Bile acid

Other Names

5beta-cholanic acid5β-cholan-24-oic acid5β-cholanic acid5β-cholanoic acidbile acid/saltbile acidsbile acids/saltsbile saltbile saltsC24 bile acidC27 bile acidCDCAchenodeoxycholatechenodeoxycholic acidchenodiolcholan-24-oic acidcholanic acidcholanoic acidcholanoidcholanoidscholatecholestanoidcholestanoidscholic acidconjugated bile acidconjugated bile acidsDCAdeoxycholatedeoxycholic acidGDCAglycochenodeoxycholateglycochenodeoxycholic acidglycocholateglycocholic acidglycodeoxycholateglycodeoxycholic acidglycoursodeoxycholic acidhyodeoxycholatehyodeoxycholic acidlithocholatelithocholic acidprimary bile acidprimary bile acidssecondary bile acidsecondary bile acidssteroid acidsteroid acidssteroidal acidtaurochenodeoxycholatetaurochenodeoxycholic acidtaurocholatetaurocholic acidtaurodeoxycholatetaurodeoxycholic acidtauroursodeoxycholic acidTCAUDCAunconjugated bile acidunconjugated bile acidsursodeoxycholic acidursodiol

Synopsis

Bile Acids: A Comprehensive Reference

1. Identity, Chemistry, and Natural Sources

1.1 Chemical Identity and Nomenclature

Bile acids, also known as steroid acids, are amphiphilic water-soluble molecules that are mainly synthesized by the liver (primary forms) and by bacterial transformation in the colon (secondary forms). Bile acids are amphiphilic molecules with 24 carbon atoms, consisting of a hydrophobic and rigid steroid nucleus to which are attached a hydrophilic hydroxyl group and a flexible acidic aliphatic side chain. The steroidal core constitutes a saturated cyclopentanoperhydrophenanthrene skeleton, consisting of three six-membered (A, B, and C) rings and one five-membered ring (D).

The pKa of the unconjugated bile acids is between 5 and 6.5. Conjugating bile acids with amino acids lowers the pKa of the bile-acid/amino-acid conjugate to between 1 and 4, dramatically improving their solubility and ionization at physiological pH. Bile acids are usually found as conjugates with taurine or glycine in the bile of mammals and vertebrates. The sodium and potassium salts of these negatively charged molecules are called bile salts, which is a more appropriate term from the chemical perspective.

1.2 Classification

The classification of bile acids is diverse. Based on their origin, they can be categorized into primary bile acids (PBA), secondary bile acids (SBA), and tertiary bile acids. Furthermore, according to molecular groups, they can be classified as hydrophilic or hydrophobic bile acids.

Primary Bile Acids: Chenodeoxycholic acid (CDCA) and cholic acid (CA) are the two primary bile acids in humans, and are conjugated mainly to glycine (G) and taurine (T). Primary bile acids are produced in the hepatocytes. Prior to secreting bile acids (primary or secondary), liver cells conjugate them with either glycine or taurine, to form a total of 8 possible conjugated primary bile acids.

Secondary Bile Acids: Secondary bile acids are formed by modifying the primary bile acids in the intestinal lumen — specifically by 7α-dehydroxylation and deconjugation of cholic acid (CA) and chenodeoxycholic acid (CDCA). The most important secondary bile acids are deoxycholic acid (DCA) and lithocholic acid (LCA).

Tertiary Bile Acids: The 7α-dehydrogenation of CDCA forms the dihydroxy 7α-oxo-LCA, which does not accumulate in bile but is metabolized to a "tertiary" bile acid by hepatic or bacterial reduction to CDCA, mainly in the liver, or to its 7β-epimer, the dihydroxy ursodeoxycholic acid (UDCA), primarily by colonic bacteria.

Nearly all primary bile acids and bile alcohols have a 7α-hydroxyl group; ursodeoxycholic acid (UDCA) being a notable exception.

1.3 Natural Sources

Bile acids are synthesized in the hepatocytes as the main product of cholesterol catabolism. Although there are several different biosynthetic routes to bile acids from cholesterol, there are four main steps, and the liver is the only organ concerned in the production of the primary bile acids. In fact, there are at least 16 enzymes that catalyze up to 17 reactions to convert insoluble cholesterol into a highly soluble conjugated bile salt. At least one transporter and multiple cellular compartments — including the cytosol, endoplasmic reticulum, mitochondria and peroxisomes — are involved.

More than 95% of the bile acid pool is reabsorbed from the intestine, predominantly by an active sodium-dependent apical bile acid transporter (ASBT) in the terminal ileum, and transported back to the liver bound mainly to albumin and to a lesser extent to lipoproteins.

A limited pool of bile acids that is not reabsorbed in the small intestine undergoes dehydroxylation and deconjugation in the large intestine by bacterial enzymes, leading to the formation of secondary bile acids — deoxycholic acid (DCA) from CA, and lithocholic acid (LCA) from CDCA.

1.4 Common Forms and Preparations

The clinically and commercially relevant bile acid preparations include the following individual compounds:

Ursodeoxycholic acid (UDCA; also known as ursodiol): A naturally occurring bile acid that constitutes a small proportion of the human bile acid pool.
Tauroursodeoxycholic acid (TUDCA): Recognized as a neuroprotectant that can attenuate neuroinflammation and inhibit pro-inflammatory factors. TUDCA is a substance naturally produced by the body and found in small trace amounts in bile.
Chenodeoxycholic acid (CDCA): One of the two primary human bile acids, also brought to market as a pharmaceutical agent for gallstone dissolution.
Obeticholic acid (OCA): A semisynthetic bile acid derivative serving as a potent FXR agonist used in clinical settings.
Deoxycholic acid (DCA): A secondary bile acid used in injectable cosmetic formulations for submental fat reduction.

In spite of the extremely valuable therapeutic activities and the long historic medical uses of bile acids as therapeutically active agents and as carriers and/or adjuvants, the commercial administration of bile acids is limited to pharmaceutical formulations in solid form — tablet, capsule, and suspension. Ursodeoxycholic acid, chenodeoxycholic acid, and lithocholic acid are practically insoluble in water. Deoxycholic acid and cholic acid have solubilities of 0.24 g/L and 0.2 g/L, respectively.

2. Traditional and Historical Use

2.1 Ancient Egyptian and East Asian Use

In the ancient Egyptian Ebers papyrus (~1550 BCE), a medical summary of about 700 diseases on 110 papyrus pages, bile was first mentioned as a potentially useful remedy and purge. An ancient medical anthology from a tomb in Southern China dated back to about 300 BCE recommended the use of animal bile for jaundiced patients based on the therapeutic principle Yi Du Gong Du, that is, combatting poison with poison. Strikingly, bear bile was already considered the "king" of animal biles in that anthology.

Bile from 44 different animals (both invertebrates and vertebrates, including human bile) has been used for centuries for a host of maladies in traditional Chinese medicine beginning in the Zhou dynasty (~1046–256 BCE).

2.2 Traditional Chinese Medicine

Bear bile has been used in Traditional Chinese Medicine clinical practice for thousands of years. It was used for detoxification, reduction of inflammation, swelling, fever and pain, and for several liver diseases, including fibrosis, biliary cirrhosis, and even liver cancer. Bile acids were recognized as the main compounds in bear bile responsible for pharmacodynamic activity.

In the Chinese Tang Materia Medica, the worldwide first state pharmacopoeia collected during the classical period of Chinese art and literature of the T'ang dynasty (618–907 CE), it was stated that "bear bile which tastes bitter can be used to treat jaundice, … intractable diarrhea in summer and cardialgia."

2.3 Transition to Modern Science

Although the bile acid structure, function, and application have been investigated for more than 150 years, new signaling pathways and their varied roles in metabolism and overall physiology are still being uncovered. In 1927, a four-ring structure with a varying side chain of carbon atoms was first proposed for bile acids.

The application of bile acids, as major organic components of bile, for gallstone dissolution and of ursodeoxycholic acid (UDCA) for cholestatic liver diseases began in the second half of the 20th century. A small pharmaceutical company, Dr. Falk Pharma, based in Freiburg, Germany, was the first European company to bring CDCA to market for gallstone dissolution.

3. Key Constituents and Active Compounds

3.1 Primary Bile Acids

The two main primary bile acids in humans — cholic acid (CA) and chenodeoxycholic acid (CDCA) — are synthesized directly from cholesterol in hepatocytes. Primary bile acids are steroids produced via the liver, specifically in peroxisomes. There, the acids conjugate or connect to hydrophilic amino acids, namely glycine/taurine (i.e., conjugated bile acids called glycocholic and taurocholic acids, respectively); alongside sodium/potassium, they are termed bile salts.

3.2 Secondary Bile Acids

Secondary bile acids are formed from bacterial deconjugation/dehydroxylation of primary bile acids and removal of amino acid groups, creating four more different types of bile acids (including deoxycholic and lithocholic acids). These acids are absorbed through the bloodstream and brought back to the liver via the enterohepatic circulation to then be resecreted.

Secondary bile acids function primarily as signaling molecules, which can influence such processes as immune responses, fat digestion, and cell proliferation.

3.3 Conjugated Forms

The final step in bile acid synthesis involves conjugation of the terminal side-chain carboxylic acid with the amino acids glycine or taurine, carried out by the enzyme bile acid CoA: amino acid N-acyltransferase (BAAT). These additions substantially increase the acidity of the molecules and their solubility in water. At the physiological pH values in the intestines, the bile acid conjugates ionize and exist in salt form.

3.4 Amphiphilicity and Detergent Properties

Due to their amphiphilic structure, bile acids allow the emulsification, digestion, and absorption of lipophilic xenobiotics after a meal. Bile acids are physiological detergents needed for absorption of dietary fat, steroids, and lipid-soluble vitamins, and are also signal molecules and endogenous ligands that activate nuclear farnesoid X receptor (FXR) and membrane Takeda G protein-coupled receptor 5 (TGR5, i.e., G protein-coupled bile acid receptor-1).

4. Mechanisms of Action

4.1 FXR (Farnesoid X Receptor) Signaling

The regulatory function of bile acids is predominantly mediated by the bile acid-activated nuclear receptor farnesoid X receptor (FXR) and G protein-coupled receptor TGR5. FXR is a nuclear receptor that modulates gene transcription upon ligand binding, giving it a genomic, transcriptional mode of action. FXR activation improves metabolic homeostasis primarily through two mechanisms. On one hand, it lowers blood glucose by inhibiting gluconeogenesis and promoting glycogen storage, processes mediated by fibroblast growth factor 19/15.

FXR plays a central role in maintaining bile acid homeostasis, and also exerts metabolic effects indirectly by inducing the expression of fibroblast growth factor 15/19 (FGF15/19), which acts as an endocrine signal regulating glucose and energy metabolism.

4.2 TGR5 (Takeda G Protein-Coupled Receptor 5) Signaling

TGR5 was first identified by Takaharu Maruyama and colleagues in 2002. It is a rhodopsin-like, G protein-coupled receptor (GPCR) activated by conjugated and unconjugated bile acids. TGR5 is ubiquitously expressed in murine models and humans, and its activation has been highlighted by several studies as an important metabolic regulator, influencing body weight, energy expenditure, glucose metabolism, satiety, insulin resistance, liver steatosis, and atherosclerosis.

In contrast to FXR, TGR5 triggers rapid, non-genomic effects through second messenger pathways, specifically through cAMP-dependent mechanisms. Overall, downstream signaling mediated by TGR5 is involved in gene transcription modulation, influencing cell proliferation, survival, apoptosis, inflammation, and metabolism.

4.3 GLP-1 and Gut Hormone Modulation

Bile acids are now recognized as signaling molecules that orchestrate blood glucose, lipid and energy metabolism. Changes in FXR and/or TGR5 signaling modulate the secretion of gastrointestinal hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), hepatic gluconeogenesis, glycogen synthesis, energy expenditure, and the composition of the gut microbiome.

4.4 Central Nervous System Signaling

Bile acid signaling to the CNS encompasses both direct and indirect pathways. Bile acids can act directly in the brain via central FXR and TGR5 signaling. In addition, there are two indirect pathways that involve intermediate agents released upon interaction with bile acid receptors in the gut. Activation of intestinal FXR and TGR5 receptors can result in the release of fibroblast growth factor 19 (FGF19) and glucagon-like peptide 1 (GLP-1), both capable of signaling to the CNS.

4.5 Cholesterol Catabolism

Bile acid synthesis is the most significant pathway for catabolism of cholesterol and is responsible for the daily output of approximately 90% of cholesterol in the body.

4.6 Antimicrobial and Signaling Effects

Bile acids act as signaling molecules, have antimicrobial effects, regulate cholesterol homeostasis, and prevent the formation of gallstones and kidney stones.

5. Scientific Evidence by Area of Use

5.1 Cholestatic Liver Disease — Primary Biliary Cholangitis (PBC)

This is the best-supported clinical indication for a specific bile acid (UDCA) and represents the highest level of evidence in this field.

Currently, UDCA is regarded as an effective first-line treatment for primary biliary cholangitis (PBC), the most common chronic cholestatic liver disease, and is also applied in other cholestatic disorders, including primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy.

Ursodeoxycholic acid (UDCA) has been recommended as the first-line therapy for PBC patients according to guidelines since its approval by the Food and Drug Administration (FDA) in 1977, as it benefits biochemical mitigation and transplantation-free survival. UDCA was also found to slow the patient's histological progress compared with a placebo. Studies have revealed quantitative and compositional changes in the bile pool of PBC patients, and a positive correlation was found between the response and enrichment of UDCA in the patient's bile pool.

Despite the efficacy, it was estimated that nearly 40% of PBC patients on standard UDCA therapy did not achieve a complete response. Many clinical trials have been carried out to explore alternative options for those nonresponders, one of which was an increased dosage of UDCA. A prior clinical trial comparing the effectiveness between 20 mg/kg/d and 10 mg/kg/d UDCA found that the 20 mg/kg/d dosage resulted in greater biochemical decreases.

Evidence strength: Multiple randomized controlled trials, regulatory approval (FDA and MHRA), and first-line guideline status constitute strong evidence for UDCA in PBC.

5.2 Gallstone Dissolution

UDCA is FDA-approved for two specific indications: dissolution of radiolucent, noncalcified gallbladder stones less than 20 mm in patients with increased surgical risk, and prevention of gallstone formation in obese patients experiencing rapid weight loss.

A clinical study in which patients with idiopathic acute pancreatitis attributed to microscopic gallstones or biliary sludge showed complete resolution of gallbladder microlithiasis after UDCA treatment, demonstrating its therapeutic effect. The dose of 10 to 15 mg/kg used in most large trials was mostly for gallstone dissolution.

Gallstones arise from an imbalance in bile acid composition or reduced bile flow, which can lead to cholesterol crystallization and gallstone formation. Evidence for UDCA in symptomatic gallstones is heterogeneous, with 7 of 8 studies showing favorable results for biliary pain, though clinical equipoise exists and Level 1 evidence is needed.

Evidence strength: Moderate to strong for specific subpopulations of radiolucent cholesterol stones; less certain for broader gallstone indications.

5.3 Primary Sclerosing Cholangitis (PSC)

UDCA is used for the treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC), for which it has a positive effect on laboratory values and may delay the development of liver failure; however, standard doses of UDCA (8–15 mg/kg daily) have been shown to be ineffective in the treatment of primary sclerosing cholangitis (PSC).

One early double-blind, placebo-controlled preliminary study examined high-dose UDCA (20 mg/kg daily) in 26 PSC patients over two years, assessing symptoms, clinical signs, biochemical tests, cholangiography, and liver biopsy. High-dose UDCA treatment was suggested to increase the risk of colorectal cancers in PSC patients, a finding that has significantly tempered enthusiasm for high-dose UDCA in this condition.

Evidence strength: Standard-dose UDCA is not established as effective in PSC; high-dose regimens have raised safety concerns. Evidence is currently insufficient and mixed.

5.4 Metabolic Syndrome, Obesity, and Type 2 Diabetes

Research in the past two decades has unveiled important roles for bile acids in the regulation of hepatic lipid, glucose and energy metabolism. Small molecule ligands that target TGR5 and FXR have shown promise in treating various metabolic and inflammation-related human diseases.

Investigations into the mechanisms underlying bariatric surgery and bile acid binding resin treatment suggest that modulation of the enterohepatic bile acid signaling represents a new strategy to treat obesity and type 2 diabetes. The mechanisms by which bile acids improve glycemic control following gastric bypass may involve FXR signaling in glucose metabolism and/or TGR5 signaling in energy metabolism and insulin sensitivity.

A 2009 randomized trial showed no cholesterol-lowering effect for UDCA in primary type IIa or IIb hypercholesterolemia.

Evidence strength: Mechanistic and animal data are compelling. Clinical evidence remains largely preliminary or indirect (e.g., inferred from bariatric surgery outcomes). Direct intervention trials using bile acids as supplements for metabolic syndrome in humans are limited.

5.5 Non-Alcoholic Fatty Liver Disease (NAFLD) and Steatohepatitis (NASH)

Pre-clinical and clinical trials of FXR and TGR5 agonists for NASH therapies are ongoing. FGF19 is a downstream signal of intestinal FXR that has been shown to inhibit bile acid synthesis, reduce inflammation, and promote energy metabolism in experimental NAFLD models.

Despite UDCA's hepatoprotective properties, NICE guidance explicitly advises against using UDCA for NAFLD due to insufficient evidence of clinical benefit.

Evidence strength: Preclinical data are promising for FXR/TGR5 agonists in NASH. Clinical evidence for UDCA itself in NAFLD/NASH is negative or insufficient by current regulatory standards.

5.6 Neurodegenerative Disease — ALS (Amyotrophic Lateral Sclerosis)

Tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities. A proof-of-concept phase IIb study showed that, in patients who received TUDCA (a potentially cytoprotective drug) in addition to riluzole for 54 weeks, the per-year decline rate in the revised ALS functional rating scale was about seven points smaller compared to riluzole alone.

A large-scale phase III trial (TUDCA-ALS) was subsequently conducted to confirm these findings. The Phase 3 clinical trial of TUDCA investigated the safety and efficacy of the drug over 18 months. The trial did not meet its primary endpoint. A greater than 20% reduction in the slope of the ALSFRS-R score after 18 months was not observed, which indicates there was no reduction in disease progression. Statistically significant differences in secondary endpoints, such as survival and a marker of nerve damage (neurofilament light chain), were also not observed.

The trial recruited 334 participants across 26 centres across Italy, Germany, UK, France, Belgium, the Netherlands and Ireland. The trial was randomized, double-blind and placebo-controlled, and participants were assessed over an 18-month period for both safety and potential effect of TUDCA on disease progression.

Evidence strength: Phase IIb results were encouraging, but the definitive Phase III trial failed to meet its primary endpoint. Current evidence does not support TUDCA as an effective treatment for ALS.

5.7 Bile Acid Malabsorption and Chronic Diarrhea

Bile acid malabsorption (BAM) is a common entity in patients experiencing chronic watery diarrhea. Literature suggests that BAM is underdiagnosed and undertreated. The 75-selenium homocholic acid taurine (SeHCAT) test is a nuclear medicine investigation considered to be the gold standard for the diagnosis of bile acid malabsorption (BAM).

One retrospective study investigated the frequency of BAM using 75SeHCAT scintigraphy and the response to treatment with bile acid sequestrants by evaluating the clinical data of 420 patients who had a 75SeHCAT scan from January 2016 to January 2023. Out of 420 patients, 192 (46%) had a positive result for BAM.

Overall, treatment with bile acid sequestrants (BAS) was effective (complete or partial response) in 76% of patients with BAM, regardless of type or severity.

Cholestyramine resin is a bile acid sequestrant indicated for treating primary hypercholesterolemia and select cases of bile-acid diarrhea or choleretic enteropathy due to limited ileal disease or resection. Cholestyramine can be used to treat patients with bile-acid diarrhea or choleretic enteropathy due to limited ileal disease or resection. Diarrhea develops in these patients because bile acids stimulate active chloride secretion in the colon.

Evidence strength: Clinical evidence for bile acid sequestrants in bile acid diarrhea is well-established. Evidence for 75SeHCAT-guided management is strong in countries where the test is available.

5.8 Colorectal Cancer Risk

In a recently conducted prospective, nested case-control study, circulating bile acids were strongly and directly associated with risk for incident colorectal cancer (CRC). Furthermore, secondary bile acids, derived via metabolism by gut bacteria of primary bile acids that escape enterohepatic circulation, are promoters of oxidative stress, inflammation, and DNA damage.

Patients with gallstone disease and cholecystectomy, who are believed to have higher concentrations of secondary bile acids due to continuous flow of bile acids to the bowel, have an increased risk of CRC. Secondary bile acids might contribute to development of CRC because they generate reactive oxygen and nitrogen species that cause DNA damage and promote resistance to apoptosis.

Ursodeoxycholic acid (UDCA) has been found to inhibit tumor development, while deoxycholic acid (DCA) and lithocholic acid (LCA) are generally considered potential carcinogens. Conversely, certain bile acids, such as lithocholic acid, have also been shown to possess anti-cancer properties in some experimental contexts, illustrating the complexity of the relationship.

Evidence strength: Epidemiological associations between elevated secondary bile acids and CRC risk are supported by prospective data. Causal mechanisms are biologically plausible but causal human intervention data are limited.

5.9 Gut Microbiome and Dysbiosis

Bile acids and the composition of the bile acid pool have historically been hypothesized to be associated with several disease states, including recurrent Clostridium difficile infection, inflammatory bowel diseases, metabolic syndrome, and several cancers. Recently, however, emphasis has been placed on how microbial communities in the dysbiotic gut may alter the bile acid pool to potentially cause or mitigate disease onset.

Inefficient biosynthesis and metabolism of bile acids can cause health problems from the neonatal period to adulthood, with diverse clinical symptoms that range from cholestatic liver disease to metabolic disorders, intestinal inflammation, and neuropsychiatric symptoms, which include spastic paraplegias.

Evidence strength: Largely associative and mechanistic; direct causality in many gut-microbiome-bile acid-disease axes is not yet established in well-powered human interventional studies.

6. Body Systems Associated with Bile Acid Activity

Hepatobiliary system: Bile acid synthesis, secretion, and cholestatic liver disease management (PBC, PSC, intrahepatic cholestasis of pregnancy).
Gastrointestinal tract: Emulsification and absorption of dietary fats and fat-soluble vitamins; regulation of gut motility; bile acid diarrhea and malabsorption.
Metabolic system: The gut-to-liver axis plays a critical role in the transformation of primary bile acids to secondary bile acids, in the regulation of bile acid synthesis to maintain composition within the bile acid pool, and in the regulation of metabolic homeostasis to prevent hyperglycemia, dyslipidemia, obesity, and diabetes.
Immune system: Liver metabolic disorders have an inflammatory component, and regulation of liver/intestinal immunity may be part of the beneficial effects of bile acid-based therapies.
Central nervous system: Bile acids function as gut hormones capable of influencing metabolic processes via receptors such as FXR and TGR5. These effects are not restricted to the gastrointestinal tract, but can affect different tissues throughout the organism.
Cardiovascular system: Via cholesterol catabolism and LDL-lowering effects of bile acid sequestrants (the reduction in LDL cholesterol achieved with cholestyramine is dose-dependent).
Endocrine system: Through modulation of GLP-1, insulin secretion, and FGF19 signaling. Via receptor-mediated pathways, bile acids influence the progression of metabolic diseases by regulating glucose and lipid metabolism, immune function and energy expenditure.

7. Dosage Forms and Dosages Reported in Studies

The following dosages are reported in published scientific studies; they are not recommendations:

UDCA for PBC: The dose of 10 to 15 mg/kg used in most large trials was for gallstone dissolution; for PBC, the standard recommended dose in guidelines is 13–15 mg/kg/day (oral).
UDCA for PBC (higher-dose pilot study): A clinical trial compared the effectiveness between 20 mg/kg/d and 10 mg/kg/d UDCA, finding that the 20 mg/kg/d dosage resulted in greater biochemical decreases.
UDCA for PSC (high-dose, preliminary study): Twenty-six patients with PSC were randomized to high-dose (20 mg/kg daily) UDCA or placebo.
TUDCA for ALS (Phase IIb): Treatment with TUDCA for 1 year at a dose of 2 g daily was associated with a potentially slower deterioration of function in ALS patients.
TUDCA for insulin resistance (clinical trial): The dose proposed in one study was 1.75 g/day, corresponding to an average dose of 15–20 mg/kg/day, a dose that has been shown to be effective in other human studies with few side effects.
UDCA formulation (crossover RCT in PBC): UDCA 300 mg tablets and capsules were developed and manufactured in one institutional study.

Commercial administration of bile acids is limited to pharmaceutical formulations in solid form — tablet, capsule, and suspension.

8. Safety Considerations and Interactions

8.1 Toxicity of Specific Bile Acids

In increased amounts, lithocholic acid promotes a reduction in bile flow with subsequent cholestasis, gallstone formation, and bile duct proliferation. In animal models it has been shown to cause bile duct injury. Lithocholic acid is a 7α-dehydroxylated derivative of cholic acid and is highly toxic when administered to rodents.

UDCA has been shown to have potentially toxic molecular properties. UDCA breaks down into toxic lithocholic acid. After being absorbed in the small intestine, UDCA undergoes hepatic conjugation. Beyond conjugation, UDCA does not experience further breakdown by the liver or intestinal mucosa. It becomes oxidized or reduced, yielding either 7-keto-lithocholic acid or lithocholic acid.

At high concentrations, bile acids are proinflammatory and cytotoxic.

8.2 High-Dose UDCA Risk in PSC

High-dose UDCA treatment was suggested to increase the risk of colorectal cancers in patients with PSC, a finding that has led regulatory authorities and clinical guideline bodies to caution against high-dose UDCA use in this setting.

8.3 Gastrointestinal Adverse Effects

Clinical studies showed that TUDCA was well-tolerated at the doses used in clinical trials. Mild diarrhea occurred in two patients treated with TUDCA and in two treated with placebo; anorexia was reported in a placebo-treated patient. Based on available animal and human data, other than the potential for diarrhea, TUDCA appears to be very well tolerated even at doses 30-fold greater than that proposed in one clinical trial.

8.4 Bile Acid Sequestrant Interactions

The use of bile acid sequestrants is contraindicated in patients with complete biliary obstruction where bile is not secreted into the intestine. These agents adsorb and combine with bile acids in the intestine to form an insoluble complex that is excreted in the feces, resulting in partial removal of bile acids from the enterohepatic circulation. Bile acid sequestrants are ineffective if bile does not reach the intestine.

As an anion exchanging resin, cholestyramine may also bind other drugs administered concurrently. Cholestyramine resin may delay or reduce the absorption of concomitant oral medications such as thyroid and thyroxine preparations, warfarin, hydrochlorothiazide, phenylbutazone, phenobarbital, tetracycline, penicillin G, and digitalis, as well as therapeutic bile acids such as ursodiol and obeticholic acid.

Bile acid sequestrants have been reported to impair the absorption of numerous nutrients and fat-soluble vitamins, including calcium, folate, iron, vitamin A, vitamin B12, and vitamin E. It appears, however, that only folate supplementation may be needed by persons on long-term therapy with bile acid sequestrants.

Bile acid sequestrants have also been reported to interact with numerous medications. They have been shown to narrow the therapeutic index of blood thinners such as warfarin, and lower the availability of thyroid medications like levothyroxine.

8.5 Obeticholic Acid (OCA) Drug Interaction

Patients taking bile acid sequestrants (including cholestyramine and its derivatives, colestipol, colesevelam, or other sequestrants) or aluminum hydroxide- or smectite-containing antacids should be instructed to stagger their dosing of OCA, ensuring at least 4 hours between doses of the sequestrant and OCA.

OCA taken concomitantly with warfarin may result in decreased international normalized ratio (INR) levels; therefore, INR should be monitored and the dosage of warfarin adjusted as needed during treatment with OCA and after its cessation, to maintain the target INR range.

8.6 Steatorrhea and Fat-Soluble Vitamin Deficiency

Patients with extensive ileal resection experience a decrease in bile acid pool, and use of a conventional bile acid-binding resin may worsen fat malabsorption. Therefore, conventional cholestyramine should be used with caution in patients with short bowel syndrome, and clinicians and patients should monitor for steatorrhea, fat-soluble vitamin deficiencies, and decreased efficacy of concomitant medications that result from impaired absorption.

8.7 Disease-State Considerations

The normal hepatic synthesis and enterohepatic circulation of bile acids are altered in some pathological conditions. This can be expected in chronic liver diseases such as hepatitis or cirrhosis, which indirectly impair bile secretion, but this is also the case in other pathologies that do not directly affect hepatocyte secretory function, but in which changes in bile acid metabolism secondary to the primary disease have been described.

References

Health Conditions

Health conditions that Bile acid may help support.

Gallbladder HealthScientific
Bile acids are essential components of bile produced in the liver, stored in the gallbladder, and used to emulsify fats and solubilize cholesterol. Bile acid therapy (UDCA, CDCA) is the primary pharmacological approach to gallstone dissolution and prevention. Bile acid supplementation is directly relevant to gallbladder health.

Body Systems

Body systems that Bile acid may help support.

No body systems available.