UDCA vs Silymarin: what is the difference

Ursodeoxycholic acid (UDCA) and silymarin are often placed on the same shelf labelled «for the liver». In reality these are substances of a different nature, with different points of action and very different evidence bases. The editorial team explains how they differ at the level of chemistry, mechanism of action, clinical data and regulatory status.

Two different substances: origin and chemistry

UDCA is a bile acid, that is, a steroid molecule derived from cholesterol. It is present in small amounts in human bile, and in large amounts in the bile of bears, which is where the name comes from («ursus» - bear). Modern preparations are obtained semi-synthetically, and in composition they are a single, clearly defined chemical compound of known purity.

Silymarin is not a single molecule but an extract of the seeds of milk thistle (Silybum marianum). It contains a mixture of flavonolignans: silibinin (silybin) A and B, isosilibinin, silychristin, silydianin and other components. Silibinin is considered the main active fraction, but its share in different extracts varies considerably.

This difference has practical consequences. Whereas two packs of UDCA with the same dosage are almost identical in the content of active substance, two «silymarin» products may differ in standardisation, the ratio of components and solubility. That is why the results of one study of a milk thistle extract cannot always be transferred to another product.

Finally, the classification differs too. UDCA belongs to the group of bile acids and agents affecting bile secretion, whereas silymarin is classified as a plant-based hepatoprotector. Even at this level it becomes clear that these are not «stronger» and «weaker» versions of one agent, but different tools.

Mechanisms of action: bile versus the cell membrane

The main effect of UDCA is linked to the composition of bile. With regular use it becomes the predominant bile acid in the pool and displaces the more hydrophobic bile acids that are toxic to cells. Bile becomes less «aggressive» towards the membranes of hepatocytes and bile duct cells, and its outflow is enhanced - this is called the choleretic effect.

The review by Paumgartner and Beuers describes three main groups of UDCA mechanisms: protection of cholangiocytes from the toxic action of bile acids, stimulation of secretion in hepatocytes, and an anti-apoptotic action. In addition, UDCA reduces the cholesterol saturation of bile, which underlies its ability to dissolve cholesterol gallstones.

Silymarin acts through other pathways. Its components have antioxidant properties, bind free radicals and, according to experimental data, maintain glutathione levels in liver cells. Stabilisation of cell membranes has also been described, which in theory makes it harder for some toxins to penetrate the hepatocyte.

Another group of silymarin effects is anti-inflammatory and anti-fibrotic action, shown mainly in cell and animal models: suppression of the NF-κB signalling pathway and an effect on the hepatic stellate cells. The problem is that the concentrations at which these effects occur in the test tube are not always achievable in the human body.

Pharmacokinetics and bioavailability

UDCA is well absorbed in the small intestine, reaches the liver, is conjugated with glycine or taurine and is excreted with bile. It then takes part in enterohepatic circulation - it returns repeatedly from the intestine to the liver. This is precisely why the effect builds up gradually: the composition of the bile pool changes over weeks of regular use.

With silymarin the situation is the opposite: poor solubility in water and low bioavailability when taken orally. A significant part of silibinin is rapidly conjugated and excreted with bile. To overcome this problem, manufacturers create complexes with phosphatidylcholine (phytosomes), solid-dispersion forms and other technologies that increase absorption.

For UDCA it is important that in clinical practice the dose is calculated per kilogram of body weight, and the effect depends on the duration of intake. For silymarin, dosing in studies varied greatly, as did the extracts themselves, which makes it hard to compare results between works.

These pharmacokinetic differences explain why UDCA has a predictable, reproducible effect in certain conditions, while the results of silymarin studies often diverge: part of the «ineffectiveness» may simply be down to the fact that the active substance did not reach its target in sufficient concentration.

The evidence base: what is confirmed and what is not

UDCA has officially recognised indications. The EASL clinical guidelines on cholestatic liver diseases regard it as a first-line drug in primary biliary cholangitis. The EASL guidelines on gallstone disease define a limited place for UDCA in dissolving small cholesterol stones in carefully selected patients.

At the same time, UDCA is not a universal «liver protector». In non-alcoholic fatty liver disease large studies have not shown a convincing benefit, and current guidelines do not recommend it as standard treatment for this condition. That is, even for a drug with a strong evidence base, that base applies to specific diagnoses.

As for silymarin, the most cited Cochrane systematic review (Rambaldi et al., 2007) on alcoholic and viral liver injury found no reliable effect on mortality and complications in high-quality studies. The authors concluded that effectiveness has not been proven and that better trials are needed.

The European Medicines Agency (EMA), in its monograph on milk thistle fruit, classes it as a traditional herbal medicine: use is based on long experience rather than on convincing clinical data. This is an honest, if not overly «promotional», assessment.

• UDCA:proven effectiveness in primary biliary cholangitis, certain forms of cholestasis, and for dissolving small cholesterol stones.
• Silymarin:traditional use, experimental data, and a few small clinical studies with ambiguous results.

Safety and regulatory status

UDCA is usually well tolerated. The most common adverse reaction is loosening of the stool or diarrhoea. There are contraindications: acute inflammation of the gallbladder and ducts, obstruction of the bile ducts, frequent biliary colic, calcified stones. That is precisely why the drug is prescribed after examination, in particular an ultrasound.

In studies silymarin has a favourable safety profile: mild gastrointestinal upset is possible and, rarely, allergic reactions, especially in people allergic to plants of the Asteraceae family. An effect on some drug-metabolising enzymes is discussed in theory, so when taking other medicines it is worth consulting a doctor.

The status differs fundamentally. UDCA is a medicinal product with a patient leaflet, indications and quality control. Silymarin exists both as a registered medicine and as a dietary supplement; in the second case the requirements for standardisation and confirmation of content are usually softer. The review by Navarro and co-authors reminds us that herbal supplements in general do not always match their declared composition.

For people who train and take oral anabolic steroids it is important to understand: neither of these agents neutralises the hepatotoxicity of 17-alpha-alkylated substances. The LiverTox database describes steroid-related liver injury - from cholestasis to tumours - and prophylactic use of a «hepatoprotector» does not make such drugs safe.

Editorial conclusions

UDCA and silymarin differ in literally everything: chemical nature, target, pharmacokinetics, evidence base and regulatory status. UDCA changes the composition of bile and has clear indications confirmed by guidelines. Silymarin is a plant-based antioxidant complex with interesting experimental pharmacology but weak clinical evidence.

Comparing them on a «which is stronger» basis is incorrect. It is more correct to ask what the problem in the liver or bile ducts is and whether the chosen agent has a proven effect precisely in that situation. The answer to that question is given by an examination, not by a label.

The practical choice between them we cover separately in the piece «UDCA vs Silymarin: what to choose and for whom». We also recommend reading our articles on TUDCA and essential phospholipids, on the ALT and AST liver tests and on the hepatotoxicity of oral steroids.

References

1. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51(2):237–267.
2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones. J Hepatol. 2016;65(1):146–181.
3. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36(3):525–531.
4. Rambaldi A, Jacobs BP, Gluud C. Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database Syst Rev. 2007;(4):CD003620.
5. Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs. 2001;61(14):2035–2063.
6. European Medicines Agency, Committee on Herbal Medicinal Products. Community herbal monograph on Silybum marianum (L.) Gaertn., fructus. London: EMA.
7. Navarro VJ, Khan I, Björnsson E, et al. Liver injury from herbal and dietary supplements. Hepatology. 2017;65(1):363–373.
8. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Androgenic steroids. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–.