Bile acid reference intervals for evidence‐based practice

Abstract

In this edition, Huri et al. (BJOG 2022) have added to the growing literature defining pregnancyspecific reference ranges for total serum bile acid (TSBA) concentrations. Reference intervals in clinical pathology are typically calculated using an ‘indirect resource’, such as stored laboratory samples. Results are partitioned into biologically relevant groups (typically age and sex), outliers are excluded to remove anomalous results due to disease, and the central 95% of the population is calculated for each group. Two large studies, that of Huri et al. and our own (Mitchell et al. BJOG 2021;128:1635– 44), have recently calculated reference intervals for nonfasting TSBA concentrations in the third trimester of pregnancy, finding strikingly similar results for the upper limit (20.2 and 18.3 μmol/l, respectively). Both studies excluded samples with cholestatic pathology before analysis, treating the cohorts as a ‘direct resource’ and obviating exclusion of outliers. However, the results demonstrate outliers within each dataset. In the study by Huri et al. this may have been the result of the selected participants having other gestational diseases (for example, gestational diabetes) and originating from samples taken during hospital admission; the reason for women being inpatients may have influenced serum bile acid concentrations and therefore confounded the findings. To assess the impact of excluding outliers, we used the block D/R (Zellner et al. arXiv preprint; 1907.09637.) procedure to identify outliers in our dataset (from outpatient samples routinely taken and limited to uncomplicated pregnancies), and reanalysis revealed a slight reduction in the upper limit of the reference interval and narrowing of the confidence interval (Table 1). Does this matter? When the disease outcomes and management relate closely to peak bile acid concentration (Ovadia et al. Lancet 2019;393:899– 909), what may be of more clinical relevance is a diagnostic threshold rather than a reference interval. Women previously diagnosed with intrahepatic cholestasis of pregnancy (ICP) using an upper limit of the nonfasting TSBA reference interval below 19 μmol/l had no higher rates of stillbirth and spontaneous preterm birth than the matched population, but a slightly higher rate of Accepted: 24 March 2022 | Published Online 10 May 2022