Bile Acid Therapies

Bile acid therapies change the bile acid pool to protect cholangiocytes and hepatocytes, dissolve cholesterol stones, or bind bile acids in the gut. They treat primary biliary cholangitis, intrahepatic cholestasis of pregnancy, selected gallstones, cholestatic itch and bile acid diarrhoea.

Classification. Hydrophilic bile acids (ursodeoxycholic acid), farnesoid X receptor agonists (obeticholic acid), PPAR agonists (bezafibrate, elafibranor, seladelpar), primary bile acids (cholic acid, chenodeoxycholic acid) and bile acid sequestrants (cholestyramine, colesevelam).

• Ursodeoxycholic acid: primary biliary cholangitis 13 to 15 mg/kg daily in one to three doses; cholesterol gallstone dissolution 8 to 12 mg/kg daily; cholestasis of pregnancy 10 to 15 mg/kg daily in divided doses; prevention of gallstones after rapid weight loss 500 to 600 mg daily.
• Obeticholic acid 5 mg daily, increased to 10 mg after 3 months; availability and licensing have been restricted in some regions.
• Bezafibrate 400 mg daily, elafibranor 80 mg daily, seladelpar 10 mg daily as second-line additions in primary biliary cholangitis.
• Cholestyramine 4 g once to four times daily; colesevelam 1.875 g twice daily.

Differences. Ursodeoxycholic acid is the basic first-line drug. High doses (28 to 30 mg/kg daily) harm patients with primary sclerosing cholangitis.

• Primary biliary cholangitis: start ursodeoxycholic acid; judge response at 12 months (alkaline phosphatase under 1.67 times the upper limit of normal with normal bilirubin); add a second-line drug when response is inadequate.
• Cholestasis of pregnancy: ursodeoxycholic acid for itch and raised bile acids.
• Gallstones: radiolucent cholesterol stones under 15 mm in a functioning gallbladder in people unfit for surgery; dissolution takes 6 to 24 months and stones often recur.
• Cholestatic itch: cholestyramine 4 g once or twice daily, taken 4 hours apart from ursodeoxycholic acid and other drugs; then rifampicin 150 mg daily titrated to 300 to 600 mg daily with liver enzyme monitoring; then naltrexone 12.5 mg daily, titrated; then sertraline 75 to 100 mg daily.
• Bile acid diarrhoea: cholestyramine or colesevelam.

Contraindications. Ursodeoxycholic acid: acute cholecystitis or cholangitis, biliary obstruction, non-functioning gallbladder, radiopaque stones. Obeticholic acid: decompensated cirrhosis, portal hypertensive complications. Sequestrants: complete biliary obstruction.

Adverse effects. Ursodeoxycholic acid: diarrhoea, weight gain, hair thinning, transient worsening of itch. Obeticholic acid: pruritus, hepatic decompensation. Sequestrants: constipation, bloating, hypertriglyceridaemia, deficiency of fat-soluble vitamins, hyperchloraemic acidosis.

Interactions. Aluminium antacids and sequestrants bind ursodeoxycholic acid. Ursodeoxycholic acid raises ciclosporin levels. Sequestrants bind many drugs, including warfarin, digoxin, levothyroxine and thiazides.

Special groups.

• Pregnancy: ursodeoxycholic acid used in the second and third trimesters; avoid obeticholic acid.
• Breastfeeding: ursodeoxycholic acid acceptable.
• Children: weight-based specialist dosing.
• Older adults and kidney impairment: no adjustment of ursodeoxycholic acid.
• Liver impairment: obeticholic acid dose reduced or avoided in Child-Pugh B or C.

Monitoring. Alkaline phosphatase, bilirubin, ALT every 3 to 6 months; INR and vitamin levels with sequestrants.

Referral and escalation. Inadequate response at 12 months, bilirubin rising above 50 micromol/L, ascites, variceal bleeding or encephalopathy needs hepatology and transplant assessment.