Correspondence

Elevated Liver Enzymes in Asymptomatic Patients

N Engl J Med 2000; 343:662-663August 31, 2000

Article

To the Editor:

In their useful review of liver-enzyme elevations in asymptomatic patients, Pratt and Kaplan (April 27 issue)1 do not mention liver-enzyme elevations due to occupationally associated hepatic injury, although toluene in glues and trichloroethylene and chloroform are listed as substances of abuse in Table 3 of their article. Chlorinated hydrocarbon solvents are workplace toxins that have been important historically because of carbon tetrachloride and related compounds. However, a wide variety of chemical agents have led to outbreaks of disease in more recent years, including dimethylformamide2 (used in textile coatings), hydrazine and derivatives3 (used in jet and rocket fuels), 2-nitropropane4 (a solvent contained in sealant mixes), and hydrochlorofluorocarbons 5 (used as substitutes for ozone-depleting chlorofluorocarbon coolants). Occupational exposure, especially to solvents, may lead to nonalcoholic fatty changes, in addition to chemically induced hepatocellular necrosis and, much less frequently, cholestatic liver disease.6 Given the widespread use of solvents and other hepatotoxins, some unexplained cases of liver-enzyme elevations may in fact be due to work-related exposure to chemicals.

Paul D. Blanc, M.D., M.S.P.H.
University of California, San Francisco, San Francisco, CA 94143-0924

Carrie A. Redlich, M.D., M.P.H.
Yale University, New Haven, CT 06510-2499

6 References

1. 1

   Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 2000;342:1266-1271
   Full Text | Web of Science | Medline

2. 2

   Redlich CA, Beckett WS, Sparer J, et al. Liver disease associated with occupational exposure to the solvent dimethylformamide. Ann Intern Med 1988;108:680-686
   Web of Science | Medline

3. 3

   Petersen P, Bredahl E, Lauritsen O, Laursen T. Examination of the liver in personnel working with liquid rocket propellant. Br J Ind Med 1970;27:141-146
   Medline

4. 4

   Harrison R, Letz G, Pasternak G, Blanc P. Fulminant hepatic failure after occupational exposure to 2-nitropropane. Ann Intern Med 1987;107:466-468
   Web of Science | Medline

5. 5

   Hoet P, Graf LM, Bourdi M, et al. Epidemic of liver disease caused by hydrochlorofluorocarbons used as ozone-sparing substitutes of chlorofluorocarbons. Lancet 1997;350:556-559
   CrossRef | Web of Science | Medline

6. 6

   Cotrim HP, Andrade ZA, Parana R, Portugal M, Lyra LG, Freitas LA. Nonalcoholic steatohepatitis: a toxic liver disease in industrial workers. Liver 1999;19:299-304
   CrossRef | Medline

To the Editor:

Among young, healthy male volunteers screened for clinical pharmacologic studies, mild increases in aminotransferase levels are common. Of 924 subjects who underwent screening, 4 percent had a value that exceeded the usual upper limit of the normal range (50 IU per liter).1 In most of these subjects, no disease was identified, and simply stopping physical activity or sports caused the aminotransferase levels to return to the normal range within a few days.

Diet can also affect aminotransferase levels. High-calorie and high-carbohydrate diets induce a rapid increase in aminotransferases, as established by Porikos and Van Itallie.2 In their study, 15 nonobese and 6 obese men on a metabolic unit received an ad libitum diet of conventional foods, with 25 to 30 percent of total calories in the form of sucrose, for 18 days and then received a calorically diluted diet (containing aspartame), with less than 10 percent sucrose, for 12 days. Both the alanine aminotransferase level and the aspartate aminotransferase level increased and then decreased in parallel with the sucrose load in the successive diets. The mean alanine aminotransferase level rose from 24 to 54 IU per liter in the nonobese men, and from 50 to 85 IU per liter in the obese men.

Michel Sibille, M.D.
Isabelle Durieu, M.D.
Denis Vital Durand, M.D.
Centre Hospitalier Lyon Sud, 69495 Pierre-Benite CEDEX, France

2 References

1. 1

   Sibille M, Deigat N, Durieu I, et al. Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials. Eur J Clin Pharmacol 1999;55:13-19
   CrossRef | Web of Science | Medline

2. 2

   Porikos KP, Van Itallie TB. Diet-induced changes in serum transaminase and triglyceride levels in healthy adult men: role of sucrose and excess calories. Am J Med 1983;75:624-630
   CrossRef | Web of Science | Medline

To the Editor:

A macroenzyme is a rare but important cause of an elevated liver-enzyme level. Macroenzymes are serum enzymes that have formed high-molecular-mass complexes, either by polymerization or by association with other serum components.1 Most commonly, they form a complex with an immunoglobulin (usually IgG or IgA). There is no convincing evidence that macroenzymes are associated with disease, but they can lead to increased total serum enzyme levels by interfering with common clinical laboratory testing methods.2 Failure to recognize a macroenzyme as the cause of an unexplained increase in a liver-enzyme level may result in the performance of a multitude of unnecessary diagnostic tests.

A 61-year-old woman with nonspecific abdominal symptoms was followed at our hospital over a period of 18 years because of an isolated elevation in the aspartate aminotransferase level (235 to 540 IU per liter). She underwent two liver biopsies, repeated abdominal ultrasound and computed tomographic studies, and numerous specialized blood tests. No serious disorder could be detected. Once the possibility of a macroenzyme was considered, precipitation studies with polyethylene glycol were performed, and the results finally established the presence of macromolecular aspartate aminotransferase. The patient was reassured and discharged from the clinic.

Katharina Wallis, M.B., B.S.
Stephen Price, F.R.C.Path.
David A. Gorard, M.D.
Wycombe Hospital, High Wycombe HP11 2TT, United Kingdom

2 References

1. 1

   Remaley AT, Wilding P. Macroenzymes: biochemical characterization, clinical significance, and laboratory detection. Clin Chem 1989;35:2261-2270
   Web of Science | Medline

2. 2

   Galasso PJ, Litin SC, O'Brien JF. The macroenzymes: a clinical review. Mayo Clin Proc 1993;68:349-354
   Web of Science | Medline

To the Editor:

In the excellent review by Pratt and Kaplan, Table 3 lumps herbs and homeopathic treatments together as substances that may cause elevations in liver-enzyme levels. Properly prepared homeopathic medications are diluted to a point where there is little or no raw herb or drug left. To my knowledge, there have been no reported liver-enzyme elevations associated with homeopathic treatments alone. It is not my intent to prove or disprove the benefits of homeopathy, but there is good scientific literature on its safety and efficacy. Homeopathic medications prepared according to the standards of the Food and Drug Administration do not cause abnormally high liver-enzyme levels.

Edward J. Linkner, M.D.
Parkway Center, Ann Arbor, MI 48104

To the Editor:

Pratt and Kaplan provide rational advice to physicians dealing with unexpected abnormalities on liver-enzyme screening tests in asymptomatic adults. The authors do not address the high standard of evidence required when physicians order tests for healthy patients.1 The benefits of general biochemical profiles are uncertain, and they are not recommended by the U.S. Preventive Services Task Force.2 The task force suggests instead that physicians be selective in ordering screening tests and consider their benefits, cost effectiveness, and adverse consequences. The risks of routine screening include the need to confirm abnormal test results, additional costs, pain, inconvenience, anxiety, and in some cases of abnormal liver-function tests, liver biopsy. Routine testing for uncommon conditions in ambulatory patients is unwarranted because of the low pretest and post-test probabilities of the presence of such conditions.3,4

Paul Froom, M.D.
Tel Aviv University, Tel Aviv 69978, Israel

Jack Froom, M.D.
State University of New York at Stony Brook, Stony Brook, NY 11794-8461

4 References

1. 1

   Sox HC Jr. Preventive health services in adults. N Engl J Med 1994:330:1589-95.
   

2. 2

   U.S. Preventive Services Task Force. Guide to clinical preventive services: report of the U.S. Preventive Services Task Force. 2nd ed. Baltimore: Williams & Wilkins, 1996.
   

3. 3

   Cebul RD, Beck JR. Biochemical profiles: applications in ambulatory screening and preadmission testing of adults. Ann Intern Med 1987;106:403-413
   Web of Science | Medline

4. 4

   Woolf SH, Kamerow DB. Testing for uncommon conditions: the heroic search for positive test results. Arch Intern Med 1990;150:2451-2458
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We agree with Drs. Blanc and Redlich that some unexplained cases of elevated liver enzymes may be due to unidentified exposure to chemicals. Unfortunately, we could mention only the most common exposures.

Dr. Sibille and colleagues present data from reports on two trials, one published and one presented at a meeting, that suggest that a high-carbohydrate diet can cause elevated aminotransferase levels in healthy persons. The source of the aminotransferases is not identified. Although a high-carbohydrate diet might account for an isolated set of elevated aminotransferase values, it is unlikely to be a cause of chronically elevated values unless the patient has a very unusual diet.

Dr. Wallis and colleagues relate their experience with a patient whose chronically elevated aspartate aminotransferase level was due to the presence of macromolecular aspartate aminotransferase. An evaluation for a macroenzyme should be considered only when a single enzyme is elevated and only after other, more common causes of abnormal liver-test results have been ruled out.

Dr. Linkner expresses concern about our use of the term “homeopathic treatments” as a cause of elevated liver enzymes. We only wished to alert physicians that some preparations might contain herbal products that cause abnormal results on liver-enzyme tests.

Finally, Drs. Froom and Froom make the important point that physicians should be judicious in the use of any screening test. We agree.

Daniel S. Pratt, M.D.
Marshall M. Kaplan, M.D.
New England Medical Center, Boston, MA 02111

Citing Articles (3)

Citing Articles

1. 1

   Christopher C. Coss, Matt Bauler, Ramesh Narayanan, Duane D. Miller, James T. Dalton. (2011) Alanine Aminotransferase Regulation by Androgens in Non-hepatic Tissues. Pharmaceutical Research
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2. 2

   Saber Mohammadi, Amirhoushang Mehrparvar, Yasser Labbafinejad, Mir Saeed Attarchi. (2010) The effect of exposure to a mixture of organic solvents on liver enzymes in an auto manufacturing plant. Journal of Public Health 18:6, 553-557
   CrossRef

3. 3

   Rong-Ze Yang, Greorghe Blaileanu, Barbara C Hansen, Alan R Shuldiner, Da-Wei Gong. (2002) cDNA Cloning, Genomic Structure, Chromosomal Mapping, and Functional Expression of a Novel Human Alanine Aminotransferase. Genomics 79:3, 445-450
   CrossRef