Bile Acid

Purpose:
The Bile Acids EQA programme is designed to assess laboratory and method performance in the laboratory investigation of intrahepatic cholestasis of pregnancy (ICP). ICP is defined by gestational pruritus and elevated total serum bile acids (TSBA). Until recently, diagnostic thresholds in national guidelines varied greatly with no consensus on whether fasting or postprandial samples should be used. However a Consensus statement of the Society of obstetric Medicine and New Zealand (SOMANZ), July 2023 and the Royal College of Obstetricians and Gynaecologists in their Green -top Guideline No 42 (June, 2022) made several recommendations on the diagnosis and thresholds of TSBA for the diagnosis, classification and management of ICP.

Diagnosis and Classification		Non-fasting TSBA concentration
RCOG	SOMANZ
Gestational pruritus	Normal	Itching and peak bile acid concentrations <19 micromol/La (Threshold is conditional recommendation by SOMANZ)
Mild ICP	Mild ICP	Itching and raised peak bile acid concentrations 19–39 micromol/L
Moderate ICP	Severe ICP	Itching and raised peak bile acid concentrations 40–99 micromol/L
Severe ICP	Very Severe ICP	Itching and raised peak bile acid concentrations ≥100 micromol/L

Note: Peak bile acid concentrations refer to the highest bile acid concentration recorded during a woman’s pregnancy. Thus a woman’s diagnosis may progress in severity during pregnancy.
a The upper limit of non-fasting TSBA in normal pregnancy was determined as 18.3 micromol/L. using the Total Bile Acids Assay Kit from Diazyme, (Diazyme Laboratories Inc, Poway, CA, USA). Mitchell AL, Ovadia C, Syngelaki A et al. Re-evaluating diagnostic thresholds for intrahepatic cholestasis of pregnancy: case–control and cohort study. BJOG, 2021;128: 1635-44

As threshold targets were based on the performance of the Diazyme kit, it is of paramount importance that laboratories are aware of the bias of their methods to this kit if using the thresholds above.

Ursodeoxycholic acid (UDCA), a dihydroxycholic BA is often used in the UK as a therapeutic option and is recommended by SOMANZ for treatment in women remote from term. When administered, UDCA replaces the more toxic hydrophobic BAs (such as cholic acid) in the circulating BA pool. However, it was noted that the reduction in TSBA was less in the UDCA arm of PITCHES study, likely reflecting the measurement of orally administered UDCA within the total measured TSBA concentration. Again, it is important that users are aware of the sensitivity and specificity of their methods to the different BAs, and UDCA in particular.

Scope:
Three liquid human serum samples covering an appropriate range for the diagnosis and monitoring of ICP are distributed monthly, providing 36 samples over the year. A linear series of up to 9 pools are prepared in serum containing a mixture of Cholic acid and Deoxycholic acid, the ratio of which reflects both physiological levels and pathological levels observed in ICP. Target values for both Cholic acid and Deoxycholic acid are assayed using a ID- GC Mass Spectrometer for each sample.

Challenging samples are also distributed periodically to assess specificity of the methods including those containing UDCA, Chenodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, taurocholic acid, and taurochenodeoxycholic acid.

The programme is designed to assess laboratory and method performance, including bias, within and between batch imprecision, linearity, trueness, sensitivity and specificity of TSBA.

Key Features:

Linear panels assigned by a higher meteorological order reference method.
Panel of liquid human serum samples covering an appropriate range and BA ratio for the diagnosis and monitoring of ICP.
Challenging samples containing UDCA and other BA to determine specificity.
Analytical performance Specification based on Milan Model 3.