Hepatology, December 1998, p. 1724-1724, Vol. 28, No. 6

Correspondence
Diurnal Variation of Serum Alanine Transaminase Activity in Chronic Liver Disease

 

To the Editor:

The determination of serum levels of alanine transaminase (ALT) is a critical tool in the diagnosis and follow up of patients with liver disease. We were interested in the recent article by Piton et al.,¹ which identified factors associated with ALT variability from a cohort of 1,033 blood donors and estimated the clinical impact of correcting the normal upper limit value of ALT according to these parameters. However, the authors did not mention if blood sampling was obtained at the same time of the day and if they assessed the role of this factor on ALT values. In healthy individuals there is a such a variation of ALT² and other blood analytes³of low amplitude that does not posediagnostic problems. However, in patients with high values ofALT, the changes could be of significance. Different biologicalrhythms have been shown to be abnormal in patients with cirrhosis^4-6and in rats with portacaval anastomosis.^7,8 It is unknown whether a common abnormality may also affect the diurnal variation of ALT.

We examined the diurnal variation of serum ALT in a group of 12 patients with cirrhosis (5 men, 7 women; 35-63 years; meanage, 47 years) of different etiologies (5 alcoholic, 4 hepatitis C, and 3 primary biliary cirrhosis) staged Child-Pugh class A in 4 subjects and Child-Pugh class B in 8 subjects. All were medically stable and followed a standardized protocol⁴ as part of a study to examine circadian rhythms in cirrhosis. Patients were submitted to hourly venous sampling. In each patient, ALT values were simultaneouslyassessed in all 24 samples using a standard automatic analyzer(Beckman Synchron CX-7, Beck, CA). The intra-assay coefficientof variation (5%) was calculated comparing duplicates of 120 samples (hourly samples of 5  patients).

The median of the mean values of hourly determinations of ALT was 34 IU/L (range, 6-195 IU/L). The range of change ([highestvalue  lowest value]/lowest value) was 45% (range, 18-54%). In 3 patients the values of ALT changed from below to above the upper limit of normality (Fig. 1A). Serial measurement of serum levels of liver enzymes disclosed higher levels during the day (8 AM-10PM; median, 38 IU/L; first quartile, 28 IU/L) than during the night (11 PM-7 AM; median, 33 IU/L; first quartile, 26 IU/L; paired Student’s t test P = .023). Evaluation of data by the population-mean cosinor method⁹ (fitting the curve to the mean values of the population at each data point) showed a statistically significant circadian variation (rhythm detection P < .001) with peak values for liver enzymes (acrophase) localized in the afternoon (15:37). Individual models (fitting the curve to the mean values of each patient at each data point; Fig. 1B) still kept a high goodnessof fit (R² = 44 ± 17) with a considerable range of change (2 × amplitude  = 22 ± 6%).

 

View Larger Version Fig. 1.   (A) Lowest (open circles) and highest (closed circles) values of hourly ALT (IU/L) in 12 patients with cirrhosis and time of occurrence. Lights were off (solid bar) from 23:00 to 07:00 and on (open bar) the rest of the day. At our center the upper limit of normal ALT was 25 UI/L (dotted line). (B) Hourly values of ALT in a patient with cirrhosis. The graph shows the best fitting curve (R2 = 0.84) obtained by cosinor analysis and the parameters that define the rhythm: mesor (rhythm adjusted mean), amplitude (difference between peak value and mesor), and acrophase (time of peak). Cosinor analyses consist of fitting a set of cosine curves to the data. The best fitting curve is found by minimizing the sum of squares of differences between the actual measurements and the curve. The curve is defined by the function: Y = M + A cos (t ), where M = mesor, A = amplitude,  = frequency (for a 24-hour period, = 2/24), t = time, and = acrophase. The goodness of fit (R2) represents the percentage of the variance that can be explained by the model.

 

In summary, we observed higher values of liver enzymes during the day than at night and a peak time in the afternoon. Thus, serum values of liver enzymes need to be interpreted with consideration of their diurnal variation. Piton et al.¹ reported variations in the percentage of individuals that would be classified as having normal ALT that ranged from 11% to 17% depending on the group examined (blood donors, hepatitis C patients, or responders to interferon). According to our results variations of similar range could be present comparing samples obtained at different times of the day. This could be relevant because in many centers inpatients are submitted to blood sampling in the morning whereas outpatients are submitted to blood sampling in theafternoon.

We observed that the diurnal rhythm of ALT in cirrhosis is preserved and similar to the diurnal rhythm described in healthyindividuals.^2,3 Furthermore, the rhythm is constant as shown in 5 patients that had the study repeated 1 month after the first admission and had no significant changes in rhythm parameters (Spearman’s correlation coefficient for mesor = 0.8 and for acrophase  = 1). The mechanism that regulates the diurnal variation of blood analytes is unknown but, according to these data, does not appear to be affected by cirrhosis.

In conclusion, as pointed out by Piton et al., several factors need to be considered when using liver enzymes in the clinical assessment of liver disease. Among them, circadian variation may be especially important when enzyme values are compared in a patient with chronic liver disease that had blood sampled at different times of theday.

Juan Córdoba, M.D. Ken O’Riordan, M.D. Josée Dupuis, Ph.D. Jayme Borensztajn, M.D. Andres T. Blei, M.D. Departments of Medicine, Preventive Medicine, and Pathology Lakeside Veterans Affairs Medical Center and Northwestern University Chicago, IL

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