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Bile acids – what’s all the fuss?

Bile acids – what’s all the fuss?

As we have previously mentioned, ICP is associated with potential problems for your unborn baby. It has always been suggested that the most likely cause of stillbirth comes from bile acids, and the most recent research from Ovadia (2019) has identified the level at which bile acids become a problem for the unborn baby in ICP. But what are bile acids and why are they are a problem?

What are bile acids?

Bile acids are made (synthesised) from cholesterol in the liver. They start life as primary bile acids and in a further process (conjugation) they are converted into bile salts, which is why some doctors will call them bile salts and others will refer to them as bile acids. They are then transported from the liver into the gallbladder in bile.

Bile acids are essential, as they help the body digest food and absorb the fat-soluble vitamins we need for our bodies. During a meal, the gallbladder contracts and deposits bile into the gut (if you have had your gallbladder removed, bile will be secreted directly to the gut). Once there, and with the help of bacteria in the gut, the bile acids are turned into secondary and tertiary bile acids, including UDCA. They are then recycled, and around 95% of them are transported back to the liver via the hepatic portal vein. The remaining bile acids/salts are excreted in the faeces (poo). This entire process is called the enterohepatic circulation.

Enterohepatic circulation

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In ICP there is no evidence that individual bile acids need to be measured, so most laboratories will perform a total bile acid measurement, which includes both bile acids and salts. Click here for a pictorial representation of bile acid.

Bile acids

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What happens to bile acids in ICP?

In ICP the transport of bile acids across the liver doesn’t happen as efficiently as it should. The bile acids accumulate in the liver and eventually leak back into the blood, causing raised levels in the blood. Doctors refer to this as being ‘cholestatic’.

Because the bile acids are quite toxic it is important to try to reduce the levels. They are not thought to be harmful to you during an ICP pregnancy because they are only raised for a limited amount of time, but they may be the reason why some babies have been born prematurely or stillborn. As previously discussed, exactly how bile acids are involved is still not fully understood. Some studies have investigated their effect on the placenta and other studies have looked at their possible effect on the baby’s heart. Further research is needed to identify whether either or both of these factors are implicated in the risk to the baby, and it is important that this research continues. For the moment, researchers advocate a cautious approach to managing the condition.

Bile acids have their own circadian rhythm, which means that they naturally rise and fall (within normal reference ranges) over a 24-hour period. The time of day at which you have your blood taken to measure your bile acids can make a difference to your result, and any increase (within normal reference ranges) doesn’t mean that your bile acids are going to become abnormal or are rising – it could simply be that you have had them tested at a time of day when they are generally a little higher. They also rise after eating, but there is no evidence to suggest that you need to fast for the test – in fact, based on recent research published in The Lancet, which shows that bile acids > 100 µmol/L are linked to an increased risk of stillbirth, it is clear that it is vital to know what they are after eating so that you can know how high they can become (peak bile acids).

However, we are aware that many women are now being asked to fast even though there is no evidence to do so and we wanted to get an idea of how many women might be affected. We surveyed just over 260 women and the following chart gives us an idea of how many women are being asked to fast and where in the world this practice is most common. Our message to you is: don’t fast, and if told to, ask for the evidence!

Fasting vs. non-fasting bile acids

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Since our survey, more research has been published showing the importance of not fasting and also suggesting that the threshold for diagnosing ICP should be increased.

Whilst this research identified that the greatest peak in bile acids was at an hour after lunch, we know that it simply isn’t practical for women to organise their bile acid tests for a set time. However, if you are being tested for ICP or you have already been diagnosed with the condition, it makes sense to be consistent about the time of day you have your test and what you have eaten beforehand. By doing this you will know that your results have not been affected by testing at different times or by eating different food. Experts in ICP also recommend that you leave around 30–120 minutes after eating before being tested, as levels will have peaked by then.

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References

Gao H, Chen L-J, Luo Q-Q, Liu X-X, Huu Y, Yu L-L, Zou L. Effect of cholic acid on fetal cardiac myocytes in intrahepatic choliestasis [sic] of pregnancy J Huazhong Univ Sci Technol [Med Sci] 2014; 34(5): 736–9. https://doi.org/10.1007/s11596-014-1344-7.

Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology 2004; 40: 467–74.

Mitchell A, Ovadia C, Syngelaki A, Souretis K, Martineau M, Girling J, Vasavan, T, Fan HM, Seed PT, Chambers J, Walters JRF, Nicolaides K, Williamson C. Re-evaluating diagnostic thresholds for intrahepatic cholestasis of pregnancy: case-control and cohort study. Br J Obstet Gynaecol 2021;
https://doi.org/10.1111/1471-0528.16669

McIlvride S, Dixon PH, Williamson C. Bile acids and gestation. Molecular Aspects of Medicine 2017; 56: 90–100.

Vasavan T, Ferraro E, Ibrahim E, Dixon P, Gorelik J, Williamson C. Heart and bile acids – Clinical consequences of altered bile acid metabolism. Biochim Biophys Acta 2018; 1864(4 Pt B): 1345–55. https://doi.org/10.1016/j.bbadis.2017.12.039.

Vasavan T, Deepak S, Jayawardane I A, Lucchini M, Martin C, Geenes V, Yang J, Lövgren-Sandblom A, Seed P T, Chambers J, Stone S, Kurlak L, Dixon P H, Marschall H-U, Gorelik J, Chappell L, Loughna P, Thornton J, Pipkin F B, Hayes-Gill B, Fifer W P, Williamson C. Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations. J Hepatol 2020; 74(5): 1087–1096. https://doi.org/10.1016/j.jhep.2020.11.038.