Exploring the Intricacies of Bile Acids: Understanding Their Role in Metabolism and Intrahepatic Cholestasis of Pregnancy
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.
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.
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
- 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
- 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
- Chiang JYL. Bile Acid Metabolism and Signaling. Comprehensive Physiology. 2013;3(3). doi:https://doi.org/10.1002/cphy.c120023
- 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
- 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
Total Bile Acids: The Value of Fifth Generation Tests
Bile acids are water-soluble, amphipathic end products of cholesterol metabolism and are involved in liver, biliary and intestinal diseases. They are formed in the liver and are absorbed in the small intestine before being excreted. The fundamental role of bile acids is to aid in the digestion and absorption of fats and fat-soluble vitamins in the small intestine.1
Intrahepatic Cholestasis of Pregnancy
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder. It can be indicated by pruritus, jaundice, elevated total bile acids and/or serum transaminases and usually affects women during the second and third trimester of pregnancy.2,3
Intrahepatic Cholestasis of pregnancy or Obstetric Cholestasis is a condition that restricts the flow of bile through the gallbladder resulting in a build-up of bile acids in the liver.3 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 disease are monitored carefully.
In healthy pregnancies, there is very little increase in total bile acid levels although a slight increase is likely to be seen in the third trimester. Measurement of total bile acids in serum is thought to be the most suitable method of diagnosing and monitoring ICP.6
According to several reports total bile acid 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 bile acids, results in a 200% increased risk of stillbirth with total bile acids thought to trigger the onset of preterm labour. 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 bile acids in circulation.5
Although it is a rare condition, with only 0.3-0.5% of women likely to develop ICP, it can have extreme risks and so it is important to properly diagnose and monitor the condition.6 ICP increases the risk of meconium staining of the amniotic fluid and is reported to be a sign of foetal distress. This complication is found in 16-58% of all ICP cases, worryingly 100% of cases have resulted in foetal death. The frequency of this condition is found to be greater in pregnancies with higher levels of serum total bile acids.
Risk factors
There are several risk factors associated with ICP such as a family history of ICP, 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, most likely due to the fact selenium levels are naturally less during these months.7,8
Total Bile Acids
In addition to ICP, bile acid levels are also measured in the diagnosis of other liver disorders. The bile acids test in an extremely sensitive indicator of liver function, capable of detecting changes in hepatic function before clinical symptoms arise, thus providing valuable information that standard liver function tests cannot. As a result of its high sensitivity, bile acids can be used to assess liver function in transplant patients, allowing monitoring of the transplant success and of antirejection therapy. The bile acids test is most beneficial when used in conjunction with standard liver function tests such as ALT and AST which are markers of liver damage rather than liver function.
Measurement of Total Bile Acids
The enzyme cycling method, also known as the Fifth Generation Bile Acids test, is a method that allows for signal amplification through cycled regeneration reactions as can be seen in Figure 1. In the presence of Thio-NAD, the enzyme 3-α hydroxysteroid dehydrogenase (3-α HSD) converts bile acids to 3-keto steroids and Thio-NADH. The reaction is reversible and 3-α HSD can convert 3-keto steroids and Thio-NADH to bile acids and Thio-NAD. In the presence of excess NADH, the enzyme cycling occurs efficiently and the rate of formation of Thio-NADH is determined by measuring specific change of absorbance at 405 nm and is proportional to the amount of total bile acids in the sample. The analysing capability of the fifth generation total bile acids assay is far beyond the performance of conventional bile acid tests.10,11
Figure 1: The assay principle⁹
Inadequacies of Traditional Bile Acids Assays
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 lipemia and haemolysis are common in new-borns and pregnant women, so this further supports that the fifth generation test is more sensitive for these sample types.12
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References
[1] The continuing importance of bile acids in liver and intestinal disease. A.f., Hofmann. 1999, Arch Intern Med, pp. 2647-2658.
[2] Diagnostic and Therapeutic Profiles of Serum Bile Acids in Women with Intrahepatic Cholestasis of Pregnancy – A Pseudo-Targeted Metabolomics Study. Cui, Yue. Xu, Biao. Zhang, Xiaoqing. He, Yifan. Shao, Yong. Ding, Min. s.l. : Clinica Chimica, 2018, Vol. 483.
[3] Randox Laboratories. Bile Acids Test for Obstetric Cholestasis – A serious complication of pregnancy. 2012.
[4] British Liver Trust (2019) Facts about Liver Disease, Available at: https://www.britishlivertrust.org.uk/about-us/media-centre/facts-about-liver-disease/ (Accessed: 18th June 2019).
[5] .Geenes, Victoria. Williamson, Catherine. 17, s.l. : World J Gastroenterol, 2009, Vol. 15.
[6] Howland, Genevieve. Cholestasis of Pregnancy: Why You Can’t Ditch the Itch. Mama Natural. [Online] December 22, 2018. [Cited: February 19, 2019.] https://www.mamanatural.com/cholestasis-of-pregnancy/.
[7] Bile Acid Levels and Risk of Adverse Perinatal Outcomes in Intrahepatic Cholestasis of Pregnancy: A Meta-Analysis. Cui, Donghua, et al.
[8] Intrahepatic Cholestasis of Pregnancy. Chivers, Sian. Williamson, Catherine. 7, 2018, Vol. 28.
[9] Masoud, N; Neill, S.H. Serum bile acids as a sensitive biological marker for evaluating hepatic effects of organic solvents. Available from URL: https://www.ncbi.nlm.nih.gov/pubmed/23885947 [Accessed 1 November 2018]
[10] Microassay of Serum Bile Acids by an Enzymatic Cycling Method. Komiyama, Y, et al. 10, s.l. : Chemical and Pharmaceutical Bulletin, 1982, Vol. 30.
[11] Evaluation of a Colorimetric Enzymatic Procedure for Determining the Total Bile Acids in the Blood. Agape, V, et al. 3, s.l. : Minerva Gastroenterologica e Dietologica, 1989, Vol. 35.
[12] Total Bile Acids Test & Clinical Diagnosis. Diazyme. 2019.
Liver Cirrhosis is a Global Health Burden
#LoveYourLiver this January. This month, we are taking a closer look at Liver Cirrhosis.
Liver cirrhosis occurs when the healthy tissue of the liver is replaced with scar tissue (fibrosis) due to long-term liver damage. Liver cirrhosis can result in liver failure which can be fatal.
Liver complications such as liver disease and cirrhosis can be detrimental if it is not treated or monitored. Liver disease is the only major cause of death still increasing year-on-year. Globally, deaths due to liver cirrhosis have increased from 676,000 in 1980 to over 1 million in 2010 (NCBI, 2014). Cirrhosis and other chronic liver diseases have increased by 12.4% from 2006-2016 and was the cause of 1,256,900 deaths in 2016 (Global Burden of Disease, 2016).
There are a few factors that increase the risk of liver cirrhosis. The three main factors are heavy alcohol consumption, an undiagnosed hepatitis infection, particularly hepatitis C, and non-alcoholic steatohepatitis (a more severe form of non-alcoholic fatty liver disease) due to obesity.
There are numerous symptoms associated with liver cirrhosis. Some of the more severe symptoms include:
- Jaundice – yellowing of the skin and whites of the eyes
- Personality changes, confusion, difficulty concentrating, memory loss, or hallucinations
- A tendency to bleed or bruise easily
- In women, abnormal periods
- In men, enlarged breasts, a swollen scrotum (the loose sac of skin that contains the testicles) or shrunken testicles
- Vomiting
- Diarrhea
- Stomach pain – swollen or bloated stomach
Liver cirrhosis cannot be cured, but the aim of treatment is to manage the symptoms and complications, and to stop the condition getting worse.
#LoveYourLiver and prevent or reduce the symptoms of liver cirrhosis through: moderating alcohol consumption, not sharing needles to inject drugs, using a condom during sex, taking medications as prescribed, and maintaining a healthy weight.
The early stages of liver cirrhosis usually does not present any symptoms and is often first detected using routine blood tests. Liver cirrhosis can be diagnosed and monitored through the following routine blood tests:
Alanine Aminotransferase (ALT)
ALT is one of the enzymes within the aminotransferases group and are among the most sensitive liver enzymes. The normal concentration levels of ALT in the blood are low, however, when the liver is damaged, such as liver cirrhosis, the levels of ALT increase. During the diagnosis of liver cirrhosis, the root cause of the damage can be established, such as disease, drug or injury. ALT is commonly measured alongside AST as part of the hepatic panel.
Aspartate Aminotransferase (AST)
AST is an enzyme found throughout the body. Elevated concentration levels of AST in the blood is directly correlated to the severity of the tissue damage. AST also allows for the root cause of the damage to be diagnosed. Excessive levels are indicative of damage due to acetaminophen overdose or acute viral hepatitis. Moderately high levels are indicative of alcohol abuse. Slightly high levels are indicative of cirrhosis.
AST is commonly measured alongside ALT as part of the hepatic panel, although ALT levels are higher in most types of liver damage.
Albumin
Albumin is a special protein made in the liver and provides the body with the proteins it requires to grow and repair tissue. The body requires a proper balance of albumin to prevent fluid from seeping out of blood vessels. Decreased concentrations levels of this protein in the blood is an indicator of liver cirrhosis.
Randox supply a range of third party clinical diagnostic hepatic reagents to aid in the diagnosis and managing the complications of liver cirrhosis. All reagents are available for use on a range of third party biochemistry analysers. Randox offer the following hepatic reagents to diagnose liver cirrhosis:
Alanine Aminotransferase (ALT)
Aspartate Aminotransferase (AST)
Randox also offer the following high performance and unique tests to diagnose liver cirrhosis:
Why choose Randox reagents?
- Randox offers the largest range of chemistries
- Liquid ready-to-use reagents available
- Automated applications for a wide range of clinical analysers
- Excellent correlation to reference methods
- Wide measuring ranges
- Flexible pack sizes
- Official accreditation to national and international standards including UKAS, ISO 13485:2003, and FDA.
- Easy fit reagents
- Easy read reagents
To request an application for your specific analyser, contact reagents@randox.com
For more information on liver function or to view our hepatic panel, visit https://www.randox.com/liverfunction/
