Exploring the Intricacies of Bile Acids: Understanding Their Role in Metabolism and Intrahepatic Cholestasis of Pregnancy

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Exploring the Intricacies of Bile Acids: Understanding Their Role in Metabolism and Intrahepatic Cholestasis of Pregnancy

Bile acids (BAs) are fascinating molecules that play a pivotal role in our bodies metabolic processes. From aiding in the digestion of lipids to regulating essential metabolic pathways, BAs have garnered significant interest among researchers and healthcare professionals. In this article, we will delve into the structural and functional aspects of bile acids and explore their significance in a condition called intrahepatic cholestasis of pregnancy (ICP). For additional information, we encourage you to take a look at our latest educational guide: 5th Generation Bile Acids & Intrahepatic Cholestasis of Pregnancy. So, let’s unravel the secrets of bile acids and their impact on our health!

Understanding Bile Acids

Bile acids belong to a diverse family of bile salts, characterised by their planar and amphipathic nature. They possess a hydrophilic hydroxyl and a hydrophobic methyl group, conferring their unique amphipathic properties. These properties allow bile acids to emulsify and solubilize lipids, facilitating their digestion and absorption1.

Bile acids are primarily synthesized in the liver through two pathways: the classic (neutral) pathway and the alternate (acidic) pathway. The classic pathway involves the hydroxylation of cholesterol, while the alternate pathway utilizes oxysterols as precursors. These pathways produce primary bile acids, which are further modified to generate secondary and tertiary bile acids2.

Importance of Bile Acids in Metabolism

Bile acids serve multiple functions in our bodies. Firstly, they emulsify dietary fats, breaking them down into smaller droplets that can be efficiently digested by pancreatic enzymes. Additionally, bile acids are crucial for the absorption of fat-soluble vitamins, such as vitamins A, D, E, and K. These vitamins are incorporated into micelles, facilitated by the presence of bile acids, enabling their uptake3.

Furthermore, bile acids exhibit signalling activity through various receptors, influencing metabolic responses. One key receptor associated with bile acid metabolism is the Farnesoid X receptor (FXR). Activation of FXR regulates bile acid synthesis, delivery, and clearance, maintaining their levels within a safe range. FXR also modulates lipid transport and metabolism, as well as hepatic gluconeogenesis. Another important receptor is TGR5, which influences vasodilation, gallbladder function, and exerts anti-inflammatory effects1.

Illustration of the conformation of bile acids around a central lipid, forming a micelle.

Intrahepatic Cholestasis of Pregnancy

During pregnancy, the metabolic processes in the liver undergo significant adaptations to accommodate the growing foetus. One condition that can arise during pregnancy is intrahepatic cholestasis, commonly known as ICP. It is a multifactorial disorder characterised by elevated levels of bile acids in the blood, particularly chenodeoxycholic acid (CDCA) and cholic acid (CA)4.

ICP manifests in the second or third trimester and can lead to various symptoms such as pruritus (itching), abnormal liver enzyme levels, jaundice, abdominal pain, and depression. The exact mechanisms underlying ICP are not fully understood, but it is believed that elevated bile acid levels may have adverse effects on the cardiovascular system of the foetus, potentially leading to stillbirth or preterm birth5.

The detection and monitoring of ICP are essential for managing the condition and ensuring the well-being of both the mother and the foetus. Total bile acid (TBA) concentration is a commonly measured parameter to assess the severity of ICP. Monitoring TBA levels can aid in identifying potential risks and enabling timely interventions5.

Introducing the 5th Generation Total Bile Acids Assay

To facilitate the accurate quantification of total bile acids in serum and plasma, the 5th Generation Total Bile Acids Assay has emerged as a reliable and advanced diagnostic tool. This assay utilizes a highly sensitive enzymatic cycling method to measure total bile acid levels, providing precise and reproducible results. With its improved sensitivity and specificity, the 5th Generation Total Bile Acids Assay offers a valuable tool for the early detection and monitoring of intrahepatic cholestasis of pregnancy.

The assay is easy to use and can be incorporated into routine laboratory workflows. It requires a small sample volume, making it convenient for both patients and healthcare professionals. The assay provides rapid results, allowing for prompt diagnosis and timely intervention when necessary.

By accurately quantifying total bile acid levels, the 5th Generation Total Bile Acids Assay aids in assessing the severity of ICP and monitoring the response to treatment. This information is vital for guiding clinical decisions and optimizing patient care during pregnancy.

Furthermore, the assay can contribute to ongoing research on bile acids and their role in ICP. By analysing a larger population and monitoring the dynamics of bile acid levels, researchers can gain deeper insights into the mechanisms underlying this condition and explore potential therapeutic targets.

Assay Principle

Two reactions are combined in this kinetic enzyme cycling method. In the first reaction, bile acids are oxidised by 3-α hydroxysteroid dehydrogenase with the subsequent reduction of Thio-NAD to Thio-NADH. In the second reaction, the oxidised bile acids are reduced by the same enzyme with the subsequent oxidation of NADH to NAD. The rate of formation of Thio-NADH is determined by measuring the specific absorbance change at 405nm. Enzyme cycling means multiple Thio-NADH molecules are generated from each bile acid molecule giving rise to a much larger absorbance change, increasing the sensitivity of the assay.

Assay Principle for the 5th Generation Total Bile Acids Assay

In conclusion, understanding the intricacies of bile acids is essential for comprehending their impact on our metabolism and health. Intrahepatic cholestasis of pregnancy is a condition that warrants attention, and accurate measurement of total bile acid levels is crucial for its diagnosis and management. The 5th Generation Total Bile Acids Assay offers an advanced and reliable solution for assessing bile acid levels, enabling timely interventions, and improving patient outcomes. With ongoing research and advancements in diagnostic techniques, we can continue to unravel the complexities of bile acids and enhance our understanding of their role in health and disease.

Don’t underestimate the strength of knowledge and awareness. Empower yourself, stay informed, and prioritize your health and well-being!

If you’d like to learn more about Bile Acids and ICP we encourage you to read our new educational guide, 5th Generation Bile Acids & The Importance of Of Intrahepatic Cholestasis of Pregnancy 

If you would like an additional information on our 5th Generation Total Bile Acids Assay, or anything else, don’t hesitate to reach out the marketing@randox.com. Additionally, feel free to visit our Reagent resource hub where you will find all of our brochures, support tools and a collection of educational material, to aid you in maintaining the highest possible levels of quality.

 

References

  1. McGlone ER, Bloom SR. Bile acids and the metabolic syndrome. Annals of Clinical Biochemistry. 2019;56(3):326-337. doi:https://doi.org/10.1177/0004563218817798
  2. Chiang JYL, Ferrell JM. Bile Acid Metabolism in Liver Pathobiology. Gene Expression. 2018;18(2):71-87. doi:https://doi.org/10.3727/105221618×15156018385515
  3. Chiang JYL. Bile Acid Metabolism and Signaling. Comprehensive Physiology. 2013;3(3). doi:https://doi.org/10.1002/cphy.c120023
  4. Di Mascio D, Quist-Nelson J, Riegel M, et al. Perinatal death by bile acid levels in intrahepatic cholestasis of pregnancy: a systematic review. The Journal of Maternal-Fetal & Neonatal Medicine. Published online November 19, 2019:1-9. doi:https://doi.org/10.1080/14767058.2019.1685965
  5. Piechota J, Jelski W. Intrahepatic Cholestasis in Pregnancy: Review of the Literature. Journal of Clinical Medicine. 2020;9(5):1361. doi:https://doi.org/10.3390/jcm9051361

Bile Acids Reagent

Bile Acids Reagents

Features & Benefits of the Randox Bile Acids reagents

Excellent linearity

The Randox Bile Acids method is linear up to a concentration of 150 µmol/l

Exceptional correlation with standard methods

The Randox methodology was compared against other commercially available methods and the Randox Bile Acids assay showed a correlation coefficient of 0.99

Flexibility

Liquid and lyophilised reagents available for greater customer choice

 

Analyser protocols

Protocols are available for a range of analysers

Excellent stability

Stable to expiry when stored at +2 to +8°C

Ordering information

Cat NoSize
BI3863 (5th)R1 2 x 18ml (L)
R2 2 x 8ml
EnquireKit Insert RequestMSDSBuy Online
BI7982 (5th)R1 6 x 50ml
R2 6 x 18ml
EnquireKit Insert RequestMSDSBuy Online
BI8150 (5th)R1 2 x 17.7ml (L)
R2 2 x 8.9ml
EnquireKit Insert RequestMSDSBuy Online
(L) Indicates liquid reagent

Instrument Specific Applications (ISA’s) are available for a wide range of biochemistry analysers.  Contact us to enquire about your specific analyser.

What are Bile Acids used for?

  • Clinical Significance
  • Biological Significance
  • Inadequacies of traditional bile acid assays

Liver Function

Measuring total bile acid (TBA) levels may prove useful for the detection of liver diseases such as viral hepatitis, mild liver injury through drug use and for further evaluation of patients with chronic hepatitis who were previously treated successfully. TBA levels may rise up to 100 times the normal concentration in patients with liver disease due to impairment of hepatic synthesis and extraction of bile acids. Measurement of TBA in serum can be used in the diagnosis and prognosis of liver diseases and may detect some forms of liver disease earlier than standard liver markers due to the correlation of TBA with liver function, rather than liver damage.

Bile Acid Deficiency

TBA deficiency is caused by a genetic error in one of the 17 enzymes that produce bile acids. Deficiency can lead to liver failure and even death in infants, therefore early detection is vital. People with TBA deficiency may exhibit symptoms, including:

• Vitamin deficiencies, specifically of fat-soluble vitamins such as A, D, E, and K
• Jaundice
• Stunted or abnormal growth
• Diarrhoea
• Loss of liver function
• Liver failure

Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) or obstetric cholestasis is a pregnancy-specific liver disorder. It can be indicated by pruritus, jaundice, elevated TBA levels and/or serum transaminases and usually affects women during the second and third trimester of pregnancy. ICP is a condition that restricts the flow of bile through the gallbladder resulting in a build-up of TBA in the liver. Due to the build-up, Bile Acids leak into the bloodstream where they are detected at concerning levels. It is an extremely serious complication of pregnancy that can lead to the increased risk of premature birth or even stillbirth as such it is vital that women with the condition are monitored carefully.

According to several reports TBA levels in ICP can reach as high as 100 times the upper limit of a normal pregnancy. It has been reported that a doubling in maternal serum TBA levels, results in a 200% increased risk of stillbirth. Additionally, bile acids can affect the foetal cardiovascular system as it has been found that there are often cardiac rhythm disturbances in the foetus due to the elevated TBA in circulation.

There are several risk factors associated with ICP such as family history, use of oral contraceptives, assisted reproduction techniques and multiple gestation. Genetic influence accounts for approximately 15% of ICP cases. Dietary selenium is a contributing environmental factor as serum selenium levels often decrease throughout pregnancy. Further to this, incidences of ICP rise in the winter months and are most likely due to the fact selenium levels are naturally less during these months. In healthy pregnancies, there is very little increase in TBA levels although a slight increase is likely to be seen in the third trimester.

Measurement of TBA in serum is thought to be the most suitable method of diagnosing and monitoring ICP.

Bile acids are water-soluble and amphipathic end products of cholesterol metabolism formed in the liver. Bile is stored in the gall bladder and released into the intestine when food is consumed. The fundamental role of bile acids is to aid in the digestion and absorption of fats and fat-soluble vitamins in the small intestine. In doing so, bile acids have five physiological functions within the body as shown below:

Determining the cause and extent of liver damage is important in guiding treatment decisions and preventing disease progression. Standard liver function tests include; ALT, AST, ALP, GGT and Bilirubin. The measurement of TBA is most beneficial in conjunction with these standard liver tests and offers unrivalled sensitivity allowing identification of early stage liver dysfunction.

There are several commercial methods available for the detection and measurement of TBA in serum. Traditional TBA tests based on the enzymatic method use nitrotetrazolium blue (NBT) to form a formazan dye. The reaction is measured at 546nm and the intensity of the colour is proportional to the concentration of bile acids.

Newer methods such as the enzyme cycling method or fifth generation methods offer many advantages including greater sensitivity, liquid reagents, small sample volumes and reduced instrument contamination from formazan dye. Additionally, the fifth generation assay does not suffer from interference from lipaemic or haemolytic samples. Both lipaemia and haemolysis are common in new-borns and pregnant women.

Enzyme cycling methods offer superior analytical performance, two reactions are combined. In the first reaction, bile acids are oxidised by 3-α hydroxysteroid dehydrogenase with the subsequent reduction of Thio-NAD to Thio-NADH. In the second reaction, the oxidised bile acids are reduced by the same enzyme with the subsequent oxidation of NADH to NAD. The rate of formation of Thio-NADH is determined by measuring the specific absorbance change at 405nm. Enzyme cycling means multiple Thio-NAD molecules are generated from each bile acid molecule giving rise to a much larger absorbance change and signal amplification, increasing the sensitivity of the assay.

The assay principle is demonstrated in the diagram below:

The Randox fifth generation assay utilises the advanced enzyme cycling method which displays outstanding sensitivity and precision compared to traditional enzymatic based tests. The assay shows excellent linearity of up to 188 µmol/l with the normal upper range of TBA in a fasting serum sample being at 10 µmol/l. The liquid ready-to-use reagent is available along with complementary controls and calibrators for a complete testing package.


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