0

The full content of Annals is available to subscribers

Subscribe/Learn More  >
Articles |

Brief Communication: Clinical Implications of Short-Term Variability in Liver Function Test Results

Mariana Lazo, MD, ScM; Elizabeth Selvin, PhD, MPH; and Jeanne M. Clark, MD, MPH
[+] Article and Author Information

From Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.


Grant Support: Dr. Selvin was supported by a National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (grant K01 DK076595).

Potential Financial Conflicts of Interest: None disclosed.

Reproducible Research Statement: The protocol for this study is not available. The statistical code is available to interested readers by contacting Dr. Lazo at mlazo@jhsph.edu. The data, which came from the NHANES III First and Second Examinations, are publicly available at http://www.cdc.gov/nchs/about/major/nhanes/nh3data.htm.

Requests for Single Reprints: Mariana Lazo, MD, ScM, Welch Center for Prevention, Epidemiology, and Clinical Research, 2024 East Monument Street, Suite 2-600, Baltimore, MD 21205-2223; e-mail, mlazo@jhsph.edu.

Current Author Addresses: Drs. Lazo, Selvin, and Clark: Welch Center for Prevention, Epidemiology, and Clinical Research, 2024 East Monument Street, Suite 2-600, Baltimore, MD 21205.

Author Contributions: Conception and design: M. Lazo, E. Selvin, J.M. Clark.

Analysis and interpretation of the data: M. Lazo, E. Selvin, J.M. Clark.

Drafting of the article: M. Lazo.

Critical revision of the article for important intellectual content: M. Lazo, E. Selvin, J.M. Clark.

Final approval of the article: M. Lazo, E. Selvin, J.M. Clark.

Statistical expertise: M. Lazo, E. Selvin.

Administrative, technical, or logistic support: J.M. Clark.

Collection and assembly of data: M. Lazo.


Ann Intern Med. 2008;148(5):348-352. doi:10.7326/0003-4819-148-5-200803040-00005
Text Size: A A A

The Figure shows the number of participants who were included in the analyses. The study population was 45% male, had a mean age of 49 years (SD, 18.8), and was racially or ethnically diverse (Table 1). The prevalence of antibodies to hepatitis A, hepatitis B core, and hepatitis C was 54%, 8%, and 3%, respectively. With regard to alcohol use, 53% reported consuming at least 12 drinks in the past 12 months.

First Page Preview

View Large
First page PDF preview

Figures

Grahic Jump Location
Figure.
Study flow diagram.

NHANES = National Health and Nutrition Examination Survey. *Values with a difference (examination 2 minus examination 1) >4 SDs from the mean difference. These values are likely to have arisen from non–method-related error processes (inadequate mixing, evaporation, or mislabeling).

Grahic Jump Location

Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Response
Posted on March 4, 2008
Pieter A Cohen
Cambridge Health Alliance
Conflict of Interest: None Declared

TO THE EDITOR:

Lazo and colleagues' research documenting the intraindividual variability of liver function tests has the potential to prevent unnecessary evaluation of asymptomatic patients (1). If liver function tests are repeated as recommended, clinicians will need to decide how to evaluate the subset of patients who had one elevated measurement which returned to normal. To help guide clinicians in managing these patients, could the authors comment on the odds of a patient with one abnormal alanine aminotransferase (ALT) measurement having positive serology for hepatitis B or C or a transferritin saturation >50% as compared to patients who had two normal measurements of ALT.

1. Lazo M, Selvin E, Clark JM. Clinical implications of short-term variability in liver function test results. Ann Intern Med. 2008; 148:348 -352.

Conflict of Interest:

None declared

Effect of statins on transiently elevated aminotransferase levels
Posted on March 6, 2008
Weekitt Kittisupamongkol
Surin Hospital, Surin 32000, Thailand
Conflict of Interest: None Declared

I read with interest the article by Lazo and colleagues (1). However, they do not mention statins in their study. The participants they enrolled are the middle aged who have diabetes and hypertension; these brought awareness of metabolic syndrome. The volunteers may be prescribed with statins, a widely used group of cholesterol-lowering drugs known to cause increasing aminotransferases levels (2),(3),(4). The increases in aminotransferase with statins are asymptomatic and may return to normal with continuation of the statins(4). And approximately one-third of adults in their result had transient increase in aminotransferease levels(1), these might be contributed from unrecognized statins rather than intraindividual variability. So it is indispensable to ask whether the participants take statins during the study.

References

1. Lazo M, Selvin E, Clark JM. Clinical implications of short-term variability in liver function test results. Ann Intern Med.2008; 148: 348- 352. PMID: 18316753

2. Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology.2002; 123: 1367"“1384. PMID: 12360498

3. Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer : insights from large randomized statin trials. J Am Coll Cardiol.2007; 50: 409-18. PMID: 17662392

4. Armitage J. The safety of statins in clinical practice. Lancet.2007; 370: 1781"“90. PMID: 17559928

Conflict of Interest:

None declared

Clinical Implications of Short-Term Variability in Liver Function Test Results
Posted on March 8, 2008
Gaurav Arora
Stanford University School of Medicine
Conflict of Interest: None Declared

We read with great interest the recent study by Lazo et al reporting the short-term variability of various biochemical liver tests, and have some concerns regarding the same. (1) First, given the fact that this study is based on a non-random, convenience sample and which at the same time represents only 9.5% (1864/19618) of the original NHANES study population that it was derived from raises questions about the generalizability of the findings, given the strong likelihood for selection bias. Second, the very small percentage of persons from racial- ethnic groups other than White, Black and Hispanics restricts the applicability of the results, particularly so for Asians.

The cutoff values of "˜normal' serum alanine aminotransferase (ALT) of 40 IU/L for men and 31 IU/L for women, as used in this study, are likely overestimates as has been shown in two large studies from Italy and Korea. (2, 3) These studies recommend using cutoff values of 30 IU/L and 19 IU/L for men and women, respectively. Based on these, in the Lazo study, a substantial percentage of patients classified as having elevated ALT at examination 1 (median 43 IU/L) who returned to normal in examination 2 (median 27 IU/L) would likely still have abnormal ALT. These distinctions are not trivial as evidenced by increased risk of mortality in individuals with ALT level over 20 IU/L compared to those under 20 IU/L (RR 2.9 for ALT 20-29 and RR 9.5 for ALT 30-39). (3) The American Association for Study of Liver Diseases (AASLD) has also called for recalibration of the normal range for ALT. (4)

Finally, Gilbert's syndrome, a genetic disease with prevalent homozygosity of 9% in the Western population, can result in values outside of the normal range for total bilirubin, varying with fasting status or stress. This may affect the determination of "˜normal' versus "˜abnormal' values in this study.

1. Lazo M, Selvin E, Clark JM. Brief communication: clinical implications of short-term variability in liver function test results. Ann Intern Med. 2008 Mar 4;148(5):348-52.

2. Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137:1"“9.

3. Kim HC, Nam CN, Jee SH, et al. Normal serum aminotransferase concentration and risk of mortality from liver disease (prospective cohort study). BMJ. 2004;328:983"“989.

4. American Association for the Study of Liver Diseases. "Know your ALT." Press Release. Available at: https://www.aasld.org/eweb/docs/meetings/06annualmeeting/pressadvisoryalt.pdf. Accessed March 6, 2008.

Conflict of Interest:

None declared

Effect of inheritance on intraindividual variability in common liver tests
Posted on March 15, 2008
Liu Hong
Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University
Conflict of Interest: None Declared

To the editor:

As Lazo et al report, clinicians should be aware of the high intraindividual variability in common liver tests, and practice guidelines should explicitly recommend retesting of asymptomatic individuals with abnormal liver test results [1]. They evaluate the association of intraindividual variability with alcohol consumption; hepatitis A, B, or C serologic status; recent infection; body mass index; or sociodemographic characteristics. However, they don¡¯t clearly show the statistical factors affecting intraindividual variability. If liver function tests are repeated as recommended, clinicians will need to know the clinical implications of intraindividual variability in liver function test. For example, the readers will strongly suggest a prognostic evaluation by follow-up. Could the authors comment on the prognosis of a patient with one abnormal alanine aminotransferase (ALT) measurement having positive serology for hepatitis A, B, or C as compared to patients who had normal measurements of ALT?

This study is based on the participants living in the United States, so the results may not be applicable for Asians. We performed similar experiments for 258 asymptomatic adults with hepatitis B living in China. Although the sample was small, the results were interesting. The results showed that 23% of adults with initially elevated ALT levels had normal levels at the second examination. The intraindividual variability was found significantly associated with heredity. The short-term variability in ALT levels was familial prevalence. Thus we assume that the epigenetic inheritance may be the mechanisms underlying the intraindividual variability. Could the authors comment on the potential effect of inheritance on intraindividual variability in common liver tests?

References:

1. Lazo M, Selvin E, Clark JM. Brief communication: clinical implications of short-term variability in liver function test results. Ann Intern Med. 2008 Mar 4;148(5):348-52.

Conflict of Interest:

None declared

Normalization and Normality
Posted on March 31, 2008
Agostino Colli
Ospedale Alessandro Manzoni, Lecco, Italy
Conflict of Interest: None Declared

The recent article by Mariana Lazo and colleagues [1] shows that in the context of an epidemiological survey, such as NHANES III First and Second Examination, more than one third of subjects with abnormal liver tests (AST,ALT, alkaline phosphatase , ã-glutamil transferase and bilrubin) would be reclassified as "normal" if retested 17 days apart. On the basis of their findings, the authors recommend that individuals with abnormal liver test results on a first determination should be routinely retested before undergoing further evaluation, to avoid unnecessary testing.

In our opinion, caution should be used in drawing practice recommendations from epidemiologial studies. We are particularly concerned that the proposed strategy could be highly misleading in a clinical setting. Liver tests, particularly aminotransferases and ã-glutamil transferase, typically fluctuate in chronic liver disease [2]. When evaluating a patient with abnormal liver biochemistries, even if asymptomatic, results should interpreted according to the clinical context, and an adequate work up should be considered [2,3]. A repeated value in the normal range does not ensure that the initial value was truly erroneous.

In addition, there is substantial evidence that high aminotransferase values are significantly correlated with increased future mortality, suggesting that these blood tests are valuable indicators of long-term prognosis [4,5]. How to discriminate, in a single individual, a clinically insignificant fluctuation of normality from a predictor of mortality? To support their recommendations, Lazo and colleagues should have documented that subjects with two discordant results have the same long-term outcome of those with two concordant normal tests. Otherwise, normalization cannot be defined as a proof of normality.

References

1. Lazo M, Selvin E, Clark J. Clinical implications of short-term variability in liver function test results. Ann Intern Med 2008; 148: 348-52

2. Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137:1-10.

3. American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of liver chemistry tests. Gastroenterology. 2002;123:1364-6.

4. Kim HC, Nam CM, Jee S, Han KH, Oh DK, Suh I. Normal serum aminotransferse concentration and risk of mortality from liver disease: prospective cohort study BMJ 2004;328:983-6

5. Lee HT, Kim WR, Benson JT, Therneau TM, Melton J III Serum aminotransferse activity and mortality risk in a United States Community Hepatology 2008; 47: 880-7

Conflict of Interest:

None declared

Prognostic evaluation of individuals with abnormal liver function tests
Posted on April 3, 2008
Hidekatsu Yanai
The Jikei University School of Medicine
Conflict of Interest: None Declared

I read the article by Lazo M, et al. with interest (1). They suggested that repeating liver function tests when the results are elevated may reduce uncertainty in the clinical assessment of individuals with abnormal test results and substantially decrease further unnecessary tests. However, I think that their conclusion is premature. Liver disease is generally asymptomatic, elevated liver function test result is sometimes the only sign in asymptomatic individuals with hepatitis B and C infection. Further, I often find liver tumors in asymptomatic patients with abnormal liver function tests, using ultrasonography. I believe that serologic tests for hepatitis B and C, and ultrasonography are important to determine the prognosis for individuals with elevated liver function tests.

1. Lazo M, Selvin E, Clark JM. Brief communication: clinical implications of short-term variability in liver function test results. Ann Intern Med. 2008;148:348-52.

In Response
Posted on April 20, 2008
Mariana Lazo
Department of Epidemiology, Johns Hopkins University
Conflict of Interest: None Declared

We appreciate the readers' interest in our study. As indicated by Drs. Arora and Triadafilopoulos, since this was based on a non-random sample of the NHANES III population, selection bias is always a possibility. However, even if selection bias were present, while sociodemographic and other subject-level characteristics may be associated with the absolute level of liver enzymes, such factors are unlikely to affect variability per se (variability is a biologic phenomenon). Indeed we did not observe any variability by demographic or other subject level characteristics. We agree that since Asians constitute only a very small percent of the NHANES III study population (<5%), it is not possible to draw firm conclusions regarding this population. Results of analyses using the cutoffs of ALT>=19 for women and >=30 for men, were essentially identical (31% returned to normal), however, the proportion of participants with elevated ALT was higher: 17% vs. 6%.

We agree that defining the reference range for liver tests is an area of debate 1-3 and needs further study. Finally, although Gilbert Syndrome is a common cause of elevated bilirubin, to our knowledge there is no evidence that it affects the variability per se. Additionally, the results were unchanged when excluding adults with recent illness or those who fasted >8 hours at both exams. As pointed out by Dr. Kittisupamongkol, the use of statins can cause abnormal transaminases. Since this data was collected from 1988 to 1994, only 4.8% of participants reported taking lipid-lowering medications. Their use was not associated with elevated liver enzyme levels or variability in our study. Drs. Hong, Wu and Fan raise an important question regarding factors that affect intra-individual variability. However, our paper focused on describing the intra-individual variability in liver tests in the U.S. population. Further studies are needed to examine those factors which may contribute to variability in liver enzyme levels across individuals. As Drs. Colli and Prati mention, one should certainly be cautious when drawing practice recommendations from epidemiological studies. The development of guidelines for the reporting of observational studies, such as STROBE 4, was the result of similar concerns and the appreciation that much of the clinical and population based knowledge has been derived from observational studies. We took the advantage of a large multi-racial population-based sample of the U.S., with a vast amount of standardized data. This study would have been very difficult to conduct otherwise.

Mariana Lazo1,2, Elizabeth Selvin1,2 and Jeanne M. Clark1,2,3

1 Department of Epidemiology, 2 Welch Center for Prevention, Epidemiology, and Clinical Research, 3 Department of Medicine. Johns Hopkins University, Baltimore, MD, USA

Reference List

(1) Prati D, Taioli E, Zanella A et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002 July 2;137(1):1-10.

(2) Neuschwander-Tetri BA, Unalp A, Creer MH. Influence of Local Reference Populations on Upper Limits of Normal for Serum Alanine Aminotransferase Levels. Arch Intern Med 2008 March 24;168(6):663-6.

(3) Kaplan MM. Alanine aminotransferase levels: what's normal? Ann Intern Med 2002 July 2;137(1):49-51.

(4) Vandenbroucke JP, von EE, Altman DG et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Ann Intern Med 2007 October 16;147(8):W163-W194.

Conflict of Interest:

None declared

Submit a Comment

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Buy Now

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)