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Mildly Elevated Liver Transaminase Levels in the Asymptomatic Patient PAUL T

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Mildly Elevated Liver Transaminase Levels in the Asymptomatic Patient PAUL T Mildly Elevated Liver Transaminase Levels in the Asymptomatic Patient PAUL T. GIBONEY, M.D., Keck School of Medicine, University of Southern California, Los Angeles, California Mild elevations in liver chemistry tests such as alanine transaminase and aspartate transaminase can reveal serious underlying conditions or have transient and benign etiologies. Potential causes of liver transaminase elevations include viral hepatitis, alcohol use, medica- tion use, steatosis or steatohepatitis, and cirrhosis. The history should be thorough, with special attention given to the use of medications, vitamins, herbs, drugs, and alcohol; family history; and any history of blood-product transfusions. Other common health conditions, such as diabetes, heart disease, and thyroid disease, can cause or augment liver transaminase elevations. The recent American Gastroenterologi- cal Association guideline regarding the evaluation and management of abnormal liver chemistry tests proposes a practical, algorithmic approach when the history and physical examination do not reveal the cause. In addition to liver chemistries, an initial serologic evalu- ILLUSTRATION BY TODD BUCK ation includes a prothrombin time; albumin; complete blood count with platelets; hepatitis A, B, and C serologies; and iron studies. Depending on the etiology, management strategies may include cessation of alcohol use, attention to medications, control of diabetes, and modification of lifestyle fac- tors such as obesity. If elevations persist after an appropriate period of observation, further testing may include ultra- sonography and other serum studies. In some cases, biopsy may be indicated. (Am Fam Physician 2005;71:1105-10. Copyright© 2005 American Academy of Family Physicians.) epatic transaminase tests such as who have more patients with obesity, diabe- alanine transaminase (ALT) and tes, and hyperlipidemia will have to address aspartate transaminase (AST) this issue more often. often are part of standard labo- Given the frequency of this problem, physi- H ratory panels in asymptomatic outpatients, cians should develop an informed approach to similar to screening tests for blood donors the investigation of transaminase elevations. and for life insurance applicants. The evalu- An audit of primary care practices found that ation of an abnormal ALT or AST level in these abnormalities are not always investi- an asymptomatic patient therefore is a com- gated appropriately and that opportunities mon challenge encountered by primary care to intervene in treatable cases sometimes are physicians. missed.3 No controlled clinical trials have According to the American Gastroen- compared approaches to the management of terological Association (AGA), 1 to 4 percent abnormal transaminase levels. However, the of the asymptomatic population may have AGA recently published a technical review1 elevated serum liver chemistries.1 This is and a position statement4 on the evaluation consistent with the usual definition of an of liver chemistry tests. This article reviews elevated transaminase level of the interpretation of ALT and AST levels and the top 2.5 percent of the pop- summarizes the AGA recommendations on Up to 4 percent of the ulation range. Although one addressing reported elevations. asymptomatic population study2 of 19,877 asymptom- may have elevated serum atic young Air Force trainees Markers of Hepatic Injury and Necrosis liver chemistries. found that only 0.5 percent had ALT and AST are two of the most reliable elevated ALT levels, physicians markers of hepatocellular injury or necrosis. March 15, 2005 ◆ Volume 71, Number 6 www.aafp.org/afp American Family Physician 1105 Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright© 2005 American Academy of Family Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. Strength of Recommendations TABLE 1 Etiology of ALT or AST Elevations Key clinical recommendation Label References When Less Than Five Times Normal An algorithmic approach to evaluating mildly C 1 Common hepatic causes abnormal liver functions is recommended. Alcohol In the asymptomatic patient with negative serum C 1 Cirrhosis testing and mild transaminase elevations, a period of lifestyle modification can be tried. Hepatitis B (chronic) If abnormalities persist at the six-month follow- C 1 Hepatitis C (chronic) up visit, an ultrasonography of the liver is the Steatosis/steatohepatitis recommended imaging modality. Medications/toxins ALT and AST are not useful screening tests in an C 1, 10 Acute viral hepatitis otherwise healthy population. Less common hepatic causes The AST/ALT ratio is only somewhat helpful in C 5, 7 Autoimmune hepatitis diagnosis. Hemochromatosis ALT = alanine transaminase; AST = aspartate transaminase. Alpha1-antitrypsin deficiency Wilson’s disease A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited- quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual Nonhepatic causes practice, opinion, or case series. See page 1046 for more information. Celiac disease Hemolysis Myopathy Their levels can be elevated in a variety of Hyperthyroidism hepatic disorders. Of the two, ALT is thought Strenuous exercise to be more specific for hepatic injury because Macro-AST it is present mainly in the cytosol of the liver ALT = alanine transaminase; AST = aspartate trans- and in low concentrations elsewhere. AST aminase. has cytosolic and mitochondrial forms and Adapted with permission from Pratt DS, Kaplan MM. is present in tissues of the liver, heart, skel- Evaluation of abnormal liver-enzyme results in asymp- etal muscle, kidneys, brain, pancreas, and tomatic patients. N Engl J Med 2000;342:1267, with additional information from reference 5. lungs, and in white and red blood cells. AST is less commonly referred to as serum glu- tamic oxaloacetic transaminase and ALT as serum glutamic pyruvic transaminase. mary care medicine. The range of possible Although levels of ALT and AST can be etiologies at this level of transaminase eleva- extremely elevated (exceeding 2,000 U per L tion is broader (Table 15,6) and the tests less in cases of hepatocyte injury and necro- specific. It also is important to recall that sis related to drugs, toxins, ischemia, and patients with normal ALT and AST levels hepatitis), elevations less than five times the can have significant liver disease in the set- upper limit of normal (i.e., about 250 U per L ting of chronic hepatocyte injury (e.g., cir- and below) are much more common in pri- rhosis, hepatitis C). The ratio of AST to ALT has some clinical utility, but has important limitations. In many The Author forms of acute and chronic liver injury or ste- PAUL T. GIBONEY, M.D., is assistant professor of clinical family medicine at the atosis (fatty infiltration of the liver), the ratio Keck School of Medicine, University of Southern California, Los Angeles. He is less than or equal to 1. This is particularly received his medical degree from Northwestern University School of Medicine, true in patients with hepatitis C. However, an Chicago, and completed a residency in family medicine at John Peter Smith AST/ALT ratio greater than 2 characteristically Hospital, Fort Worth, Tex. is present in alcoholic hepatitis. A recent study7 Address correspondence to Paul T. Giboney, M.D., 123 S. Alvarado St., Los of 140 patients with nonalcoholic steatohepa- Angeles, CA 90057. Reprints are not available from the author. titis (NASH; confirmed by liver biopsy) or 1106 American Family Physician www.aafp.org/afp Volume 71, Number 6 ◆ March 15, 2005 Elevated Transaminase Levels alcoholic liver disease found a mean AST/ALT and fatty liver disease in male ALT is thought to be more ratio of 0.9 in patients with NASH and 2.6 in bank employees and found the specific than AST for patients with alcoholic liver disease. Within positive predictive value of the hepatic injury because it is the population studied, 87 percent of patients test to be low. Only 3.9 percent present mainly in the cyto- with an AST/ALT ratio of 1.3 or less had NASH of the men with an abnormal sol of the liver and in low (87 percent sensitivity, 84 percent specific- ALT level had hepatitis C; 8 concentrations elsewhere. ity). The severity of NASH as measured by percent were excessive users of the degree of fibrosis increased, as did the alcohol; and 35.7 percent had AST/ALT ratio. A mean ratio of 1.4 was found fatty liver. in patients with cirrhosis related to NASH. Wilson’s disease, a rare problem, can cause the Management AST/ALT ratio to exceed 4.5 While these ratios A thorough medical history and physi- are suggestive of certain conditions, there is cal examination are the cornerstone of the too much overlap between groups to rely on evaluation of patients with mildly elevated them exclusively when making a diagnosis. liver transaminase levels.1 The history should Lactate dehydrogenase (LDH) is a less spe- attempt to identify risk factors for disease, cific marker of hepatocellular necrosis and with special attention directed toward fam- usually does not add diagnostic information ily history, medications, vitamins, herbal to that obtained with ALT and AST testing. supplements, drug use, alcohol use, abnor- An exception to this is the transient but mas- mal liver testing, blood-product transfusions, sive rise of LDH in cases of ischemic hepatitis and symptoms of liver disease. Table 26 lists and its sustained elevation that, along with selected medications and herbal supplements elevated alkaline phosphatase levels, suggests that may cause elevated transaminase lev- malignant infiltration of the liver.5 els. Physicians should ask patients directly Elevations of ALT and AST are not exclu- about their use of illicit drugs, herbal supple- sive to liver pathology. Hyperthyroidism has ments, and other alternative “supplements” been found in several studies to increase serum levels of liver enzymes including ALT TABLE 2 and AST.8 Genetic influences on the level of 9 Common Agents That Can Cause Liver Transaminase ALT also are possible.
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