Article in press - uncorrected proof Clin Chem Lab Med 2009;47(10):1309–1310 2009 by Walter de Gruyter • Berlin • New York. DOI 10.1515/CCLM.2009.282
2009/220
Letter to the Editor
Should gender-related reference values be used for total bilirubin?
Veroniek S. Saegeman, Isa Vierendeels, Marc J. Moens and Jan Moerman* Department of Laboratory Medicine, Imelda Hospital, Bonheiden, Belgium
Keywords: bilirubin; gender; reference values.
For the analysis of total bilirubin in serum and plasma of adults and neonates, we use a diazo reagent total bilirubin liquid on a modular P-type automated clinical chemistry analyser (Roche, GmbH, Mannheim, Germany). In November 2008, Roche announced a restandardisation of the total bilirubin reference and asked users to lower the setpoint for the C.f.a.s. calibrator (–17%) (Roche, Product Information, 14 November 2008). At the same time, a new reference value for adults of 21 mmol/L, instead of 17 mmol/L, was proposed. This value resulted from a large internal study that included defined samples from 249 men to 251 women. We were surprised that, although a striking difference with respect to gender in the values for total bilirubin were found wpercentile (p)97.5 for men: 24.45 mmol/L, p97.5 for women: 15.73 mmol/Lx (data provided by the Biostatistics Department, Roche), only one general reference value (21 mmol/L) was proposed (Roche, Product Information, 14 November 2008). In a later communication, continuation of local or regional reference intervals was also suggested (Roche, Product Information, 5 February 2009). We wondered whether there was a gender-related difference in total serum/plasma bilirubin values in our population as well. Since we have no data from a healthy population, it was not our purpose to define new reference values for this method. We chose a random study population that consisted of outpatients at least 2 years of age who visited the Imelda Hospital from January to November 2008. Although this is a heterogeneous group with unknown fasting state, we considered it to be a representative group of the regional population (1). Results of serum/plasma bilirubin and the gender of patients were extracted a posteriori from the laboratory information system. We did not look for age-related changes in *Corresponding author: Dr. Jan Moerman, Imeldalaan 9, 2820 Bonheiden, Belgium Phone: q32 (0) 15 50 54 68, Fax: q32 (0) 15 50 54 79, E-mail:
[email protected]
gender difference, as age difference seemed to have minor importance in total bilirubin concentrations in the study of Manolio et al. (2). After collecting the data, descriptive statistics were performed using Analyse-it software (Ltd, Leeds, UK). We examined the results prior to and following restandardisation. Outliers were excluded statistically from the raw data according to the formulas: p25 –1.5=(p75 –p25) and p75q1.5=(p75 –p25) (3). One of the reasons for doing this was, to exclude persons with Gilbert’s disease or ambulant patients with possible severe illness who might have significantly higher serum/plasma bilirubin concentrations. Since total bilirubin values were not normally distributed, with positive skewness for each of the genders, we used non-parametric statistics. The reference interval for this study population was determined using the 2.5th and 97.5th percentile of the data after restandardisation and after exclusion of outliers. Our results (Figure 1) showed a significant difference in total bilirubin values when comparing men and women both prior to and following restandardisation (Mann-Whitney U-test, p-0.001, Analyse-it). Following restandardisation, the median value for women (ns966) was 5.64 mmol/L (95% CI 5.47– 5.81 mmol/L) and for men (ns560) 7.18 mmol/L (95% CI 6.84–7.52 mmol/L). The interval bounded by the 2.5th and 97.5th percentiles was 2.39–11.97 mmol/L for women and 3.08–17.4 mmol/L for men.
Figure 1 Boxplot of total serum bilirubin concentrations for men and women after restandardisation and exclusion of outliers. IQR, interquartile range.
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Article in press - uncorrected proof 1310
Saegeman et al.: Gender-related difference in total bilirubin
Several authors have reported previously that men have higher concentrations of serum bilirubin compared with women (2, 4). However, these findings have never led to the implementation of different reference values for men and women. With this letter, we aim to highlight the need for reconsidering the use of gender-related reference intervals in order to avoid falsely normal bilirubin values in women and falsely high bilirubin values in men.
Conflict of interest statement There is no conflict of interest to report.
References 1. Solberg HE. Establishment and use of reference values. In: Burtis CA, Ashwood ER, Bruns DE, editors. Tietz fundamentals of clinical chemistry, 6th ed. Saunders Elsevier, 2008:229–38. 2. Manolio TA, Burke GL, Savage PJ, Jacobs DR, Sidney S, Wagenknecht LE, et al. Sex- and race-related differences in liver-associated serum chemistry tests in young adults in the CARDIA study. Clin Chem 1992;38:1853–9. 3. Solberg HE, Lahti A. Detection of outliers in reference distributions: performance of Horn’s algorithm. Clin Chem 2005;51:2326–32. 4. White GL, Nelson JA, Pedersen DM, Owen Ash K. Fasting and gender (and altitude?) influence reference intervals for serum bilirubin in healthy adults. Clin Chem 1981;27: 1140–2.
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