A-360 On importance of monitoring UDCA treatment in Intrahepatic Cholestasis of Pregnancy

Abstract Background Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific condition characterized by pruritus and elevated levels of serum bile acids (BAs). High serum BAs in pregnancy are associated with adverse perinatal outcomes, including preterm birth and stillbirth. Ursodeoxycholic acid (UDCA), a bile acid with anticholestatic effect, is widely used in ICP and considered safe. However, its efficacy remains controversial as several studies have shown no significant change in total BAs (TBA) and uncertain clinical benefits. Since TBA includes UDCA, the effect of exogenous UDCA supplementation on other BAs may be hidden by the assessment of TBA only. The goal of this study was to evaluate changes in the concentrations of various bile acids in women with ICP on UDCA treatment. Methods Retrospective data analysis was performed on de-identified patient results from serum bile acid testing by LC-MS/MS. This test reports total (conjugated/unconjugated) concentrations of cholic (tCA), chenodeoxycholic (tCDC), deoxycholic (tDCA), ursodeoxycholic (tUDC) acids, and TBA. A total of 315 samples from 196 patients (age 31+3 years) with TBA >7.0 µmol/L and diagnostic codes indicating liver/biliary tract disorders in pregnancy were included in the study. All patients had at least one BA measurement before and after UDCA treatment. Reference range for TBA, tCA, tCDC, tDCA and tUDCA were =7.0µmol/L, =1.9µmol/L, =3.4µmol/L, =2.5µmol/L and =1.0 µmol/L, respectively. Results The mean pre-treatment serum concentrations of TBA, tCA, tCDC and tDCA were 30.2µmol/L, 18.3µmol/L, 8.9µmol/L and 2.8µmol/L, respectively. tUDCA was detected in traces (=0.3µmol/L). UDCA treatment resulted in significant increase in tUDCA (mean 10.7µmol/L; range 1.1-75 µmol/L). However, the effect of the UDCA treatment on other BAs significantly varied. Normalization of elevated pre-treatment levels of tCA, tCDC or tDCA occurred in 36%, 55% and 61% of samples, respectively. Paradoxically, patients with normalized tCA, tCDC or tDCA on treatment had significantly lower serum tUDCA concentrations compared to those that maintained abnormal values, p<0.0001. Moreover, quantitative analysis confirmed that higher serum tUDCA concentrations were associated with less reduction or even increase in non-UDCA BAs. Compared to pre-treatment levels, samples with low tUDCA (<5µmol/L) on treatment showed an average -57%, -51% and -26% decrease in tCA, tCDC and tDCA, respectively. In contrast in samples with tUDCA >20 µmol/L, tCA, tCDC, and tDCA levels were on average 58%, 69%, and 150% higher than before treatment. This suggests a potential toxicity of high UDCA concentrations on biliary function. Conclusion In patients with ICP on UDCA treatment, low serum concentrations of tUDCA associated with significant decrease in tCA, tCDC and tDCA levels. However, the beneficial effect was less pronounced or even reversed with higher serum concentrations of tUDCA. For the accurate clinical assessment, the changes in primary and secondary bile acids should be closely monitored during UDCA treatment. Currently, this is not standard of care. Clinical studies are necessary to define optimal serum levels of UDCA in order to maximize therapeutic benefits while minimizing potential toxicity.