TUDCA vs Essential phospholipids: what is the difference

TUDCA and essential phospholipids are often sold as interchangeable «liver» agents. However, the first substance is a bile acid with the properties of a chemical chaperone, while the second is a building material for cell membranes. The editorial team breaks down where the fundamental difference between them lies and what is actually known from studies.

What TUDCA is and what EPL are

TUDCA (tauroursodeoxycholic acid) is ursodeoxycholic acid joined to the amino acid taurine. In humans it is formed in the liver in small amounts as one of the conjugates of UDCA. As a standalone substance, TUDCA is registered as a medicinal product in some countries, while in others it is sold as a dietary supplement.

Essential phospholipids (EPL) are a purified fraction of soy phospholipids with a high content of polyunsaturated phosphatidylcholine. The main component is 1,2-dilinoleoylphosphatidylcholine, in which both fatty acid residues are represented by linoleic acid. In the literature the same substance is often called polyenylphosphatidylcholine.

So by chemical nature these are different classes of compounds: a steroid bile acid and a phospholipid, that is, a lipid from the composition of membranes. The quantities also differ: TUDCA is taken in hundreds of milligrams a day, while phospholipids are usually taken in larger mass doses because they play the role of a structural substrate.

The origin is also different. TUDCA is historically linked to bear bile, used for centuries in traditional Chinese medicine, and the modern substance is synthesised. EPL are obtained from soybeans, and their history as a medicinal product began in Europe in the mid-20th century.

Mechanisms: a chaperone versus a membrane building block

TUDCA shares with UDCA the main «bile» properties: it is less hydrophobic than most human bile acids, so it reduces the toxicity of bile to cells and promotes its outflow. However, what has attracted researchers most is another property - the ability to reduce endoplasmic reticulum stress.

The endoplasmic reticulum is the cell's «factory» for folding proteins. When too many misfolded proteins accumulate, the so-called unfolded protein response is triggered, and with prolonged stress - inflammation and apoptosis. In the work by Özcan and co-authors (Science, 2006) TUDCA, acting as a chemical chaperone, reduced reticulum stress and improved insulin sensitivity in obese mice.

The review by Kusaczuk (2019) systematises other described effects of TUDCA as well: an anti-apoptotic action at the level of mitochondria, neuroprotective properties in experimental models, and an effect on inflammatory signalling pathways. Most of these data were obtained in cells and animals.

EPL work differently. The idea is that polyunsaturated phosphatidylcholine is incorporated into the membranes of hepatocytes, restoring their fluidity and function, and can also affect lipid metabolism and oxidative stress. The review by Gundermann and co-authors (2011) summarises experimental data on membrane-stabilising, anti-fibrotic and antioxidant action.

What human studies show

For TUDCA, one of the most cited human studies is the work by Kars and co-authors (Diabetes, 2010). In obese people a four-week intake of TUDCA increased insulin sensitivity in the liver and muscles, but not in adipose tissue. The study was small, and it concerned metabolism rather than liver diseases.

Another high-profile chapter in the history of TUDCA is amyotrophic lateral sclerosis. A combination of sodium phenylbutyrate and taurursodiol was studied in the CENTAUR trial (Paganoni et al., NEJM, 2020). However, a subsequent large phase 3 trial did not confirm the benefit, and the manufacturer withdrew the drug from the market. This story is a good illustration of how cautiously one should treat promising but unconfirmed effects.

As for EPL, the largest and most rigorous study is the US Veterans Affairs cooperative trial (Lieber et al., 2003). In patients with alcoholic liver disease, polyenylphosphatidylcholine over several years did not reduce the progression of fibrosis compared with placebo. The authors noted that some participants substantially cut their alcohol consumption in both groups, which could have affected the result.

In fatty liver disease a number of studies, mainly from Eastern European and Asian countries, described an improvement in enzymes and ultrasound signs with EPL. However, the quality of many of these works is low, and the EASL-EASD-EASO guidelines do not include phospholipids in standard treatment. So both substances have a limited human evidence base, but for different reasons.

Pharmacokinetics and dosage forms

After oral intake, TUDCA is absorbed in the intestine and enters the enterohepatic circulation of bile acids. Part of the substance in the intestine is deconjugated by bacteria to UDCA, so the effects of TUDCA and UDCA on oral intake partly overlap. The debate about how much «better» TUDCA is than UDCA on oral intake is still not settled.

In the intestine EPL are largely broken down to lysophosphatidylcholine, then reassembled in the enterocytes and enter the lymph and blood as part of lipoproteins. Studies with labelled molecules have shown that some polyunsaturated phosphatidylcholine reaches the liver, but the exact fraction that is incorporated into hepatocyte membranes remains a matter of discussion.

The dosage forms also differ. TUDCA is usually available in capsules, as a medicinal product in some European countries or as a supplement. EPL are produced in capsules and as a solution for intravenous administration - the latter is used only in hospital.

For the consumer it is important that the word «phospholipids» on the label does not guarantee the same substance that was used in studies. Ordinary soy lecithin contains far less phosphatidylcholine than standardised EPL. In the same way, for TUDCA it is important whether the purity and source of the raw material are stated.

Safety and regulatory status

Both substances were well tolerated in studies. For TUDCA the most common adverse effects are digestive upset, in particular diarrhoea, as with other bile acids. For EPL, abdominal discomfort, loose stools and rarely allergic reactions have been described, especially in people allergic to soy.

Bile acids, including TUDCA, have contraindications shared with UDCA: acute inflammation of the gallbladder, obstruction of the bile ducts, frequent biliary colic. So taking TUDCA when there are gallstones without consulting a doctor may be risky.

• TUDCA:in a number of countries a medicinal product, in others a supplement; caution in gallstone disease.
• EPL:registered as medicinal products in many countries of Europe and the CIS; in the USA mostly as supplements.
• Both:no evidence that they prevent liver injury from hepatotoxic substances, in particular oral steroids.

In amateur sport TUDCA is often positioned as an agent «for a cycle» of oral steroids. The editorial team emphasises that there are no scientific data on preventing steroid cholestasis with TUDCA. The only reliable way to reduce such a risk is not to use hepatotoxic substances.

Editorial conclusions

TUDCA and essential phospholipids are two different concepts of «liver support». TUDCA changes the composition of bile and affects intracellular stress, while EPL are meant to be a building material for hepatocyte membranes.

Both agents have convincing experimental pharmacology but limited clinical evidence: small TUDCA studies on metabolism and a large negative EPL study in alcoholic liver injury. Neither has the status of standard treatment under the European guidelines on fatty liver disease.

The practical choice between them we cover in the article «TUDCA vs Essential phospholipids: what to choose and for whom». We also recommend the editorial pieces comparing UDCA and silymarin, on NAC as a glutathione precursor and on liver tests in athletes.

References

1. Özcan U, Yilmaz E, Özcan L, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313(5790):1137–1140.
2. Kars M, Yang L, Gregor MF, et al. Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes. 2010;59(8):1899–1905.
3. Kusaczuk M. Tauroursodeoxycholate — bile acid with chaperoning activity: molecular and cellular effects and therapeutic perspectives. Cells. 2019;8(12):1471.
4. Paganoni S, Macklin EA, Hendrix S, et al. Trial of sodium phenylbutyrate–taurursodiol for amyotrophic lateral sclerosis. N Engl J Med. 2020;383(10):919–930.
5. Gundermann KJ, Kuenker A, Kuntz E, Droździk M. Activity of essential phospholipids (EPL) from soybean in liver diseases. Pharmacol Rep. 2011;63(3):643–659.
6. Lieber CS, Weiss DG, Groszmann R, et al. II. Veterans Affairs Cooperative Study of polyenylphosphatidylcholine in alcoholic liver disease. Alcohol Clin Exp Res. 2003;27(11):1765–1772.
7. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388–1402.