From the Guidelines
Ursodeoxycholic acid (UDCA) works in liver disease by exerting anticholestatic effects, protecting injured cholangiocytes, and stimulating impaired hepatocellular secretion, as demonstrated in studies such as the EASL clinical practice guidelines 1. The primary mechanism of UDCA involves replacing toxic bile acids with a non-toxic bile acid, reducing inflammation and cell death in the liver. Key benefits of UDCA include:
- Decreasing serum bilirubin, alkaline phosphatase, and cholesterol levels
- Ameliorating histological features in patients with primary biliary cholangitis (PBC)
- Delaying the histological progression of the disease when treatment is started at an early stage
- Possibly reducing the likelihood of liver transplantation or death, as suggested by a combined analysis of the French, Canadian, and Mayo cohorts 1 UDCA is typically used to treat PBC at a dose of 13-15 mg/kg/day, taken orally in divided doses. Its effects on other cholestatic liver diseases are also beneficial, improving bile flow, reducing inflammation, and protecting liver cells from damage. Some of the key actions of UDCA include:
- Reducing the concentration of hydrophobic bile acids that can damage cell membranes
- Exerting anti-inflammatory effects by reducing cytokine production
- Stabilizing cell membranes to prevent apoptosis (programmed cell death)
- Stimulating bicarbonate secretion to create a protective layer on bile ducts
- Increasing bile flow to flush out toxic substances For optimal results, UDCA should be taken with food to enhance absorption, and treatment is typically long-term, often lifelong for conditions like PBC. Regular liver function tests are necessary to monitor response to therapy, with improvements usually seen within 3-6 months of starting treatment.
From the FDA Drug Label
About 90% of a therapeutic dose of Ursodiol is absorbed in the small bowel after oral administration. After absorption, ursodiol enters the portal vein and undergoes efficient extraction from portal blood by the liver (i.e., there is a large “first-pass” effect) where it is conjugated with either glycine or taurine and is then secreted into the hepatic bile ducts. Ursodiol suppresses hepatic synthesis and secretion of cholesterol, and also inhibits intestinal absorption of cholesterol It appears to have little inhibitory effect on synthesis and secretion into bile of endogenous bile acids, and does not appear to affect secretion of phospholipids into bile.
Mechanism of Action: Ursodiol works by suppressing the hepatic synthesis and secretion of cholesterol and inhibiting the intestinal absorption of cholesterol. It also changes the bile composition, making it more conducive to cholesterol solubilization.
- Key Effects:
- Suppresses hepatic synthesis and secretion of cholesterol
- Inhibits intestinal absorption of cholesterol
- Increases the concentration level at which saturation of cholesterol occurs
- Changes the bile composition to make it more conducive to cholesterol solubilization 2
From the Research
Mechanism of Action of Ursodeoxycholic Acid (UDCA) in Liver Disease
- UDCA is administered to patients with primary biliary cirrhosis, a chronic progressive inflammatory autoimmune-mediated liver disease with unknown aetiology 3.
- The exact mechanism of action of UDCA in liver disease is not fully understood, but it is thought to improve liver biochemistry measures and histological progression compared to the control group 3.
- UDCA has been shown to decrease serum bilirubin concentration and activity of serum alkaline phosphatases compared to placebo or no intervention 3.
Effects of UDCA on Liver Disease Symptoms
- UDCA does not seem to have a significant effect on all-cause mortality, all-cause mortality or liver transplantation, pruritus, or fatigue in patients with primary biliary cirrhosis 3.
- However, UDCA may have a beneficial effect on worsening of histological stage and liver biochemistry measures, such as serum levels of gamma-glutamyltransferase, aminotransferases, total cholesterol, and plasma immunoglobulin M concentration 3.
- In patients with primary sclerosing cholangitis, UDCA may improve liver chemistries and histology, but its effect on clinically relevant endpoints is unclear 4.
Treatment of UDCA Non-Responders
- For patients with primary biliary cholangitis who do not respond to UDCA, obeticholic acid or a fibrate may be a reasonable choice as an adjunctive treatment 5.
- Other medications, such as methotrexate, colchicine, budesonide, mycophenolate mofetil, and azathioprine, may also be considered, but their benefits are marginal and more research is needed 5.
- Combination therapy with UDCA and immunosuppressants may be superior to UDCA monotherapy in selected patients with primary biliary cirrhosis 6.
Current Research and Recommendations
- Further investigation is needed to provide high-quality evidence for the treatment of primary biliary cholangitis and primary sclerosing cholangitis 7, 5.
- Randomized controlled trials are necessary to formulate standardized therapies for patients with liver disease who do not respond to UDCA 5.
- Early identification of high-risk patients and the use of novel treatment options, such as fibrates and obeticholic acid, may improve the management of patients with primary biliary cirrhosis 7.