Total Bile Acids Test and Clinical Diagnosis

Background

Bile Acid Chemistry and Physiology

Introduction Bile acids are 24-carbon steroids formed from cholesterol in the liver. Five major bile acid forms compose over 99% of the bile acid pool formed in body fluids. The chemistry and physiology of bile acids have been extensively studied, and the pioneering work on the molecular structural determination of bile acids was mainly accomplished by Dr. Heinrich Otto Wieland at the University of Munich, Germany, in 1920s. “For his investigations of the constitution of the bile acids and related substances,” Dr. Wieland was awarded the Noble Prize in Chemistry in 1927. In the last half century, the chemistry and biology of bile acids have been well developed, and serum total bile acids (TBA) level as an indicator for liver diseases has been well established and accepted in clinical practices. This brochure summarizes serum TBA as a marker for clinical diagnosis of liver diseases, prognostic test for HCV, testing for cholestasis during pregnancy, TBA for veterinary testing, and the methods for serum TBA testing.

Bile Acids and Compositions The liver synthesizes two primary bile acids, cholic acid and chenodeoxyclolic acid from cholesterol. The primary bile acids are converted to the secondary bile acids, deoxycolic acid and lithocholic acid by intestinal bacteria. A fraction of chenodeoxycholic acid is also transformed into the tertiary bile acid, ursodeoxycholic acid, in the liver. All bile acids secreted by the liver are conjugated with an amino acid, either with glycine or with taurine. The conjugated bile acids form further complex with sodium to become bile salts. In clinical diagnosis, TBA testing refers to the testing of the sum of all these forms of bile acid conjugates (primary, secondary, and tertiary bile acids and their conjugates). The average bile acid composition of healthy human adult bile is 38% cholate conjugates, 34% chenodeoxycholate conjugates, 28% deoxycolate conjugates, 1-2% lithocholate conjugates as shown in Table 1

Class

Name

Chemical

Forms of Conjugates

Percent of
Total Bile Acid
Conjugates in human Adults
in Healthy

Primary

Cholic acid
Chenodeoxycholic Acid

3a-7a, 12a- Trihydroxy-
5b cholanic acid
3a,7a-Dihydroxy-5bcholanic acid

 

Glycine
Or
Taurine

 

36- 38 %
Or
32 - 34%

Secondary

Converted from Primary
by intestinal bacteria

Deoxycholic acid

Lithocholic acid

3a,12a-Dihydroxy-5bcholanic
acid
3a-Hydroxy-5bcholanic acid

Glycine
or
Taurine

26 -28%

1-2 %

Tertiary
From Chenodeoxy cholic acid in liver

Ursodexycholic
acid

3a,7b-Dioxycholanic

Glycine
or
Taurine

1-2 %

Table 1. Major bile acids in body fluids

Physiological Functions of Bile Acids Bile acids are the major constituents of bile, and in mammals, compose approximately 67% of bile secretion. Bile acids are released from the liver as conjugated salts into the small intestine via the bile duct during intestinal contraction. Because conjugated bile acids possess both polar and non-polar regions, molecules like bile acids are able to solubilize biliary lipids, act like a detergent to emulsify dietary fat droplets through the formation of mixed micelles. This significantly increases the surface area of fat, making it available for digestion by lipase, which otherwise can not access the interior of lipid droplets. Bile acids are lipid-carriers and are able to solubilize many lipds by forming mixed micelles with fatty acids, cholesterol for the solubilization and absorption of fat-soluble vitamins such as vitamin E. The ability of bile acids to solubilize cholesterol in bile is the major mechanism of cholesterol elimination from the body to prevent cholesterol accumulation with the attendant risk of atherosclerosis.

Bile Acids Metabolism and Enterohephatic Circulation

More than 90% of the bile acids are actively reabsorbed (by a sodium-dependent co-transport process) from the ileum into the hepatic portal circulation from where they are cleared and re-secreted by the liver to once again be stored in the gallbladder. This secretion/reabsorption cycle is called the enterohepatic circulation as shown in Figure 2. The bile acids pool cycles 5-10 times daily through the enterohepatic circulation where it is almost completely confined. The liver normally clears 20 g of bile salt from the blood each day. Less than 1% of the total bile acid pool is present in the peripheral blood due to the high efficiency of the hepatic transport mechanism for bile acids. Normally, the liver is very efficient at capturing and removing bile acids from the hepatic-portal circulation. This is why the peripheral blood levels of total bile acids are quite low in healthy subjects. The levels of circulating bile acids at any moment are determined by the balance between intestinal absorption and hepatic elimination of bile acids. However, when the enterohepatic circulation system is impaired, blood levels of bile acids are increased as a result of diminished hepatic elimination of bile acids from the portal blood, which results from diminished hepatic clearance and from portosystemic shunting as shown in Figure 3.


Figure 2
Figure 3