Chenodeoxycholic acid is a primary bile acid, synthesized in the liver and present in high concentrations in bile that is used therapeutically to dissolve cholesterol gallstones. Chronic therapy is associated with transient elevations in serum aminotransferase levels in up to 30% of patients, but Chenodeoxycholic acid has been linked to only rare instances of clinically apparent liver injury with jaundice.

Background

Chenodeoxycholic acid is a naturally occurring bile acid that is used therapeutically to dissolve cholesterol gallstone in patients with a functioning gall bladder who have contraindications to cholecystectomy or refuse surgery.[1] Chenodeoxycholic acid is the major bile acid synthesized by the liver and is usually the bile acid in highest concentration in serum, hepatocytes and bile. When given orally, Chenodeoxycholic acid is passively absorbed from the small intestine and taken up by the liver via anion transport proteins. High concentrations of Chenodeoxycholic acid in liver decrease the hepatic synthesis of both cholesterol and other bile acids, thereby increasing the cholic acid and decreasing cholesterol concentration in bile. This combination of events results in a decrease in cholesterol saturation of bile, the major impetus to the formation of cholesterol gallstones. When given for 2 years or more, chenodeoxycholic acid can dissolve cholesterol gallstones in 15% to 30% of patients. Chenodeoxycholic acid is most effective on small “floating” gallstones. It is not effective for calcified gallstones or in patients with a non-functioning gallbladder. Even with successful therapy, however, gallstone recurrence is as high as 50% within a few years of stopping Chenodeoxycholic acid. Chenodeoxycholic acid was approved for use in patients with radiolucent gallstones in 1983 and remains available, although it has largely been replaced by ursodiol which appears to be more effective and is better tolerated. In addition, the introduction of laparoscopic cholecystectomy has markedly decreased the need for medical therapy of gallstones. Chenodeoxycholic acid is available as tablets of 250 mg generically and under the commercial names Chenix and Chenodal. The recommended dose is 13 to 16 mg/kg daily in two divided doses for up to 2 years. Side effects include gastrointestinal upset with diarrhea, bloating, cramps, dyspepsia, nausea and vomiting.

Synthesis of Chenodeoxycholic acid

37 mL of 28 % NaOH (aq) was added in a solution of CDCA-OMe (69 g, 169.70 mmol) in EtOH (1 L). [2]After 3 h at 20–25 °C the solution was neutralized to pH = 6 by 1 M/L HCl, and then concentrated to remove EtOH. The residue was washed with 300 mL of 1 M NaOH(aq) and extracted with EtOAc (100 mL × 2). The water layer was neutralized to pH = 4 by 1 M/L HCl and extracted with EtOAc (100 mL × 2). The combined organic layers were recrystallized by 50 mL CH3CN, then filtered to give 58 g Chenodeoxycholic acid as a white solid, with yield of 87 %. M.p. 166.3 ～ 168.1 °C. [α]D 25 + 11.9 (c 1 g/100 mL MeOH). IR (ATR) cm?1: 3418, 2932, 2867, 2648, 1710. 1H NMR (300 MHz, DMSO?d6) δ 11.95 (br, 1H), 4.32 (s, 1H), 4.10 (s, 1H), 3.62 (s, 1H), 3.37 (s, 1H), 3.18 (s, 1H), 2.30–2.02 (m, 3H), 1.96–1.59 (m, 8H), 1.52–0.94 (m, 14H), 0.87 (d, J = 6.4 Hz, 4H), 0.83 (s, 3H), 0.60 (s, 3H). 13C NMR (75 MHz, DMSO?d6) δ 174.91, 70.38, 66.20, 55.55, 50.01, 41.95, 41.46, 39.63, 39.43, 39.15, 35.35, 34.98, 34.84, 34.74, 32.30, 30.76, 30.57, 27.82, 23.18, 22.72, 20.29, 18.17, 11.65. HRMS (ESI): calcd for C24H40O4 [M+Na]+, 415.2824, found 415.2820.

Hepatotoxicity

In multiple clinical trials of Chenodeoxycholic acid therapy for dissolution of gallstones, serum aminotransferase elevations occurred in up to 30% of patients. The elevations generally arose within 2 months of starting therapy and were typically mild, transient and not accompanied by symptoms or jaundice. Liver biopsies done during Chenodeoxycholic acid therapy generally showed mild, nonspecific changes. Clinically apparent liver injury with jaundice was not reported. The liver enzyme elevations were generally dose related and usually did not recur on restarting Chenodeoxycholic acid at lower doses. While the serum enzyme abnormalities that occurred on Chenodeoxycholic acid therapy generated considerable concern, they appeared to be relatively benign. Since the approval of Chenodeoxycholic acid and its more widespread use, at least four instances of liver injury with jaundice have been reported to the sponsor, but the clinical features and outcomes of these cases have not been published. Nevertheless, the product label for Chenodeoxycholic acid includes a boxed warning about hepatotoxicity although it does not provide advice on the frequency or how to respond to abnormalities. Thus, the reliability of reports of clinically apparent liver injury with Chenodeoxycholic acid therapy remains unclear. Once ursodiol was found to be equally as effective as Chenodeoxycholic acid, even at lower doses, and was rarely associated with serum enzyme elevations, it rapidly replaced Chenodeoxycholic acid as medical therapy for gallstones.

Mechanism of Liver Injury

Chenodeoxycholic acid is thought to cause serum aminotransferase elevations because of conversion to lithocholic acid which has intrinsic, proven hepatotoxicity. In animal models, Chenodeoxycholic acid is less hepatotoxic than lithocholic acid, but is more injurious than ursodiol. The more marked hepatotoxicity of Chenodeoxycholic acid and lithocholic acid in rodent and primate models compared to humans has been attributed to a more effective sulfation of lithocholic acid in humans that renders it more water soluble, less toxic and more readily excreted.

Outcome and Management

Patients on Chenodeoxycholic acid should be monitored with liver tests, including serum bilirubin, ALT, AST and alkaline phosphatase at periodic intervals. Chenodeoxycholic acid should be discontinued for persistent increases in liver test abnormalities, ALT elevations above 8 times the upper limit of normal, elevations of bilirubin more than twice normal or any symptom or sign of liver injury. Replacing Chenodeoxycholic acid with ursodiol is probably appropriate in that there does not appear to be cross sensitivity to liver injury or adverse events between Chenodeoxycholic acid and other therapeutic bile acids. Other bile acids used in digestive diseases include cholic acid, obeticholic acid and ursodeoxycholic acid (ursodiol).

An Update on Its Therapeutic Applications

Chenodeoxycholic acid (CDCA), 3α,7α-dihydroxy-5β-cholan-24-oic acid, is a primary bile acid generated in the liver from cholesterol. In liver cells Chenodeoxycholic acid is conjugated with glycine or taurine to form two bile salts, Glyco-CDCA and Tauro-CDCA, before being released into the bile ducts. In the intestine, CDCA is further metabolized to generate a 7β epimer, i.e., the ursodeoxycholic acid (UDCA), or dehydroxylate to generate lithocolic acid (LCA).[3] In humans, Chenodeoxycholic acid is the physiological ligand for the bile acid sensor farnesoid X receptor (FXR), while LCA is a potent agonist for a G protein-coupled receptor, known as GPBAR1 (TGR5). Along with UDCA, CDCA has been clinically used for the dissolution of gallbladder stones at doses ranging from 375 to 750 mg/day, with a success rate of 8 to 18%. Because the efficacy of Chenodeoxycholic acid was significantly lower than that of UDCA and 18-30% of patients developed significant side effects, the most frequent being diarrhea and a reversible increase in aminotransferases plasma levels, this application has lost its therapeutic relevance. Additionally, the combination of CDCA with UDCA, generally at doses of 5-10 mg/kg each, has failed to provide significant advantages over UDCA alone. In 2017, CDCA has been approved as an orphan indication for the treatment of patients with cerebrotendinous xanthomatosis (CTX), a rare autosomal recessive disorder caused by mutations of sterol 27-hydroxylase (CYP27A1) gene. Since CYP27A1 is essential for cholesterol breakdown, CTX patients develop abnormal lipid storage with increased plasma and tissue levels of cholestanol and very low/absent production of CDCA. Chenodeoxycholic acid is a potent inhibitor of CYP27A1, and early initiation of CDCA therapy, at doses up to 750 mg/day, is considered the standard medical therapy for CTX resulting in decreased plasma levels of cholestanol and stabilization of neurologic symptoms. Studies in CTX patients have also shown that CDCA might suppress the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in the liver. Furthermore, Chenodeoxycholic acid promotes the release of glucagon-like peptide-1 (GLP-1) in diabetic patients, likely by activating GPBAR1.

References

[1] LiverTox. (2016). Chenodiol (Chenodeoxycholic Acid). National Library of Medicine.

[2] He, Z., Liang, N., Zou, S., Yu, F., Zeng, Y., Chen, X., Wang, Y., Zhou, L., & Wang, Q. (2024). Practical synthesis of chenodeoxycholic acid from phocaecholic acid. Steroids, 209, 109470.

[3] Fiorucci, S., & Distrutti, E. (2019). Chenodeoxycholic acid: An update on its therapeutic applications. Pharmacological Research, 164, 226