis C antibody indi- The degree of elevation of aminotransferase levels serum cates chronic hepatitis C Test for hepatitis B surface anti- Presence of hepatitis B surface antigen may also be helpful in identifying alcohol abuse. It gen, surface antibody, and and core antibody indicates chronic is rare for the aspartate aminotransferase level to be core antibody in serum hepatitis B Measurement of serum iron and Iron overload suggests hemochroma- more than eight times the normal value in patients total iron-binding capacity tosis with alcohol abuse, and it is even less common for Measurement of serum cerulo- Decreased ceruloplasmin levels suggest the alanine aminotransferase level to be more than plasmin Wilson’s disease (if patient is «40 7 years old) five times the normal value in such patients. In fact, Serum protein electrophoresis Increase in polyclonal immunoglobu- the alanine aminotransferase level may be normal, even lins suggests autoimmune hepatitis in patients with severe alcoholic liver disease. Serum protein electrophoresis Marked decrease in a-globulin bands suggests alpha1-antitrypsin deficiency Medication Additional tests* Reverse-transcriptase polymer- Presence of viral RNA indicates chronic A careful history-taking and meticulous review of ase chain reaction for hepati- hepatitis C laboratory data are critical for identifying a medica- tis C virus RNA Alpha1-antitrypsin phenotyping Presence of the ZZ phenotype indicates tion as the cause of elevated aminotransferase levels. alpha1-antitrypsin deficiency A drug effect is a possibility if the increase in liver- Tests for antiendomysial and an- Presence of antibodies indicates celiac tigliadin antibodies in serum sprue enzyme levels was associated with the initiation of a Measurement of creatine kinase Elevated enzyme levels indicate dis- medication. Almost any medication can cause an el- and aldolase orders of striated muscle evation in liver-enzyme levels. Common ones include *If the results of the initial set of tests are normal, these additional tests nonsteroidal antiinflammatory drugs, antibiotics, an- may pinpoint the cause. tiepileptic drugs, inhibitors of hydroxymethylglutar- yl–coenzyme A reductase, and antituberculosis drugs (Table 3). In addition to medications, herbal prepa- rations and illicit drugs or substances may cause el- evations in liver-enzyme levels (Table 3). liver biopsy. Of these 81 patients, 41 had steatosis, The easiest way to determine whether a medica- 26 had steatohepatitis, 4 had fibrosis, 2 had cirrho- tion is responsible for the elevation is to stop treat- sis, and 8 had normal histologic findings. The pa- ment and see whether the test results return to nor- tients with histologic evidence of fibrosis and cirrho- mal.