How does Ursodeoxycholic acid (UDCA) dissolve gallstones in a patient with a history of cholestatic hepatitis?

Mechanism of UDCA Gallstone Dissolution

UDCA dissolves cholesterol gallstones by suppressing hepatic cholesterol synthesis and secretion, inhibiting intestinal cholesterol absorption, and uniquely dispersing cholesterol as liquid crystals in bile, thereby converting cholesterol-precipitating bile into cholesterol-solubilizing bile. 1

Primary Mechanisms of Action

Cholesterol Metabolism Alteration

• UDCA suppresses hepatic synthesis and secretion of cholesterol while simultaneously inhibiting intestinal absorption of cholesterol, creating a dual effect that reduces the cholesterol available for gallstone formation 1
• The drug has minimal inhibitory effect on synthesis and secretion of endogenous bile acids into bile, and does not significantly affect phospholipid secretion 1

Unique Cholesterol Solubilization

• UDCA acts through an apparently unique mechanism to disperse cholesterol as liquid crystals in aqueous media, in addition to the conventional micellar solubilization seen with other bile acids 1
• Even though high doses (15-18 mg/kg/day) result in UDCA comprising only up to 60% of the total bile acid pool, UDCA-rich bile effectively solubilizes cholesterol 1
• The overall effect is to increase the concentration level at which cholesterol saturation occurs, fundamentally changing bile from cholesterol-precipitating to cholesterol-solubilizing 1

Steady-State Dynamics

• With repeated dosing, bile ursodeoxycholic acid concentrations reach steady-state in approximately 3 weeks 1
• After UDCA dosing is stopped, the concentration falls exponentially, declining to about 5-10% of steady-state levels within 1 week 1

Clinical Efficacy for Gallstone Dissolution

Optimal Dosing

• The FDA-approved dose for gallstone dissolution is 8-10 mg/kg/day given in 2 or 3 divided doses, based on clinical trials in 868 patients 1
• This dose appeared to be the best balance between efficacy and tolerability across multiple international studies 1

Expected Dissolution Rates

• With 10 mg/kg/day, complete stone dissolution can be anticipated in approximately 30% of unselected patients with uncalcified gallstones <20 mm in maximal diameter treated for up to 2 years 1
• The chance of dissolution increases to 50% in patients with floating or floatable stones (high cholesterol content) 1
• Complete dissolution was observed in 81% of patients with stones up to 5 mm in diameter, demonstrating inverse relationship between stone size and dissolution success 1

Predictors of Success and Failure

• Patients with calcified gallstones, those who develop stone calcification during treatment, or those with stones >20 mm in maximal diameter rarely dissolve their stones 1
• Gallbladder nonvisualization developing during treatment predicts failure of complete stone dissolution and therapy should be discontinued 1
• Partial stone dissolution within 6 months is associated with >70% chance of eventual complete dissolution; partial dissolution within 1 year indicates 40% probability of complete dissolution 1

Important Clinical Caveats

Absorption Characteristics

• UDCA absorption is incomplete and dose-dependent: absorption rates decrease from 60.3% at 250 mg to only 20.8% at 2000 mg doses, which is why higher or multiple doses are needed for adequate therapeutic effect 2
• This contrasts with chenodeoxycholic acid (CDCA), which has nearly complete absorption at 77.6% 2

Stone Recurrence Risk

• Stone recurrence after dissolution occurs in 30% of patients within 2 years and up to 50% within 5 years of complete dissolution 1
• Serial ultrasonographic examinations should be obtained to monitor for recurrence, and radiolucency should be re-established before instituting another course 1

Monitoring Protocol

• Ultrasound images should be obtained at 6-month intervals for the first year to monitor gallstone response 1
• If partial stone dissolution is not seen by 12 months of therapy, the likelihood of success is greatly reduced 1
• If gallstones appear dissolved, therapy should be continued and dissolution confirmed on repeat ultrasound within 1-3 months 1

Context in Cholestatic Hepatitis

• In patients with chronic active hepatitis, UDCA at 8-11 mg/kg/day for gallstone dissolution resulted in decreased transaminases during therapy, with stone dissolution in 5 of 6 patients 3
• This suggests UDCA may provide dual benefit in patients with both gallstones and cholestatic hepatitis, though the primary indication remains gallstone dissolution 3